_:b46911224 . _:b594468777 . _:b594468134 . _:b594468177 . . . _:b594468141 . _:b594469839 . _:b594468667 . _:b594468194 . . _:b46911272 "enhances therapeutic efficacy by increasing receptor-mediated uptake of drug-encapsulated liposomes into target cells, subsequent to the accumulation of the nanocarriers in the diseased tissues (Kirpotin et al., 2006; Puri et al., >>2009<<)." . _:b594468654 . . . . _:b46911219 . _:b594469858 . . . _:b594468293 . . _:b594469619 . _:b594468193 . _:b594468929 . . . _:b594468577 . _:b594469005 . . . . _:b46911188 "Opsonization of liposomes by serum proteins depends on a variety of factors including size, surface charge and stability (Cullis et al., 1998; Ishida et al., 2001a). The extent of this interaction has been shown to decrease with liposome size from 800 to 200 nm in diameter, as small liposomes cannot support opsonic activity (Chrai et al., 2002). This profound effect of liposome size on complement" . _:b594468691 . _:b46911417 "Then we can determine whether therapeutic efficacy in preclinical animal studies translate to success in humans (Allen and Cullis, 2004, 2013; Narang et al., >>2013<<). Even at this stage, the cost-benefit analysis may be a limitation to the clinical translation of some liposomal based therapies when compared to an approved counterpart or existing therapies, in terms of efficacy or drug-related side" . _:b594468176 . . _:b594469284 . _:b594469549 . _:b594468237 . _:b46911393 "wall recurrences of breast cancerPhase IPEGylatedYarmolenko et al., 2010IrinotecanAdvanced refractory solid tumors and colorectal cancerPhase IPEGylatedChang et al., 2015Camptothecin analogOvarian cancerPhase IPEGylatedZamboni et al., >>2009< . . _:b594468083 . _:b594469396 . . . . . _:b594468864 . _:b46911324 . . _:b594468964 . _:b594468805 . _:b46911349 "Higher doses of LEP-ET can be safely administered compared to paclitaxel alone (Fetterly et al., >>2008<<). Additionally, the use of cholesterol and cardiolipin allows for greater stability and reduced cardiotoxicity, respectively (Chang and Yeh, 2012). DOPC is a recently developed neutral liposome carrier for siRNA delivery and is currently" . . . _:b594468853 . . . _:b594468353 . _:b594469722 . . . . . . _:b594469531 . _:b594469737 . . . _:b46911373 "et al., 2003; Immordino et al., 2006Irinotecan SN-38Metastatic colorectal cancerPhase I/IIConventionalZhang et al., 2004; Suenaga et al., 2015AnnamycinAcute lymphoblastic leukemiaPhase I/IIConventionalWetzler et al., >>2013< . _:b594469347 . _:b594468178 . _:b594468757 . _:b46911145 "types of liposomal drug delivery platforms" . . _:b594468814 . _:b594469436 . _:b594469851 . _:b46911279 "Furthermore, modifications of the lipid bilayer with charged lipids have also attracted much attention (Bozzuto and Molinari, >>2015<<). Addition of charged lipids to the liposomal bilayer has played an important role in developing bioadhesive, mucoadhesive and nucleic acid-based delivery systems." . . _:b594469922 . . _:b594468666 . . . _:b594469694 . _:b46911371 "et al., 2015TretinoinAcute promyelocytic leukemia and hormone-refractory prostate cancerPhase IIConventionalOzpolat et al., 2003; Immordino et al., 2006Irinotecan SN-38Metastatic colorectal cancerPhase I/IIConventionalZhang et al., >>2004<<; Suenaga et al., 2015AnnamycinAcute lymphoblastic leukemiaPhase I/IIConventionalWetzler et al., 2013Amphotericin BAnti-fungal prophylaxisFDA approved in 1997ConventionalChandrasekar, 2008; Allen and Cullis, 2013DaunorubicinLeukemia and" . _:b594469790 . . _:b46911326 "Another type of PEGylated liposome currently in Phase I trials is PEPO2, an irinotecan-encapsulated liposomal formulation used to treat advanced refractory solid tumors (Chang et al., >>2015<<). Camptothecin, which is formulated in PEGylated stealth liposomes, is also in Phase I trials for ovarian cancer treatment (Zamboni et al., 2009)." . _:b594468756 . . . . _:b594468685 . _:b46911358 "I/IIsiRNAZhang et al., 2005; Immordino et al., 2006siRNAOvarian cancerPhase IDOPC neutral liposomesMangala et al., 2009Paclitaxel EndoTAG-1Advanced triple-negative breast cancerPhase IICationicChang and Yeh, 2012; Awada et al., >>2014< . _:b594469438 . . _:b594469509 . . . _:b594469926 . . . . _:b46911294 . _:b46911295 . _:b594469902 . _:b594468273 . . . _:b46911333 . . _:b594469551 . . _:b594469708 . _:b46911334 . _:b46911329 . _:b594469469 . . _:b46911278 "addition, detailed analysis of the degree of liposome accumulation, cellular internalization, intracellular functionality and intracellular degradation will be important parameters for clinical validation and translation (Puri et al., >>2009<<). Through extensive experimentation, we are gaining a better understanding of the more appropriate clinical indications for ligand-targeted liposomal formulations." . _:b46911331 . . _:b46911330 . _:b594469335 . . _:b594469165 . _:b594469047 . _:b46911337 . _:b594468829 . _:b594469239 . _:b594469081 . . . _:b594469273 . . . _:b594468114 . _:b594468352 . _:b594468427 . _:b594468656 . _:b46911348 . . _:b46911350 . _:b46911345 . _:b594469432 . _:b594468107 . _:b46911344 . . _:b594469900 . . _:b594469606 . . _:b46911357 . . _:b46911291 "interaction between the positively charged phospholipids [e.g., dioleoylphosphatidylethanolamine (DOPE)] and negatively charged nucleic acids (Felgner et al., 1987; Campbell et al., 2002, 2009; Kunstfeld et al., 2003; Wu et al., >>2007<<). Such liposomes have also been demonstrated to have greater interaction with tumor vessels due to the overexpression of negatively charged functional groups on the angiogenic endothelial cell membrane (Ran et al., 2002)." . . . . _:b46911152 "This rapid clearance was due to opsonization of plasma components and uptake by fixed macrophages of the reticuloendothelial system (RES), mainly in the liver and spleen (Hua and Wu, >>2013<<)." . . _:b594469351 . _:b594468920 . . . . . . _:b594469847 . . "10.3389%2Ffphar.2015.00286" . . . _:b46911292 . . . . _:b594469045 . _:b594469174 . _:b594469387 . _:b46911283 "Colonic mucins carry a negative charge since their carbohydrates are substituted with numerous sulfate and sialic acid residues (Larsson et al., 2009; Antoni et al., >>2014<<). Conversely, anionic nano-delivery systems preferentially adhere to inflamed GI tissue via electrostatic interaction with the higher concentration of positively charged proteins in inflamed regions. In particular, high amounts of" . . _:b46911407 . _:b594468966 . _:b594468741 . . _:b46911395 . . . _:b594468561 . _:b594469510 . . _:b594469578 . . . _:b594469368 . _:b594468917 . _:b594469603 . . _:b594469243 . . . . . _:b594469687 . . . . _:b46911233 . . _:b594468128 . . _:b46911268 . . _:b594469408 . . _:b46911415 . _:b46911270 . . . _:b46911127 . _:b46911271 . _:b594469841 . . _:b594468169 . _:b46911251 . _:b594469466 . _:b46911412 "will require further evaluation to understand the interaction of the nanoparticles with biological tissues and cells (Allen and Cullis, 2004, 2013; Zhang et al., 2008; Sawant and Torchilin, 2012; Narang et al., 2013; Tinkle et al., >>2014<<). Improvements in the regulatory framework for the assessment of nanoformulations will require consultation with academia and industry." . _:b46911250 . . _:b594469156 . . _:b46911130 . . _:b46911253 "level for a variety of biomedical applications, and particularly following parenteral administration (e.g., intravenous and intraperitoneal injection) (Torchilin, 1994; Vingerhoeds et al., 1994; Willis and Forssen, 1998; Noble et al., >>2004<<; Deshpande et al., 2013; Hua and Cabot, 2013; Rip et al., 2014; Hua et al., 2015)." . _:b594468908 . _:b594469177 . . _:b594469097 . _:b46911135 . . . _:b594469196 . . _:b594468650 . . . . . . _:b594469053 . _:b46911261 . _:b594468796 . . _:b594469484 . . _:b46911141 . . . _:b46911359 . _:b46911147 . _:b594468310 . . _:b594469822 . _:b594469728 . . _:b594468746 . . . . _:b594468780 . _:b594469300 . . _:b594469914 . . . _:b594469494 . _:b594469281 . _:b46911397 . _:b46911335 . . _:b594469030 . . _:b594468215 . _:b594469232 . _:b594468505 . . _:b594469489 . _:b594469448 . . . _:b46911222 "Interestingly, administration of higher doses of the initial PEGylated liposomes (>1 \u03BCmol phospholipids/kg) have been shown to reduce the magnitude of the ABC phenomenon (Ishida et al., >>2005<<). Increasing the phospholipid dose has been suggested to cause PEG-reactive B cells to become apoptotic, reducing anti-PEG IgM production and thus abating the ABC phenomenon (Ishida et al., 2006b; Ishida and Kiwada, 2008). The ABC" . _:b46911343 . _:b594469062 . _:b594469297 . _:b594468323 . _:b594468583 . . _:b46911183 "The use of PEG significantly minimizes, but does not completely circumvent, liposomal uptake by the RES\u2014with pathways independent of opsonization also possible (Laverman et al., >>2001<<; Sawant and Torchilin, 2012)." . . _:b594469599 . _:b46911316 "addition, multi-functional systems will need to address the potential mismatch between the doses required for the effective use of each component in patients, for example imaging and therapy for theranostic nanosystems (Teli et al., >>2010<<). At this stage, packaging multiple payloads in the same carrier would appear most promising, however sequencing and scale up of this kind of approach would still be challenging (Zhang et al., 2011; Allen and Cullis, 2013)." . . _:b594468529 . . _:b594469188 . . . _:b594468100 . . . . _:b46911409 . _:b594468079 "18"^^ . _:b46911180 "Conjugation of PEG polymers to the liposomal membrane is a key strategy for improving circulation times and preventing removal by the RES through steric stabilization (Oku and Namba, >>1994<<; Ishida et al., 2001a)." . _:b594468483 . _:b594468077 "23"^^ . . _:b594468078 "20"^^ . _:b594468081 "18"^^ . _:b594468228 . _:b594468087 "13"^^ . _:b594468080 "18"^^ . _:b594468769 . _:b594468076 "35"^^ . _:b594468464 . _:b594468086 "13"^^ . _:b594468082 "17"^^ . _:b594468085 "13"^^ . _:b594468083 "15"^^ . . _:b594468084 "14"^^ . _:b594468925 . _:b594469431 . _:b594468075 "40"^^ . _:b594469688 . . _:b594469715 . . _:b594468095 "10"^^ . _:b594468094 "10"^^ . _:b594469504 . _:b594468093 "10"^^ . . _:b594468092 "10"^^ . . _:b46911204 "For example, inflammation results in a dramatic change in blood vessel permeability as the capillary vasculature undergoes structural remodeling to allow leukocyte diapedesis into the peripheral tissue (Klimuk et al., >>1999<<; Hua, 2013)." . . _:b594468091 "11"^^ . _:b594468977 . _:b594468090 "11"^^ . _:b594468089 "12"^^ . _:b594468249 . _:b594468495 . _:b594468088 "12"^^ . . . _:b594468325 . _:b594468102 "9"^^ . . . _:b594468103 "9"^^ . _:b594468100 "9"^^ . . _:b594468101 "9"^^ . _:b594468724 . _:b594469322 . _:b594469071 . . _:b594468098 "10"^^ . . . _:b594468099 "9"^^ . _:b594468097 "10"^^ . _:b46911301 "Of these strategies, the use of an external hyperthermic trigger to release therapeutic compounds from liposomal formulations (e.g., ThermoDox\u00AE) appears to be the most promising to date (Needham et al., >>2000<<). Thermosensitive liposomes are modified with temperature-sensitive lipids (e.g., 1,2-distearoyl-sn-glycero-3-phosphocholine, DSPC) and/or polymers [e.g., poly(N-isopropylacrylamide)], which enables the nanocarrier to remain stable and" . _:b594468759 . _:b594468096 "10"^^ . . . _:b46911240 . _:b594468110 "8"^^ . _:b594468111 "8"^^ . . . _:b46911366 . _:b594468108 "9"^^ . _:b594469286 . _:b594468109 "9"^^ . . _:b594468106 "9"^^ . _:b594468107 "9"^^ . . _:b594468104 "9"^^ . _:b594468105 "9"^^ . _:b594468544 . _:b594468118 "8"^^ . _:b594469419 . . _:b46911133 "Furthermore, the large aqueous center and biocompatible lipid exterior permits the delivery of a variety of macromolecules, such as DNA, proteins and imaging agents (Ulrich, >>2002<<; Monteiro et al., 2014)." . _:b594468119 "8"^^ . _:b594468116 "8"^^ . _:b594468763 . . _:b594468682 . _:b594468117 "8"^^ . . . . . . _:b594468114 "8"^^ . _:b594468081 . _:b594468115 "8"^^ . . _:b46911242 "The development of immunogenic reactions to liposomal therapies may lead to altered pharmacokinetics, loss of efficacy, and the rise of potentially serious toxicities (e.g., anaphylaxis) (Szebeni and Moghimi, >>2009<<). This should therefore be considered in formulation design and closely monitored for in clinical practice." . . _:b594468112 "8"^^ . . _:b594468116 . _:b594468113 "8"^^ . _:b594468126 "7"^^ . _:b46911277 "each liposome still remains to be resolved, and will likely depend on characteristics of the molecular target (e.g., location, expression, internalization rate, and immunogenicity) (Puri et al., 2009; Hua and Wu, 2013; Kraft et al., >>2014<<). In addition, detailed analysis of the degree of liposome accumulation, cellular internalization, intracellular functionality and intracellular degradation will be important parameters for clinical validation and translation (Puri et al." . _:b46911250 "surface of liposomes have been extensively studied at the experimental level for a variety of biomedical applications, and particularly following parenteral administration (e.g., intravenous and intraperitoneal injection) (Torchilin, >>1994<<; Vingerhoeds et al., 1994; Willis and Forssen, 1998; Noble et al., 2004; Deshpande et al., 2013; Hua and Cabot, 2013; Rip et al., 2014; Hua et al., 2015)." . . _:b46911405 "Increasing the number of physicochemical variables in a nanoformulation system also makes it more complicated to assess the pharmacokinetics, pharmacodynamics and toxicology of a formulation following administration (Teli et al., >>2010<<; Tinkle et al., 2014)." . _:b594469194 . _:b594468127 "7"^^ . . _:b594469665 . _:b594469644 . _:b594468124 "7"^^ . . . _:b594468384 . _:b594468125 "7"^^ . . _:b594468122 "7"^^ . _:b594469433 . _:b594469886 . _:b594468123 "7"^^ . . . _:b594468120 "8"^^ . _:b46911334 "Regardless, many of these drugs are still undergoing clinical trials to test their effects of dose escalation and therapeutic efficacy (Chang and Yeh, >>2012<<). For example, liposomal amphotericin B is in a prospective Phase II trial to test the safety and tolerability of high doses (Giannella et al., 2015). Advantages of these marketed drugs include a reduced toxicity by increased vasculature" . _:b594468506 . _:b594468121 "7"^^ . . _:b594468134 "7"^^ . . . _:b594469175 . _:b594468135 "7"^^ . _:b594468132 "7"^^ . _:b594469748 . _:b594469744 . . . _:b594468133 "7"^^ . _:b594468428 . _:b594468487 . _:b594468130 "7"^^ . . _:b594468131 "7"^^ . _:b594468808 . _:b594469492 . _:b594468128 "7"^^ . . . _:b594468129 "7"^^ . . . _:b594468142 "6"^^ . . _:b594469637 . . _:b594468143 "6"^^ . _:b594468140 "6"^^ . _:b594468141 "6"^^ . . . . _:b594468138 "7"^^ . . _:b594469329 . _:b594468139 "6"^^ . . _:b594468136 "7"^^ . _:b594468137 "7"^^ . _:b594468150 "6"^^ . . _:b594468151 "6"^^ . _:b594468463 . _:b594468148 "6"^^ . _:b594468433 . _:b46911383 "2012; Jahn et al., 2015Morphine sulfatePain ManagementFDA Approved in 2004ConventionalChang and Yeh, 2012; Allen and Cullis, 2013LurtotecanOvarian cancer, head, and neck cancerPhase I/IIConventionalDark et al., 2005; Chang and Yeh, >>2012< . _:b594468149 "6"^^ . . _:b46911375 . . _:b46911154 . _:b594468146 "6"^^ . . _:b594468147 "6"^^ . . _:b594468144 "6"^^ . _:b46911356 "of liposomal-based delivery systemSource(s)Paclitaxel LEP-ETUAdvanced triple-negative breast cancerPhase I/IIsiRNAZhang et al., 2005; Immordino et al., 2006siRNAOvarian cancerPhase IDOPC neutral liposomesMangala et al., >>2009< "6"^^ . _:b594468144 . _:b594469467 . _:b594468158 "6"^^ . _:b594469411 . _:b594468159 "6"^^ . _:b594469223 . _:b594468156 "6"^^ . . . _:b594468387 . _:b46911197 . _:b46911368 . _:b594469753 . _:b594468157 "6"^^ . _:b594468154 "6"^^ . . _:b594468155 "6"^^ . . _:b594468152 "6"^^ . . _:b46911276 "on the surface of each liposome still remains to be resolved, and will likely depend on characteristics of the molecular target (e.g., location, expression, internalization rate, and immunogenicity) (Puri et al., 2009; Hua and Wu, >>2013<<; Kraft et al., 2014)." . _:b594468153 "6"^^ . _:b46911192 . _:b46911363 . . _:b594468165 "5"^^ . _:b594468905 . . _:b46911190 . _:b594468164 "5"^^ . . _:b594469521 . _:b594468167 "5"^^ . _:b46911367 . _:b594468166 "5"^^ . _:b594469041 . . _:b594468161 "5"^^ . _:b46911153 . . _:b594468160 "6"^^ . _:b594468163 "5"^^ . _:b594469037 . . _:b594468162 "5"^^ . . . . _:b46911386 . _:b594469217 . _:b594468173 "5"^^ . . _:b594469611 . _:b594468172 "5"^^ . _:b46911384 . _:b594468175 "5"^^ . _:b46911159 "While coating liposomes with PEG results in prolonged circulation times, there can be an offsetting reduction in the ability to interact with the intended targets (Willis and Forssen, >>1998<<; Ulrich, 2002)." . . _:b46911280 . . _:b594468174 "5"^^ . _:b594468764 . . _:b594468169 "5"^^ . _:b46911381 . _:b594468168 "5"^^ . _:b46911293 . _:b594468608 . _:b594468171 "5"^^ . _:b594468818 . _:b594468170 "5"^^ . _:b594469288 . . _:b594468181 "5"^^ . _:b46911377 . _:b594468180 "5"^^ . _:b594469517 . _:b594468183 "5"^^ . _:b594468835 . _:b594468182 "5"^^ . . _:b594468177 "5"^^ . _:b594468840 . _:b46911275 "ligand density on the surface of each liposome still remains to be resolved, and will likely depend on characteristics of the molecular target (e.g., location, expression, internalization rate, and immunogenicity) (Puri et al., >>2009<<; Hua and Wu, 2013; Kraft et al., 2014)." . _:b594468176 "5"^^ . _:b594468179 "5"^^ . _:b594468558 . . _:b594468101 . _:b594468178 "5"^^ . . _:b594468881 . _:b594468791 . _:b594468189 "5"^^ . _:b594468386 . _:b594468188 "5"^^ . . . _:b594468191 "5"^^ . _:b46911365 . _:b594468190 "5"^^ . _:b594469427 . _:b594469084 . _:b594468185 "5"^^ . . _:b594468184 "5"^^ . _:b594468437 . _:b46911396 . _:b594468187 "5"^^ . _:b46911361 . _:b594468186 "5"^^ . _:b594468197 "4"^^ . _:b594469495 . _:b594468196 "4"^^ . _:b46911362 . _:b594468199 "4"^^ . _:b594468465 . _:b594469055 . . _:b594468198 "4"^^ . _:b594468193 "5"^^ . _:b594468192 "5"^^ . . _:b594469837 . _:b594468195 "4"^^ . . _:b594468194 "4"^^ . _:b594469514 . . _:b594468205 "4"^^ . _:b594468227 . _:b594468775 . _:b594468204 "4"^^ . _:b46911331 "of leukemia and solid tumors (Chang and Yeh, 2012), verteporfin to treat macular degeneration (Chang and Yeh, 2012), cytarabine or cytosine arabinoside to treat neoplastic meningitis and lymphomatous meningitis (Chang and Yeh, >>2012<<; Jahn et al., 2015), and morphine sulfate for pain management are currently on the market (Chang and Yeh, 2012)." . _:b594468207 "4"^^ . _:b46911416 . . _:b594468206 "4"^^ . _:b594468946 . _:b46911380 . _:b594468201 "4"^^ . _:b594469678 . _:b46911383 . _:b594468162 . _:b594468200 "4"^^ . _:b594468133 . . _:b594468203 "4"^^ . _:b594468108 . . _:b594468202 "4"^^ . _:b594469795 . _:b46911376 . _:b594468213 "4"^^ . _:b594468212 "4"^^ . . _:b46911378 . . _:b594468215 "4"^^ . _:b46911408 . _:b594469520 . _:b594468214 "4"^^ . . _:b594468965 . . _:b594468209 "4"^^ . _:b594468208 "4"^^ . _:b594468211 "4"^^ . . _:b594468210 "4"^^ . . _:b594468221 "4"^^ . _:b594469203 . . _:b594468220 "4"^^ . . _:b594468750 . _:b46911297 "utilized include remote triggers (e.g., temperature, ultrasound, magnetic, and light) and local triggers specific to the target site (e.g., enzymes and pH), through the use of specific lipid compositions and coatings (Guo and Szoka, >>2003<<; Andresen et al., 2004; Ponce et al., 2006; Bibi et al., 2012)." . _:b594468223 "4"^^ . . . . _:b594469780 . . _:b594468222 "4"^^ . . _:b594468217 "4"^^ . _:b46911217 . . _:b594468216 "4"^^ . . . _:b594468219 "4"^^ . _:b594468271 . _:b594469871 . _:b594468218 "4"^^ . _:b594469798 . _:b46911389 "2004DoxorubicinLeukemia, breast cancer, bone cancer, lung cancer, brain cancerFDA Approved in 1995PEGylatedNing et al., 2007Doxorubicin and bortezomibRelapsed or refractory multiple myelomaFDA Approved in 2007PEGylatedNing et al., >>2007< . _:b46911213 . _:b594468229 "4"^^ . . _:b594468228 "4"^^ . _:b594468231 "4"^^ . . _:b594468230 "4"^^ . . _:b46911285 "In particular, high amounts of eosinophil cationic protein and transferrin have been observed in inflamed colon sections in patients with inflammatory bowel disease (IBD) (Carlson et al., 1999; Peterson et al., >>2002<<; Tirosh et al., 2009)." . _:b594468225 "4"^^ . _:b594468517 . _:b594468224 "4"^^ . . _:b594468227 "4"^^ . _:b46911315 "liposomes (ECl-GLuc-liposome), and demonstrated significant bioluminescence imaging and targeted drug delivery in both SKOv3 cells in vitro and in ErbB2-overexpressing metastatic ovarian tumors in vivo in a murine model (Han et al., >>2014<<). ECl-GLuc is a recombinant protein generated by fusing the ECl peptide (an artificial ligand of ErbB2) with Gaussia luciferase (GLuc)." . _:b594469398 . _:b594469896 . _:b594469118 . _:b594468226 "4"^^ . _:b594469602 . _:b594468474 . _:b594468535 . _:b594468237 "4"^^ . _:b594468236 "4"^^ . _:b594469888 . . _:b594468239 "4"^^ . _:b594468154 . . _:b594468238 "4"^^ . . _:b594469474 . . _:b594469146 . _:b594468233 "4"^^ . _:b594468232 "4"^^ . . . _:b594468235 "4"^^ . _:b594468911 . _:b46911236 . _:b594468234 "4"^^ . _:b594469487 . . . . _:b594468245 "4"^^ . _:b594468870 . _:b594468244 "4"^^ . _:b594469803 . _:b594468247 "4"^^ . _:b594468246 "4"^^ . _:b594468109 . . _:b594468241 "4"^^ . _:b594468592 . _:b594468240 "4"^^ . _:b594468383 . . _:b594468243 "4"^^ . _:b594468242 "4"^^ . _:b594468253 "4"^^ . _:b46911385 . _:b46911196 . . _:b594469648 . _:b594468164 . _:b594468252 "4"^^ . _:b594468693 . _:b594469924 . . . _:b594468255 "4"^^ . . . . . _:b594468254 "4"^^ . _:b594469891 . . . _:b594468249 "4"^^ . . _:b594469123 . _:b594468248 "4"^^ . _:b46911186 . _:b594468251 "4"^^ . _:b46911187 . _:b594468250 "4"^^ . _:b594468782 . _:b46911195 . _:b594468261 "4"^^ . _:b594468260 "4"^^ . . _:b594469672 . _:b594468257 . _:b594468263 "4"^^ . _:b594468262 "4"^^ . . _:b594468257 "4"^^ . _:b594469546 . _:b594468256 "4"^^ . . _:b594469631 . _:b594469654 . _:b594468259 "4"^^ . _:b594468359 . _:b594468258 "4"^^ . . . _:b594468269 "4"^^ . . _:b594468268 "4"^^ . . . _:b594468271 "4"^^ . _:b594469407 . _:b594469214 . _:b594468270 "4"^^ . . _:b594469294 . . . _:b594468265 "4"^^ . _:b594469153 . _:b594468721 . _:b594469200 . _:b594468264 "4"^^ . _:b594469930 . _:b594468267 "4"^^ . . . _:b594468266 "4"^^ . . . _:b594468817 . _:b594468277 "4"^^ . . _:b594468276 "4"^^ . _:b594468626 . _:b594468287 . _:b594468279 "4"^^ . . _:b46911292 "Such liposomes have also been demonstrated to have greater interaction with tumor vessels due to the overexpression of negatively charged functional groups on the angiogenic endothelial cell membrane (Ran et al., >>2002<<). It should be noted however, that there is a potential for electrostatic interactions and subsequent binding of these charged nanoparticles with other charge-modifying substances in the circulation or during GI transit (Hua et al., 2015)." . _:b594468934 . _:b594468278 "4"^^ . _:b594469191 . _:b594468273 "4"^^ . _:b594468398 . _:b594468232 . . _:b594468272 "4"^^ . _:b46911169 . . _:b594468275 "4"^^ . _:b594468274 "4"^^ . _:b594468636 . _:b594468285 "4"^^ . . . _:b594468284 "4"^^ . _:b46911165 . _:b594468287 "4"^^ . _:b594468286 "4"^^ . _:b46911154 "This not only reduces the elimination of drugs by prolonging blood circulation and providing accumulation at pathological sites, but also attenuates side effects (Torchilin et al., 1992; Northfelt et al., >>1996<<; Ishida et al., 2001b)." . _:b594468219 . _:b594468173 . _:b594468281 "4"^^ . _:b594468280 "4"^^ . _:b594468935 . _:b594468834 . . _:b46911161 . . . _:b594469632 . _:b594468283 "4"^^ . . _:b594469893 . _:b594468282 "4"^^ . _:b594469797 . _:b594468118 . _:b594468293 "3"^^ . . _:b594469892 . . . _:b594468292 "3"^^ . _:b594468729 . _:b594469895 . _:b594468295 "3"^^ . _:b594469080 . . _:b594469894 . . _:b594468294 "3"^^ . _:b594469889 . _:b46911263 . _:b594469812 . _:b46911159 . _:b594468289 "3"^^ . _:b594469888 . . _:b46911130 "Hydrophobic molecules are inserted into the bilayer membrane, and hydrophilic molecules can be entrapped in the aqueous center (Koning and Storm, >>2003<<; Metselaar and Storm, 2005; Ding et al., 2006; Hua and Wu, 2013; Figure 1)." . _:b594468288 "4"^^ . _:b594469891 . _:b46911166 "The limited in vivo performance of immunoliposomes, due to poor pharmacokinetics and immunogenicity, has been a major hurdle to achieving their potential as effective site-specific drug carriers (Puri et al., >>2009<<). Therefore, newer generation of liposomes have utilized a combination of the above design platforms to further improve liposomal targeting and associated drug delivery (discussed in Experimental use of liposomes for biomedical" . . _:b594468291 "3"^^ . _:b594468789 . _:b594469890 . _:b594468290 "3"^^ . _:b594469901 . _:b594468364 . _:b594468301 "3"^^ . _:b594469114 . _:b594469900 . _:b594468275 . _:b594468300 "3"^^ . . _:b594469903 . _:b594468139 . _:b594468303 "3"^^ . _:b594468927 . _:b594469711 . _:b594469902 . . _:b594468302 "3"^^ . . _:b594469897 . _:b594468297 "3"^^ . . _:b594469896 . _:b594468432 . _:b594468296 "3"^^ . _:b594469899 . . _:b594468299 "3"^^ . _:b594468327 . _:b46911176 "capacity or modulate other cellular functions; however there have been no reports to date of clinically significant immune suppression at therapeutic doses of non-cytotoxic liposomes (Szebeni and Barenholz, 2009; Szebeni and Moghimi, >>2009<<). The situation is different with anti-cancer liposomes that contain cytotoxic drugs, which are capable of inducing macrophage destruction." . _:b594469898 . . _:b594468298 "3"^^ . _:b594469909 . . _:b594468309 "3"^^ . _:b594469686 . _:b594469908 . _:b594468158 . _:b594469716 . _:b594468308 "3"^^ . _:b594469911 . . _:b594468311 "3"^^ . . _:b46911248 . _:b594469910 . _:b594469316 . _:b594468310 "3"^^ . _:b594468457 . _:b594469905 . . _:b594468305 "3"^^ . _:b594469904 . _:b594468304 "3"^^ . _:b594468844 . _:b594469907 . _:b594468307 "3"^^ . _:b594469906 . . _:b594468306 "3"^^ . _:b594469917 . _:b594469771 . _:b594468317 "3"^^ . _:b594469916 . _:b46911274 . _:b594469681 . _:b594468316 "3"^^ . . _:b594469919 . _:b46911157 . _:b594468319 "3"^^ . _:b46911265 "For example, attachment of folate to liposomes showed enhanced biodistribution of liposomes in folate-expressing tumors in a murine model (Gabizon et al., >>2003<<). In addition, attachment of ICAM-1 monoclonal antibodies to the surface of loperamide-encapsulated liposomes, demonstrated increased efficacy and localization of the targeted nanoparticles to peripheral inflammatory tissue in a rodent" . _:b594469918 . _:b46911326 . _:b594468318 "3"^^ . . _:b594469913 . _:b594468313 "3"^^ . . _:b594469912 . _:b594469857 . _:b46911251 "been extensively studied at the experimental level for a variety of biomedical applications, and particularly following parenteral administration (e.g., intravenous and intraperitoneal injection) (Torchilin, 1994; Vingerhoeds et al., >>1994<<; Willis and Forssen, 1998; Noble et al., 2004; Deshpande et al., 2013; Hua and Cabot, 2013; Rip et al., 2014; Hua et al., 2015)." . . _:b594468231 . _:b594468312 "3"^^ . _:b594469915 . _:b594468641 . _:b46911215 "that prior dosing of empty PEGylated liposomes influences the pharmacokinetics and biodistribution of the second dose of liposomes in rats and rhesus monkeys, when the doses were administered with an interval of 7 days (Dams et al., >>2000<<). As a result, the circulation time of the second dose of PEGylated liposomes was significantly reduced, and liposome accumulation in the liver and spleen increased (Dams et al., 2000)." . _:b594468315 "3"^^ . _:b594469914 . _:b594469671 . _:b594468999 . _:b594468314 "3"^^ . _:b594468466 . _:b594469925 . _:b594468098 . _:b594468325 "3"^^ . . _:b594469924 . _:b594469634 . _:b594468324 "3"^^ . _:b594468501 . _:b594469927 . _:b594468327 "3"^^ . _:b594469926 . _:b46911199 "Integrating cholesterol into small (approximately 100 nm), electrostatically neutral liposomes has been shown to prolong circulation time in the range of several hours (Geng et al., >>2014<<)." . _:b594468326 "3"^^ . _:b594469921 . . _:b594468321 "3"^^ . _:b594469920 . _:b46911350 "Additionally, the use of cholesterol and cardiolipin allows for greater stability and reduced cardiotoxicity, respectively (Chang and Yeh, >>2012<<). DOPC is a recently developed neutral liposome carrier for siRNA delivery and is currently in clinical testing (Mangala et al., 2009). Another drug in Phase I/II trials is annamycin to treat acute lymphocytic leukemia (Wetzler et al.," . _:b594468320 "3"^^ . _:b594469923 . . _:b594468323 "3"^^ . _:b46911269 "immunoliposomes produced significantly superior therapeutic results in comparison to all other control groups, including free doxorubicin, non-targeted liposomal doxorubicin and recombinant anti-HER2 Mab trastuzumab (Park et al., >>2002<<). The mechanism of this enhanced anti-tumor efficacy was clearly not due to enhanced accumulation via antigen binding, but rather the result of the marked difference in pharmacodynamics of the targeted liposomal formulation in vivo, by" . _:b594469922 . . . _:b594468322 "3"^^ . _:b594469206 . _:b594469933 . . _:b46911363 "LEM-ETUAcute myeloid leukemia, multiple sclerosis, and prostate cancerPhase ICationicImmordino et al., 2006; Chang and Yeh, 2012VerteporfinMolecular degenerationFDA Approved in 2000CationicChang and Yeh, 2012; Allen and Cullis, >>2013<<; Gross et al., 2013AmikacinLung infectionPhase II/IIIConventionalChang and Yeh, 2012; Clancy et al., 2013; Olivier et al., 2014VincristineNon-Hodgkin lymphomaFDA Approved in 2012ConventionalAllen and Cullis, 2013; Wang et al.," . _:b594468333 "3"^^ . _:b594469057 . _:b594469932 . _:b594469234 . _:b594468332 "3"^^ . _:b594469935 . _:b594468335 "3"^^ . _:b594469934 . . _:b594468334 "3"^^ . _:b594469929 . _:b594468329 "3"^^ . . _:b594469928 . _:b594469066 . . . . _:b594468328 "3"^^ . . _:b594469931 . _:b594469483 . _:b594468331 "3"^^ . _:b594469930 . _:b594469127 . _:b594468330 "3"^^ . . . _:b594469941 . _:b594468490 . _:b594468341 "3"^^ . _:b594469940 . _:b594468340 "3"^^ . _:b594469943 . _:b594469873 . _:b594468343 "3"^^ . _:b594469942 . _:b594468342 "3"^^ . _:b594468106 . _:b594469937 . . . _:b594468337 "3"^^ . _:b594469936 . . _:b594468336 "3"^^ . _:b594468726 . _:b594469939 . _:b46911309 . _:b46911349 . _:b594468339 "3"^^ . . _:b594469938 . _:b594468722 . _:b594469904 . _:b594468338 "3"^^ . _:b594469270 . _:b46911307 . _:b594469949 . _:b594469227 . _:b594468349 "3"^^ . _:b594469138 . _:b594469948 . . _:b594468348 "3"^^ . . _:b594468351 "3"^^ . _:b594468115 . _:b594469950 . _:b594468183 . _:b594468350 "3"^^ . . _:b594469945 . _:b594469098 . . _:b594469327 . . _:b594468345 "3"^^ . _:b594468303 . _:b594469944 . _:b594468189 . _:b594468567 . . _:b594468344 "3"^^ . . _:b594469947 . . _:b594468347 "3"^^ . _:b594469946 . _:b594469488 . _:b594468415 . _:b594469590 . _:b594468346 "3"^^ . _:b594469343 . . _:b46911226 . . _:b46911295 "Inclusion of a heterocyclic ring has been shown to spread the positive charge of the head-group, thus attenuating the toxicity level (Lv et al., >>2006<<)." . . . _:b594468897 . _:b594468186 . _:b594469568 . . . _:b594469908 . _:b594468831 . . . _:b594468307 . _:b594468566 . _:b594469506 . _:b594469280 . _:b594468338 . . . . _:b594468170 . . _:b594468142 . . . _:b594468095 . _:b594469830 . _:b46911318 . _:b594469036 . _:b46911337 "toxicity by increased vasculature permeability/accumulation at the target tissue and an ability to encapsulate drugs of different lipophilicities while protecting them from biodegradation (Immordino et al., 2006; Chang and Yeh, >>2012<<; Allen and Cullis, 2013)." . _:b594468848 . . _:b594468564 . _:b594469635 . _:b594469334 . . . _:b594469770 . _:b594468525 . . . _:b594469739 . _:b594469628 . _:b46911214 "For example, repeated injection of PEGylated liposomes has been associated with loss of their long circulating properties and subsequent clearance from the blood (Dams et al., 2000; Ishida et al., 2003, 2006b). This phenomenon is known as the \u201Caccelerated blood clearance\u201D (ABC) phenomenon. The ABC phenomenon is a major concern for the clinical application of PEGylated formulations that require multiple dosing regimens. Dams et al. first" . _:b46911248 "More recent strategies to improve on conventional or stealth liposomal systems involve active targeting, charged lipids, triggered release, and multi-functional formulations (Puri et al., 2009; Allen and Cullis, >>2013<<; Bozzuto and Molinari, 2015)." . . . _:b594468155 . . _:b594468343 . . _:b46911338 . _:b594469308 . _:b594468597 . . . . _:b594468086 . _:b594468664 . . . _:b594469823 . . . . _:b46911229 "The complement system is part of the innate immune response, and is involved in a range of immunological and inflammatory processes (Moghimi and Hunter, >>2001<<). A relatively high percentage of patients (2\u201345%) have been reported to develop infusion-related hypersensitivity reactions to liposomal drug therapy. In addition, CARPA has been reported with both experimental and clinically approved" . . . _:b594468599 . _:b594468374 . . . _:b594469650 . . . _:b594469496 . . . . _:b594468700 . _:b46911235 "is thought to be partly due to the activation of the complement system with the subsequent generation of C3 split-products (e.g., C3d) (Dempsey et al., 1996) and anaphylatoxins C3a and C5a (Szebeni, 2005; Szebeni and Moghimi, >>2009<<). Binding of anaphylatoxins to their specific receptors on immune cells (e.g., mast cells, basophils, and macrophages) elicits the release of a multitude of vasoactive mediators, including histamine, tryptase, platelet-activating factor" . . _:b46911199 . . _:b594468523 . _:b594468803 . . _:b46911344 "EndoTAG-1 is prepared in a 50:47:3 molar ratio of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and paclitaxel (Chang and Yeh, >>2012<<). EndoTAG-1 exhibits a greater antivascular effect on tumor vasculature while the usage of DOTAP, a cationic synthetic lipid, in EndoTAG-1 allows for selective affinity to the target tumor (Chang and Yeh, 2012). Another form of" . _:b594468703 . . _:b46911152 . . _:b594468890 . _:b594469820 . . . . _:b594468644 . . _:b46911336 . _:b46911346 "Another form of paclitaxel, LEP-ETU (liposome-entrapped paclitaxel easy-to-use), is in Phase I/II trials (Zhang et al., >>2005<<; Immordino et al., 2006)." . . _:b594469253 . _:b594468354 . _:b594468951 . _:b594469569 . _:b46911327 "Camptothecin, which is formulated in PEGylated stealth liposomes, is also in Phase I trials for ovarian cancer treatment (Zamboni et al., >>2009<<)." . . _:b46911149 . . _:b46911138 . . . _:b594469741 . _:b594468486 . . . _:b46911137 . . . _:b46911143 . _:b594469528 . _:b594469101 . _:b594469609 . . _:b594469885 . _:b46911355 . _:b594468943 . _:b46911172 . _:b46911129 . _:b46911213 "For example, repeated injection of PEGylated liposomes has been associated with loss of their long circulating properties and subsequent clearance from the blood (Dams et al., 2000; Ishida et al., >>2003<<, 2006b). This phenomenon is known as the \u201Caccelerated blood clearance\u201D (ABC) phenomenon. The ABC phenomenon is a major concern for the clinical application of PEGylated formulations that require multiple dosing regimens. Dams et al. first" . _:b594468570 . _:b46911173 . _:b594469377 . _:b594468407 . _:b46911132 . . _:b594468828 . _:b594468356 . _:b594468369 . . . . _:b46911347 . . _:b594468826 . . _:b594469898 . _:b46911303 "Recent studies have investigated the use of cationic thermosensitive liposomes (CTSL) for tumor targeting (Dicheva et al., >>2013<<, 2014), with promising results showing doxorubicin-encapsulated CTSLs having three-fold higher accumulation at the target site compared to the thermosensitive liposomal formulation (Dicheva et al., 2014)." . . _:b594469125 . _:b594469160 . _:b594468236 . _:b594469453 . _:b46911194 . _:b594469800 . . _:b594468941 . . . _:b46911319 "clinically approved liposomal-based therapeutics" . _:b594468089 . _:b594469464 . _:b594468852 . . _:b594468896 . . _:b594469337 . . . _:b594469119 . _:b594469052 . _:b46911252 . . . _:b594468120 . _:b594469152 . . . . . . _:b594469525 . _:b594469893 "2"^^ . . . _:b594469393 . . _:b594469892 "2"^^ . _:b594468099 . . . _:b594469895 "2"^^ . . . _:b594468318 . _:b594469894 "2"^^ . _:b46911345 "EndoTAG-1 exhibits a greater antivascular effect on tumor vasculature while the usage of DOTAP, a cationic synthetic lipid, in EndoTAG-1 allows for selective affinity to the target tumor (Chang and Yeh, >>2012<<). Another form of paclitaxel, LEP-ETU (liposome-entrapped paclitaxel easy-to-use), is in Phase I/II trials (Zhang et al., 2005; Immordino et al., 2006). LEP-ETU is prepared in a 90:5:5 molar ratio of DOPC, cholesterol, and cardiolipin" . . _:b594469889 "2"^^ . _:b46911222 . _:b594469888 "2"^^ . _:b594469891 "2"^^ . . . _:b594469890 "2"^^ . . _:b594469901 "2"^^ . _:b594469676 . _:b594468341 . _:b594469007 . _:b594469900 "2"^^ . . _:b594468576 . _:b594469903 "2"^^ . . . . _:b594469902 "2"^^ . . . _:b594469246 . . _:b594469897 "2"^^ . . . . _:b594469896 "2"^^ . . _:b594469899 "2"^^ . _:b46911395 "Similar obstacles are faced by other nano-delivery systems for translation into the clinic (Allen and Cullis, >>2004<<, 2013; Zhang et al., 2008; Sawant and Torchilin, 2012; Narang et al., 2013)." . . _:b594469898 "2"^^ . . . _:b594469831 . _:b594469909 "2"^^ . _:b594469310 . _:b594469813 . _:b594469908 "2"^^ . _:b594468993 . _:b594469911 "2"^^ . _:b594468837 . _:b594469910 "2"^^ . _:b594469905 "2"^^ . _:b594469904 "2"^^ . . _:b594469907 "2"^^ . . . _:b594468633 . _:b594469906 "2"^^ . _:b594468677 . _:b594469917 "2"^^ . . _:b594469108 . . _:b594469916 "2"^^ . _:b594469919 "2"^^ . _:b594469928 . _:b594469691 . _:b594469918 "2"^^ . _:b594469256 . _:b594469913 "2"^^ . _:b594469275 . _:b594469912 "2"^^ . _:b594469746 . _:b594469915 "2"^^ . _:b594469914 "2"^^ . _:b594468420 . _:b594469925 "2"^^ . . _:b594469924 "2"^^ . . _:b594468294 . _:b594469927 "2"^^ . . _:b594469926 "2"^^ . . _:b46911351 "DOPC is a recently developed neutral liposome carrier for siRNA delivery and is currently in clinical testing (Mangala et al., >>2009<<). Another drug in Phase I/II trials is annamycin to treat acute lymphocytic leukemia (Wetzler et al., 2013). With non-cross resistance properties and an enhanced cellular uptake and retention, annamycin's efficacy and anti-tumor activity" . _:b594469921 "2"^^ . . _:b594469920 "2"^^ . _:b594468151 . _:b594469923 "2"^^ . _:b594469922 "2"^^ . _:b594469535 . _:b46911313 "A number of studies have shown effective diagnostic imaging and therapeutic delivery of encapsulated drugs in vivo with theranostic nanosystems, especially in various cancers (Charron et al., 2015; Cole and Holland, >>2015<<). For example, Han et al. (2014) conjugated ECl-GLuc to nickel-chelating liposomes (ECl-GLuc-liposome), and demonstrated significant bioluminescence imaging and targeted drug delivery in both SKOv3 cells in vitro and in" . _:b46911185 . _:b594469933 "2"^^ . _:b594469028 . _:b594469932 "2"^^ . . . _:b594469935 "2"^^ . _:b594468160 . _:b594469934 "2"^^ . . _:b594469834 . _:b594469929 "2"^^ . _:b594468534 . _:b594469649 . . _:b594469928 "2"^^ . . _:b594469233 . _:b594469931 "2"^^ . . _:b594469930 "2"^^ . _:b594469941 "2"^^ . _:b594468655 . _:b594469940 "2"^^ . . _:b594469943 "2"^^ . . . . . _:b594469942 "2"^^ . _:b594468916 . _:b594469937 "2"^^ . . _:b594469936 "2"^^ . _:b594468403 . . _:b594468123 . _:b46911307 "surrounding therapeutic efficacy (e.g., location of diseased tissue and accessibility for remote triggers) and potential toxicity of particularly synthetic components of the drug delivery system (Bibi et al., 2012; Allen and Cullis, >>2013<<). Overall, this technology is promising and does warrant further investigation to determine which disease states would benefit from this localized treatment platform and how to make such formulations safer for clinical use." . _:b594468845 . _:b594469939 "2"^^ . . _:b594469600 . . _:b594469938 "2"^^ . _:b594469690 . . _:b594469949 "2"^^ . _:b46911377 "et al., 2013Amphotericin BAnti-fungal prophylaxisFDA approved in 1997ConventionalChandrasekar, 2008; Allen and Cullis, 2013DaunorubicinLeukemia and solid tumorsFDA Approved in 1996ConventionalChang and Yeh, 2012; Allen and Cullis, >>2013< . _:b594469948 "2"^^ . _:b594468801 . _:b594469576 . . . _:b594469950 "2"^^ . _:b594469945 . _:b594469945 "2"^^ . _:b594469944 "2"^^ . _:b46911182 "creates a local surface concentration of highly hydrated groups, which sterically inhibits both electrostatic and hydrophobic reactions with plasma proteins and/or cells and thereby reduces liposomal uptake by the RES (Ishida et al., 2001a). The use of PEG significantly minimizes, but does not completely circumvent, liposomal uptake by the RES\u2014with pathways independent of opsonization also possible (Laverman et al., 2001; Sawant and Torchilin, 2012)." . _:b594469947 "2"^^ . _:b594468548 . . . _:b594468458 . _:b46911340 . _:b594468753 . _:b594469946 "2"^^ . . _:b46911332 "and solid tumors (Chang and Yeh, 2012), verteporfin to treat macular degeneration (Chang and Yeh, 2012), cytarabine or cytosine arabinoside to treat neoplastic meningitis and lymphomatous meningitis (Chang and Yeh, 2012; Jahn et al., >>2015<<), and morphine sulfate for pain management are currently on the market (Chang and Yeh, 2012)." . . _:b594469567 . . . . . _:b46911198 . _:b594469493 . . _:b594468210 . . _:b594469313 . . . _:b46911191 . _:b594468283 . _:b594469423 . _:b46911235 . . . _:b594469766 . _:b594469478 . _:b46911238 . _:b594468344 . . _:b594469235 . _:b594468351 . . . _:b594468203 . _:b46911242 . . . . . _:b46911241 . _:b594469299 . . _:b594469418 . _:b594469825 . _:b46911140 . . . . _:b594469154 . _:b594469740 . _:b594469637 . _:b594469636 . . _:b594469639 . _:b46911160 . . _:b594469638 . _:b46911217 "Subsequent investigations have verified these findings, with a maximum clearance of liposomes 4\u20137 days after the initial dose in rats and 10 days in mice (Ishida et al., >>2003<<, 2006b)." . . _:b46911298 "triggers (e.g., temperature, ultrasound, magnetic, and light) and local triggers specific to the target site (e.g., enzymes and pH), through the use of specific lipid compositions and coatings (Guo and Szoka, 2003; Andresen et al., >>2004<<; Ponce et al., 2006; Bibi et al., 2012)." . _:b46911254 . _:b594469168 . . . _:b594469633 . . _:b594469632 . _:b594468401 . _:b594469336 . _:b46911392 . _:b46911372 . _:b594469635 . _:b594469634 . . . . _:b594469645 . _:b46911167 . _:b46911281 "Cationic nano-delivery systems have been shown to adhere to the mucosal surface within inflamed GI tissue, due to the interaction between the positively charged nanocarrier and the negatively charged intestinal mucosa (Coco et al., >>2013<<). Colonic mucins carry a negative charge since their carbohydrates are substituted with numerous sulfate and sialic acid residues (Larsson et al., 2009; Antoni et al., 2014)." . _:b594468229 . _:b594469644 . _:b594469076 . _:b594469647 . _:b594469647 . _:b594469526 . _:b594469646 . _:b594468184 . _:b594468926 . . _:b594469641 . _:b594469480 . _:b594469640 . . _:b46911384 "and Yeh, 2012; Allen and Cullis, 2013LurtotecanOvarian cancer, head, and neck cancerPhase I/IIConventionalDark et al., 2005; Chang and Yeh, 2012VinorelbineNewly diagnosed or relapsed solid tumorsPhase IConventionalAllen and Cullis, >>2013< . _:b594469643 . _:b46911205 "For example, inflammation results in a dramatic change in blood vessel permeability as the capillary vasculature undergoes structural remodeling to allow leukocyte diapedesis into the peripheral tissue (Klimuk et al., 1999; Hua, >>2013<<). The width of the tight junctional regions between endothelial cells in vivo has been reported to range from 12 to 20 nm (Antohe et al., 2004), however exposure to inflammatory mediators increases permeability of the microvasculature," . . _:b594469642 . . _:b594469653 . _:b46911184 "The use of PEG significantly minimizes, but does not completely circumvent, liposomal uptake by the RES\u2014with pathways independent of opsonization also possible (Laverman et al., 2001; Sawant and Torchilin, >>2012<<)." . _:b594468723 . _:b594469530 . _:b594469652 . _:b594468336 . _:b594469655 . _:b594468988 . _:b594468480 . . _:b594469654 . _:b46911370 . _:b594469649 . _:b594468508 . _:b594468614 . _:b594469648 . _:b594468436 . _:b594469651 . _:b594468996 . . _:b594469650 . . . . _:b594468167 . _:b594469661 . . _:b594468955 . _:b594469660 . _:b594469262 . _:b594469663 . . _:b594469662 . . _:b594469657 . . . _:b594469656 . _:b594468532 . . _:b46911360 . _:b594469925 . _:b594468311 . _:b594469659 . _:b594469658 . _:b594469170 . _:b594469669 . . _:b46911157 "of liposomes (Gabizon et al., 1993), with reported half-lives varying from 2 to 24 h in rodents (mice and rats) and as high as 45 h in humans, depending on the particle size and the characteristics of the coating polymer (Allen, >>1994<<; Moghimi and Szebeni, 2003). While coating liposomes with PEG results in prolonged circulation times, there can be an offsetting reduction in the ability to interact with the intended targets (Willis and Forssen, 1998; Ulrich, 2002)." . . . _:b594469668 . . _:b46911358 . _:b594469671 . _:b46911236 . _:b594469670 . _:b46911237 . . _:b46911233 "This pseudoallergy is thought to be partly due to the activation of the complement system with the subsequent generation of C3 split-products (e.g., C3d) (Dempsey et al., >>1996<<) and anaphylatoxins C3a and C5a (Szebeni, 2005; Szebeni and Moghimi, 2009)." . _:b594469665 . _:b46911238 . . . . . _:b594469664 . _:b46911239 . _:b46911133 . . _:b594468851 . _:b594469667 . _:b46911232 . _:b594468498 . . . _:b46911233 . _:b594469666 . _:b594469677 . _:b46911234 . . _:b594469676 . _:b46911235 . _:b594469679 . _:b46911244 . . _:b594469046 . . _:b594469678 . _:b46911245 . . _:b594469673 . _:b46911246 . _:b594468581 . . _:b594469672 . _:b46911247 . _:b594468914 . _:b594469675 . _:b46911240 . . _:b594469695 . _:b594469674 . _:b46911241 . . _:b594469685 . _:b46911242 . . _:b594469684 . _:b46911243 . _:b46911342 . _:b594468639 . _:b594469595 . _:b594469687 . _:b46911252 . _:b46911390 "Approved in 1995PEGylatedNing et al., 2007Doxorubicin and bortezomibRelapsed or refractory multiple myelomaFDA Approved in 2007PEGylatedNing et al., 2007Thermosensitive doxorubicinLiver tumorsPhase IIIPEGylatedYarmolenko et al., >>2010< . _:b594469686 . _:b46911253 . . _:b594469348 . . _:b594469681 . _:b46911254 . . _:b46911408 "the biocompatibility, biodistribution and toxicology profile of liposomal formulations, and will require further evaluation to understand the interaction of the nanoparticles with biological tissues and cells (Allen and Cullis, 2004, >>2013<<; Zhang et al., 2008; Sawant and Torchilin, 2012; Narang et al., 2013; Tinkle et al., 2014)." . _:b594469680 . _:b46911255 . . _:b594469683 . _:b46911248 . _:b46911189 "Generally, large unmodified liposomes are eliminated more rapidly than small, neutral, or positively charged liposomes (Oku and Namba, >>1994<<; Laverman et al., 1999; Ulrich, 2002)." . _:b594468740 . . _:b46911249 . _:b594469682 . . _:b594469215 . _:b594468794 . _:b594469693 . _:b46911250 . _:b594468378 . _:b594468684 . _:b594469428 . _:b46911251 . _:b594469692 . _:b594469412 . _:b594469415 . _:b594468409 . _:b594469695 . _:b46911260 . _:b594469694 . _:b46911261 . . _:b594469689 . _:b46911262 . _:b594469582 . _:b594469688 . _:b46911263 . . . . . _:b594469691 . _:b46911256 . _:b594469690 . _:b46911257 . _:b46911285 . . _:b594469523 . _:b46911258 . _:b594469701 . . _:b594468447 . _:b46911259 . _:b594469700 . _:b594469703 . _:b46911268 . . . _:b46911269 . _:b594469702 . _:b594469697 . _:b46911270 . _:b594469792 . . _:b46911271 . _:b594469696 . _:b594468618 . . _:b594469113 . _:b594469699 . _:b46911264 . . . _:b46911265 . _:b594469698 . . . _:b594469709 . _:b46911266 . . _:b594468248 . . _:b46911267 . _:b594469708 . _:b594468745 . . _:b594468630 . _:b46911276 . _:b594469711 . _:b594469710 . _:b46911277 . . _:b46911278 . _:b594469705 . . _:b46911156 . _:b594469704 . _:b46911279 . . _:b594469707 . _:b46911272 . _:b594468324 . _:b594469706 . _:b46911273 . _:b594469360 . _:b594469717 . _:b46911274 . . _:b46911275 . _:b594469716 . _:b594469719 . _:b46911284 . . _:b594469779 . _:b594469718 . _:b46911285 . _:b594468733 . . _:b594469106 . _:b594469713 . _:b46911286 . _:b594468572 . _:b46911287 . _:b594469712 . . _:b594469612 . _:b594468716 . _:b594469715 . _:b46911280 . _:b594469714 . _:b46911281 . . . _:b594468208 . . _:b594469260 . _:b46911282 . _:b594469725 . . . . _:b594468773 . _:b46911283 . _:b594469724 . . . _:b46911292 . _:b594469727 . . _:b46911323 "Furthermore, the use of PLD ensures that doxorubicin can pass through the myocardium without being released and contributing to cardiac muscle cell toxicity (Rahman et al., >>2007<<). Finally, PLD avoids the high plasma peak levels of free drug, which has been correlated with cardiotoxicity (Lyass et al., 2000). In addition to receiving FDA approval for usage of PLD in 1995, combination therapies of PLD and other" . _:b594469458 . _:b594468857 . _:b594469726 . _:b46911293 . _:b46911244 "Liposomes have been utilized as a drug delivery carrier for a wide range of therapeutic compounds and diagnostic agents, such as drug molecules, gene therapy and bioactive agents (Hua and Wu, >>2013<<). Modifications of these formulations are constantly being investigated in an effort to improve efficacy, reduce RES clearance and minimize toxicity\u2014this includes changes in lipid composition, charge, and the addition of surface coatings" . _:b46911204 . . _:b594469721 . _:b46911294 . _:b594469720 . _:b46911295 . _:b594468103 . . _:b594469626 . _:b594469723 . _:b46911288 . . _:b594468950 . _:b594469444 . _:b594469722 . _:b46911289 . . _:b594469733 . _:b46911290 . . _:b594469732 . _:b46911291 . _:b594468462 . _:b594469735 . _:b46911300 . _:b594468362 . . . . _:b594469878 . . _:b594469734 . _:b46911301 . . _:b594469326 . _:b594469729 . _:b46911302 . . _:b594469728 . _:b46911303 . . _:b594469731 . _:b46911296 . _:b46911394 "why the bottleneck for translation into clinical practice?" . _:b594469730 . _:b46911297 . . . _:b594468983 . _:b46911208 . _:b594469741 . _:b46911298 . . _:b594469740 . _:b46911299 . _:b594469743 . _:b46911308 . _:b46911178 "This effect was not present after administration of a similar free doxorubicin dose or phospholipid dose in drug-free liposomes (Gabizon et al., >>2002<<). In addition, administration of Doxil\u00AE in mice was reported to interfere with the clearance of bacteria from the blood, which was suggested to be due to macrophage suppression (Storm et al., 1998; Szebeni and Barenholz, 2009)." . _:b594468312 . _:b594469742 . _:b46911309 . _:b594469737 . _:b46911310 . . _:b594469736 . _:b46911311 . . _:b594469538 . _:b594469739 . _:b46911304 . . _:b594469738 . _:b46911305 . _:b594469749 . _:b46911306 . . _:b594469748 . _:b46911307 . _:b594469705 . . _:b594469751 . _:b46911316 . . _:b46911317 . _:b594469750 . _:b594469588 . . _:b594469745 . _:b46911318 . . _:b594469210 . . _:b594469744 . . _:b46911321 . _:b46911319 . _:b594468090 . _:b594469236 . _:b594469747 . _:b46911312 . _:b594468687 . _:b46911313 . _:b594469746 . _:b594469757 . _:b46911314 . . . . _:b46911315 . _:b594469756 . . . _:b594469759 . _:b46911324 . _:b594469318 . _:b594469758 . _:b46911325 . . . _:b594469753 . _:b46911326 . _:b594469169 . _:b46911162 "site-specific delivery of drugs to designated cell types or organs in vivo, which selectively express or over-express specific ligands (e.g., receptors or cell adhesion molecules) at the site of disease (Willis and Forssen, 1998; Hua, >>2013<<). Many types of ligands are available, such as antibodies, peptides/proteins and carbohydrates (Figure 1)." . . _:b46911327 . _:b594469752 . _:b594468689 . _:b594469755 . _:b46911320 . . _:b46911321 . _:b594469754 . _:b594469607 . _:b594469765 . _:b46911322 . . _:b594468295 . . _:b594469764 . _:b46911323 . _:b594469775 . . _:b46911332 . _:b594469767 . . _:b594468681 . . . . _:b594469766 . _:b46911333 . _:b594469593 . _:b594469400 . _:b46911334 . _:b594469761 . _:b594469508 . _:b594469760 . _:b46911335 . . . _:b594468792 . _:b594469763 . _:b46911328 . . _:b594468956 . _:b46911329 . _:b594469762 . _:b594469356 . _:b594468658 . _:b46911330 . _:b594469773 . _:b594468613 . _:b594469772 . _:b46911331 . _:b594468612 . . _:b594469775 . _:b46911340 . _:b594468615 . _:b594468819 . _:b46911341 . _:b594469774 . _:b594468614 . _:b594469769 . _:b46911342 . _:b594468265 . _:b594468609 . _:b594469768 . _:b46911343 . _:b594468608 . . _:b46911336 . _:b594469771 . . . _:b594468611 . _:b594469770 . _:b46911337 . _:b594469193 . _:b594468610 . _:b594469781 . _:b46911338 . _:b594468621 . _:b594469780 . _:b46911339 . _:b594468620 . . _:b594469783 . _:b46911348 . _:b594468623 . . _:b594469782 . _:b46911349 . _:b594468622 . _:b594469414 . _:b594469777 . _:b46911350 . . _:b594468617 . . _:b594469776 . _:b46911351 . _:b594468616 . . . _:b46911344 . _:b594469779 . _:b594468619 . _:b594469778 . _:b46911345 . _:b594469189 . _:b594468618 . _:b594469789 . _:b46911346 . _:b594468629 . . . _:b46911347 . _:b594469788 . _:b594468628 . . _:b594469791 . _:b46911356 . _:b46911144 . _:b594468631 . _:b594468815 . _:b594469790 . _:b46911357 . _:b594469909 . _:b594468630 . . _:b46911358 . _:b594469785 . . _:b594468625 . _:b594469776 . _:b594469085 . . _:b46911359 . _:b594469784 . _:b594469498 . _:b594468624 . _:b594469787 . _:b46911352 . _:b594468960 . _:b594468627 . _:b594469291 . . _:b594469656 . _:b594469263 . _:b46911353 . _:b594469786 . _:b594468626 . _:b594469399 . _:b594468299 . _:b594469797 . _:b46911354 . _:b594468637 . _:b46911359 "cancerPhase IDOPC neutral liposomesMangala et al., 2009Paclitaxel EndoTAG-1Advanced triple-negative breast cancerPhase IICationicChang and Yeh, 2012; Awada et al., 2014Paclitaxel EndoTAG-1Pancreatic cancerPhase IICationicL\u00F6hr et al., >>2012< . _:b46911355 . _:b594468636 . . _:b594468449 . _:b46911364 . _:b594469799 . _:b594468639 . _:b594468520 . _:b46911365 . _:b594469798 . _:b594468638 . _:b594468399 . _:b594469793 . _:b46911366 . _:b594468633 . _:b594469792 . _:b46911367 . _:b594468632 . _:b594469795 . _:b46911360 . _:b594469906 . _:b594468635 . _:b594469849 . _:b46911258 . _:b594469794 . _:b46911361 . . _:b594468634 . _:b594468418 . _:b594468738 . _:b46911362 . _:b594469805 . _:b594468645 . _:b594469461 . _:b594469724 . _:b46911363 . _:b594469804 . _:b594469547 . _:b594468644 . _:b594469807 . _:b46911372 . _:b594468647 . . _:b594469806 . _:b46911373 . _:b594468646 . _:b594469801 . _:b46911374 . _:b594468641 . . _:b594469802 . _:b594469800 . _:b46911375 . _:b594468640 . . _:b594469803 . _:b46911368 . _:b594468521 . _:b594468643 . . _:b594468795 . _:b46911369 . _:b594469802 . _:b594468642 . _:b594468094 . _:b594469813 . _:b46911370 . _:b594468653 . _:b594469121 . . _:b46911371 . _:b594469812 . _:b594468130 . _:b594468652 . . _:b594469201 . _:b594469815 . _:b46911380 . _:b594468655 . _:b594469814 . _:b46911381 . . _:b594468654 . . _:b594469420 . . _:b46911382 . _:b594469809 . _:b594469072 . _:b594468649 . _:b594469610 . _:b594469477 . _:b594469808 . _:b46911383 . . _:b594468195 . _:b594468648 . _:b594469811 . _:b46911376 . _:b594469403 . _:b594468651 . _:b594469810 . _:b46911377 . _:b594468650 . . _:b46911378 . _:b594469821 . _:b594469353 . _:b594468661 . . _:b594469107 . _:b594469820 . _:b46911379 . _:b594468660 . . . _:b594468469 . _:b594469823 . _:b46911388 . _:b46911176 . _:b594468663 . _:b594469872 . _:b594469822 . _:b46911389 . _:b46911177 . _:b46911294 "in vivo effects with the use of cationic lipids and polymers, including cell shrinking, reduced number of mitoses, vacuolization of the cytoplasm, and detrimental effects on key cellular proteins (e.g., protein kinase C) (Lv et al., >>2006<<). For cationic lipids, the cytotoxic effects are determined by the structure of its hydrophilic group, with quaternary ammonium amphiphiles being more toxic than their tertiary amine counterparts." . _:b46911318 "At this stage, packaging multiple payloads in the same carrier would appear most promising, however sequencing and scale up of this kind of approach would still be challenging (Zhang et al., 2011; Allen and Cullis, >>2013<<)." . _:b594468662 . _:b594469536 . _:b594469566 . _:b594469817 . _:b46911390 . _:b594468657 . . _:b594469816 . _:b46911391 . _:b594468538 . _:b594468656 . _:b594468894 . . _:b46911384 . _:b594469832 . _:b594469819 . _:b594468659 . . _:b594469818 . _:b46911385 . . _:b594468658 . _:b594469698 . _:b46911386 . _:b594469829 . . _:b594468669 . . _:b46911387 . _:b594469828 . _:b594468668 . . _:b594468694 . _:b594469831 . _:b46911396 . _:b594469136 . _:b594468671 . _:b594469830 . _:b46911397 . _:b594468670 . _:b594469825 . _:b46911398 . _:b594469684 . . . _:b594468665 . _:b594468902 . _:b594468580 . _:b46911399 . _:b594469824 . _:b594468664 . . . _:b46911392 . _:b46911311 . _:b594469827 . _:b594468472 . _:b594468667 . _:b594469826 . _:b46911393 . _:b594469048 . _:b594468666 . . _:b594469837 . _:b46911394 . _:b594468677 . _:b594469379 . _:b46911395 . _:b594469836 . . _:b594468676 . _:b594469839 . _:b46911404 . _:b594468679 . _:b594468968 . _:b46911405 . _:b594469838 . _:b594469653 . _:b594468678 . _:b594469833 . _:b46911406 . _:b594468673 . _:b594469044 . _:b46911407 . _:b46911231 . _:b594469832 . _:b594468306 . _:b594468526 . _:b594468672 . _:b594469401 . _:b46911400 . _:b46911228 . _:b594469835 . _:b594468675 . _:b594469834 . _:b46911401 . _:b46911135 "biocompatibility, capacity for self-assembly, ability to carry large drug payloads, and a wide range of physicochemical and biophysical properties that can be modified to control their biological characteristics (Koning and Storm, >>2003<<; Metselaar and Storm, 2005; Ding et al., 2006; Hua and Wu, 2013)." . . _:b594468674 . _:b594468243 . _:b594469845 . _:b46911402 . . _:b594468685 . . . _:b46911403 . _:b594469844 . _:b594468684 . _:b594469847 . _:b46911412 . _:b594468405 . . _:b594469598 . _:b594468687 . _:b594469846 . _:b46911413 . _:b594468686 . _:b594469361 . _:b594469841 . _:b46911414 . _:b594468681 . _:b594468235 . _:b594469840 . _:b46911415 . _:b594468680 . _:b594469669 . _:b594469843 . _:b46911408 . . _:b594468683 . _:b594469842 . _:b46911409 . _:b594468682 . _:b46911142 "Liposomes are generally considered to be pharmacologically inactive with minimal toxicity, as they tend to be composed of natural phospholipids (Koning and Storm, 2003; Metselaar and Storm, 2005; Ding et al., >>2006<<; Hua and Wu, 2013); however increasing number of studies have shown that liposomes are not as immunologically inert as once suggested (Szebeni and Moghimi, 2009)." . _:b594468872 . . _:b594469853 . _:b46911410 . _:b594468693 . . _:b594469852 . _:b46911411 . _:b46911219 "This phenomenon is affected by lipid dose, PEG surface density, and the interval between the first and consecutive injections (Ishida and Kiwada, >>2008<<). Repeated injection of empty PEGylated liposomes in rats has been shown to elicit marked anti-PEG IgM production (Ishida et al., 2006b). This immune response is thought to be mediated by the spleen, as the degree of anti-PEG IgM" . _:b594468692 . _:b594468146 . _:b594469855 . _:b594468695 . . _:b594469854 . . _:b594468694 . _:b594468226 . . . _:b594469849 . _:b594468689 . _:b594469031 . _:b594469425 . _:b594469848 . . _:b594468688 . _:b594469851 . _:b46911416 . . _:b594469324 . _:b594468691 . _:b594469850 . _:b46911417 . _:b594468259 . _:b594468690 . _:b594469815 . _:b594469605 . . _:b594469861 . . _:b594468701 . . _:b594469860 . _:b594468700 . _:b594469417 . _:b594469863 . . _:b594468703 . _:b594469421 . _:b594469862 . _:b594468702 . _:b594469158 . _:b594469857 . _:b46911313 . _:b594468404 . _:b594468697 . _:b594469856 . _:b594468696 . _:b594469859 . _:b594468699 . . . _:b594469858 . _:b594468668 . _:b594468698 . . _:b594469869 . _:b594469077 . _:b594468709 . _:b594469573 . _:b594469868 . _:b594468708 . . _:b594469871 . _:b594468711 . _:b594468503 . _:b594469870 . . _:b594468710 . _:b594469865 . _:b594468714 . _:b594468705 . _:b594469367 . _:b594469277 . _:b594469864 . _:b46911241 "on the phosphate oxygen of mPEG-phospholipid conjugate (Moghimi et al., 2006) or the use of other non-ionic lipopolymers and lipid conjugates, such as mPEG-substituted synthetic ceramides (Webb et al., 1998; Szebeni and Moghimi, >>2009<<). The development of immunogenic reactions to liposomal therapies may lead to altered pharmacokinetics, loss of efficacy, and the rise of potentially serious toxicities (e.g., anaphylaxis) (Szebeni and Moghimi, 2009)." . _:b594468704 . _:b594469923 . . _:b594469867 . _:b594468153 . . _:b594468707 . . _:b594469397 . _:b594468549 . _:b594469866 . _:b594468706 . _:b594469877 . . _:b594468717 . _:b46911225 "The ABC phenomenon has not been reported to occur in patients receiving PLD, even after multiple-dosing regimens (Laverman et al., >>2001<<). Generally higher doses (15 \u03BCmol phospholipid/kg) are administered clinically, which may account for this absence of the ABC phenomenon (Lyass et al., 2000). In addition, this response may also be due to doxorubicin-mediated macrophage" . _:b594469876 . _:b594469237 . _:b594468716 . . _:b594469879 . _:b594468719 . _:b594468609 . _:b594469878 . _:b594468718 . . _:b594469873 . _:b594468783 . _:b594468713 . . _:b594469872 . . _:b46911293 "It should be noted however, that there is a potential for electrostatic interactions and subsequent binding of these charged nanoparticles with other charge-modifying substances in the circulation or during GI transit (Hua et al., >>2015<<). In addition, recent studies have identified potentially toxic in vitro and in vivo effects with the use of cationic lipids and polymers, including cell shrinking, reduced number of mitoses, vacuolization of the cytoplasm, and" . _:b594468712 . _:b594469875 . _:b594468395 . _:b594468715 . . _:b594469874 . _:b594468714 . _:b594469885 . _:b594468725 . _:b594469884 . _:b594468724 . _:b594469887 . _:b46911276 . _:b594468727 . . _:b594469589 . _:b594469886 . _:b594468726 . _:b594469881 . _:b594469282 . _:b594468721 . _:b594469880 . . . _:b594468720 . _:b594468285 . _:b594469883 . _:b594468723 . _:b46911339 . . _:b594469882 . . _:b594468722 . _:b594469381 . _:b594469645 . _:b594468733 . _:b594469133 . _:b594469380 . _:b594469586 . . _:b594468732 . _:b594469500 . _:b594469383 . _:b46911299 . _:b594468735 . _:b594469382 . _:b594468734 . _:b594469377 . . _:b594468729 . _:b46911289 "such as DNA and RNA, based on electrostatic interaction between the positively charged phospholipids [e.g., dioleoylphosphatidylethanolamine (DOPE)] and negatively charged nucleic acids (Felgner et al., 1987; Campbell et al., 2002, >>2009<<; Kunstfeld et al., 2003; Wu et al., 2007)." . _:b594469376 . _:b594468545 . _:b594468728 . . _:b594469379 . _:b594469050 . _:b594468731 . _:b594469332 . . _:b594468138 . _:b594469378 . _:b594468730 . _:b594469389 . _:b594468741 . _:b594468888 . _:b594469388 . _:b594468740 . _:b594469391 . _:b594468743 . _:b594468279 . _:b594469390 . _:b594468471 . _:b594468742 . _:b594469385 . _:b594468737 . _:b594469730 . _:b594469384 . _:b594468736 . . _:b594468533 . _:b594469387 . . _:b594468739 . _:b594469386 . _:b594468507 . _:b594468738 . . _:b594469397 . _:b594468690 . _:b594468749 . _:b46911274 "Possible reasons for this discrepancy have previously been reviewed (Sawant and Torchilin, 2012; Allen and Cullis, >>2013<<), and include factors such as disease-dependent anatomical and physiological barriers, target accessibility and expression, and formulation stability." . _:b594468712 . _:b594469396 . _:b594468748 . _:b594469399 . _:b594469629 . _:b594468751 . . _:b594469398 . _:b594469752 . _:b594468750 . _:b594468793 . _:b594469393 . . _:b594468745 . _:b594469305 . _:b594469392 . _:b594468744 . _:b594468836 . _:b46911172 "The RES is the main site of liposome accumulation following their systemic administration (Poste et al., 1976; Senior, >>1987<<). Primary organs associated with the RES include the liver, spleen, kidney, lungs, bone marrow, and lymph nodes (Senior, 1987)." . _:b594468804 . _:b594469585 . _:b594469395 . _:b594468747 . . _:b594469394 . _:b594469104 . _:b594468746 . _:b46911340 "These include irinotecan SN-38 in Phase I/II to treat colorectal cancer (Zhang et al., 2004; Suenaga et al., >>2015<<) and a liposomal-based all-trans-retinoic acid (ATRA) in Phase II that contains the drug tretinoin to treat acute promyelocytic leukemia and hormone-refractory prostate cancer (Ozpolat et al., 2003)." . _:b594468869 . _:b594469405 . _:b594468757 . _:b594469404 . _:b594469241 . _:b594469826 . _:b594468179 . _:b594468756 . _:b594468743 . _:b594469407 . _:b46911244 . . _:b594468759 . _:b594469230 . _:b46911245 . _:b594469406 . . _:b46911400 "of the final product, (iii) lack of equipment and/or in-house expertise, (iv) chemical instability or denaturation of the encapsulated compound in the manufacturing process, and (v) long term stability issues (Narang et al., >>2013<<). Suitable methods for the industrial scale production of conventional liposomes have been successfully developed, without the need for numerous manufacturing steps or the use of organic solvents (Jaafar-Maalej et al., 2012; Kraft et al.," . _:b594468758 . _:b594468978 . _:b594469401 . _:b594468753 . _:b594469883 . _:b594469855 . _:b594468212 . . _:b594469400 . . _:b594468752 . _:b594469403 . _:b594468755 . _:b46911369 "et al., 2014VincristineNon-Hodgkin lymphomaFDA Approved in 2012ConventionalAllen and Cullis, 2013; Wang et al., 2015TretinoinAcute promyelocytic leukemia and hormone-refractory prostate cancerPhase IIConventionalOzpolat et al., >>2003<<; Immordino et al., 2006Irinotecan SN-38Metastatic colorectal cancerPhase I/IIConventionalZhang et al., 2004; Suenaga et al., 2015AnnamycinAcute lymphoblastic leukemiaPhase I/IIConventionalWetzler et al., 2013Amphotericin BAnti-fungal" . _:b594469402 . _:b594468754 . _:b46911240 "of the anionic charge localized on the phosphate oxygen of mPEG-phospholipid conjugate (Moghimi et al., 2006) or the use of other non-ionic lipopolymers and lipid conjugates, such as mPEG-substituted synthetic ceramides (Webb et al., >>1998<<; Szebeni and Moghimi, 2009)." . _:b594469413 . _:b594468765 . _:b594469412 . _:b594468764 . _:b46911128 "applications by stabilizing therapeutic compounds, overcoming obstacles to cellular and tissue uptake, and improving biodistribution of compounds to target sites in vivo (Koning and Storm, 2003; Metselaar and Storm, 2005; Ding et al., >>2006<<; Hua and Wu, 2013). Liposomes are defined as phospholipid vesicles consisting of one or more concentric lipid bilayers enclosing discrete aqueous spaces." . _:b594469415 . _:b594468767 . _:b594469414 . _:b594468727 . _:b594468766 . _:b594468266 . _:b594469409 . _:b594468761 . _:b46911300 . _:b594469408 . . _:b594468760 . . _:b594469411 . _:b594468763 . _:b594468122 . _:b594469410 . . _:b594469279 . _:b594468762 . _:b594469421 . _:b594468077 . _:b594469426 . _:b594468773 . _:b594469863 . _:b46911296 . _:b594469420 . _:b594469756 . _:b594468772 . _:b594469423 . . _:b594468313 . _:b594468775 . . _:b594469422 . _:b594468774 . _:b594469417 . . _:b594468769 . . _:b594469416 . _:b594468768 . _:b594468317 . _:b594469751 . _:b594469419 . . _:b594468771 . . _:b594469749 . _:b594469418 . . _:b594469503 . _:b594468770 . _:b594469429 . _:b594468781 . _:b46911374 . _:b594469074 . _:b594469428 . _:b594468780 . _:b594468954 . _:b594469431 . _:b46911414 . _:b594468783 . _:b46911306 . . _:b594469430 . . _:b594468910 . _:b594468782 . _:b594469425 . _:b594468777 . . _:b46911413 . _:b594469424 . _:b594469269 . . _:b594468640 . _:b594468776 . _:b594469427 . . _:b594468779 . _:b594469651 . . _:b594469426 . . _:b594468778 . _:b46911148 "the 1980s, whereby liposomal delivery proved useful for improving the therapeutic index of encapsulated drugs, such as doxorubicin and amphotericin (Gabizon et al., 1982; Koning and Storm, 2003; Metselaar and Storm, 2005; Ding et al., >>2006<<; Hua and Wu, 2013). Conventional liposomal formulations reduced the toxicity of compounds in vivo, through modifying pharmacokinetics and biodistribution to enhance drug delivery to diseased tissue in comparison to free drug." . _:b594469437 . . _:b594468789 . . _:b594469436 . . _:b594468788 . _:b594469439 . _:b594468749 . _:b594468791 . _:b594469438 . . _:b594468790 . _:b594469433 . _:b594468785 . . _:b594469432 . _:b594469709 . . _:b594468784 . . _:b594469435 . _:b594468787 . _:b46911236 "should be noted that the sensitivity of different species to liposomal CARPA shows substantial variation, with some species (dogs and pigs) also showing tachyphylaxis (tolerance induction) following additional doses (Szebeni et al., >>1999<<, 2007). Therefore, desensitization protocols using empty liposomes may be used to prevent CARPA, as well as pre-administration of complement inhibitors (e.g., soluble C receptor type 1, anti-C5 antibody, and indomethacin) (Szebeni and" . _:b594469357 . _:b594469434 . _:b594468786 . _:b594469445 . . . . _:b594468797 . _:b594468260 . . _:b594469444 . . _:b594468796 . _:b594469447 . . . _:b594468799 . _:b594469446 . _:b594468798 . . _:b594468247 . _:b594469441 . _:b594469029 . . _:b594468793 . _:b594468781 . _:b594469440 . _:b594468792 . _:b594469443 . _:b594468379 . _:b594468795 . _:b46911328 . _:b594469182 . _:b594469442 . . _:b594468794 . _:b594469453 . _:b594468915 . _:b594468805 . _:b594469130 . . . _:b594469763 . _:b594469452 . . _:b594468347 . _:b594468804 . _:b594469087 . . _:b594469455 . _:b594468807 . . _:b594469267 . _:b594469454 . _:b594468806 . _:b594469449 . . _:b594469854 . . _:b594468801 . . . _:b594469448 . . _:b594468800 . _:b594468216 . _:b594469451 . _:b594469539 . _:b594468765 . _:b594468803 . _:b594468234 . _:b594469450 . _:b594468802 . _:b594469369 . . _:b594469461 . _:b46911283 . _:b594468813 . _:b594469460 . _:b594468812 . _:b594469463 . _:b594468602 . . _:b594468815 . _:b594469295 . _:b594469462 . _:b594469023 . _:b594468814 . . _:b594469457 . _:b594468809 . _:b594469209 . _:b594468742 . _:b594468688 . _:b46911317 "At this stage, packaging multiple payloads in the same carrier would appear most promising, however sequencing and scale up of this kind of approach would still be challenging (Zhang et al., >>2011<<; Allen and Cullis, 2013)." . _:b594469456 . . _:b594468808 . _:b594469459 . . . _:b594468811 . _:b46911136 "ability to carry large drug payloads, and a wide range of physicochemical and biophysical properties that can be modified to control their biological characteristics (Koning and Storm, 2003; Metselaar and Storm, 2005; Ding et al., >>2006<<; Hua and Wu, 2013)." . _:b594469304 . _:b594469458 . . _:b594468810 . . _:b594469469 . _:b594468821 . _:b594469468 . _:b594468820 . _:b594469471 . _:b594468823 . _:b594469470 . _:b594469505 . _:b594468822 . . _:b46911343 "It is embedded in a cationic liposome and is in Phase II trials to treat advanced triple-negative breast cancer (Awada et al., 2014) and pancreatic cancer (L\u00F6hr et al., >>2012<<). EndoTAG-1 is prepared in a 50:47:3 molar ratio of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and paclitaxel (Chang and Yeh, 2012). EndoTAG-1 exhibits a greater antivascular effect" . _:b594469465 . _:b594468817 . _:b594469464 . _:b594468734 . _:b594468816 . . _:b594469467 . _:b594469439 . _:b594469430 . . _:b594468819 . . . _:b594469466 . _:b594468818 . . _:b594469477 . _:b594468371 . _:b594468829 . . . _:b594469476 . . . _:b594468828 . _:b594469454 . _:b594469479 . _:b594468831 . _:b594469478 . _:b594468830 . _:b594469473 . _:b594468825 . _:b594469472 . _:b594468824 . _:b594469475 . . . _:b594468827 . . . _:b594469474 . . _:b594468826 . _:b594469485 . _:b594469932 . _:b594468837 . _:b594469622 . . _:b594469484 . _:b594469375 . _:b594468836 . _:b594469134 . _:b594469487 . _:b594468839 . _:b594468390 . _:b594469486 . _:b594468838 . _:b46911412 . _:b594469481 . _:b46911309 "or more targeting ligands, response to triggers to control drug release, delivery of a combination of therapeutics (e.g., siRNA and small molecule drugs), and biomarker and imaging capabilities (Zhang et al., 2011; Allen and Cullis, >>2013<<; Charron et al., 2015; Cole and Holland, 2015). In particular, theranostic nanoparticles have generated much interest as it is both a therapeutic and diagnostic tool all-in-one (Figure 1)." . _:b594468833 . _:b46911165 "Since lipid assemblies are usually dynamic structures, surface-coupled ligands have a high motional freedom to position themselves for optimal substrate-interactions (Willis and Forssen, >>1998<<). The limited in vivo performance of immunoliposomes, due to poor pharmacokinetics and immunogenicity, has been a major hurdle to achieving their potential as effective site-specific drug carriers (Puri et al., 2009). Therefore, newer" . _:b594469480 . _:b594468832 . _:b594469483 . _:b594468835 . _:b594469482 . _:b594468131 . _:b594468834 . _:b594469446 . _:b594469493 . _:b594468845 . . . _:b594469492 . _:b594468844 . _:b46911406 . _:b594469495 . _:b594468847 . _:b594468382 . _:b594469494 . . _:b46911404 . _:b594468846 . _:b46911302 . _:b594469489 . _:b594469685 . _:b594468841 . _:b594469488 . _:b594468671 . _:b594468840 . . . _:b594469491 . _:b594468843 . _:b594468758 . _:b594469490 . _:b594468842 . _:b594469362 . _:b594469501 . _:b594468678 . _:b594468853 . _:b594469363 . . _:b594469500 . _:b594468852 . _:b594469503 . _:b46911327 . _:b594468855 . _:b594468922 . _:b594469502 . _:b594468731 . . _:b594468854 . . _:b594468187 . _:b594469497 . _:b594468849 . . _:b594469496 . _:b594469640 . . _:b594468848 . _:b594469499 . _:b594468851 . _:b594469498 . _:b594468850 . _:b46911171 "The RES is the main site of liposome accumulation following their systemic administration (Poste et al., >>1976<<; Senior, 1987). Primary organs associated with the RES include the liver, spleen, kidney, lungs, bone marrow, and lymph nodes (Senior, 1987)." . _:b594469509 . _:b594468861 . _:b594469701 . _:b594469389 . _:b594469508 . _:b594468860 . . _:b594469511 . . _:b594468863 . . _:b594469510 . _:b594468710 . _:b594468695 . . _:b594468862 . _:b594469505 . _:b594468857 . . _:b594469504 . . . _:b594468856 . _:b594469507 . _:b594468859 . _:b594469506 . _:b594468858 . _:b594468554 . _:b594469517 . _:b594468357 . _:b594468707 . _:b594468787 . _:b594469516 . . _:b594468218 . _:b594468356 . . _:b594469519 . . _:b594468359 . _:b594469001 . _:b594469116 . _:b594469518 . _:b594468358 . _:b594469513 . _:b594468353 . . _:b594469512 . . _:b594468352 . _:b594469515 . _:b594468699 . _:b594468355 . _:b594469514 . . _:b594468354 . _:b594468732 . _:b594469525 . _:b594468365 . . _:b594469534 . _:b594469524 . _:b594468364 . _:b594469527 . _:b594468367 . _:b594469526 . _:b594468357 . _:b594468366 . _:b594469521 . _:b46911347 "Another form of paclitaxel, LEP-ETU (liposome-entrapped paclitaxel easy-to-use), is in Phase I/II trials (Zhang et al., 2005; Immordino et al., >>2006<<). LEP-ETU is prepared in a 90:5:5 molar ratio of DOPC, cholesterol, and cardiolipin (Chang and Yeh, 2012). Higher doses of LEP-ET can be safely administered compared to paclitaxel alone (Fetterly et al., 2008). Additionally, the use of" . _:b594468220 . _:b594468551 . _:b594468361 . _:b594469920 . _:b594469520 . _:b594468360 . _:b594468207 . _:b594469523 . _:b594468363 . . _:b594468298 . _:b594469522 . _:b594468362 . _:b594469533 . _:b594468484 . _:b594468373 . _:b594468400 . _:b594469532 . . _:b594468372 . _:b594469535 . _:b594468375 . . _:b594469534 . _:b594468900 . _:b594468374 . _:b46911291 . _:b594468530 . _:b594469529 . _:b594468369 . _:b594469579 . _:b594469528 . _:b594468368 . . . _:b594469531 . . _:b594469135 . _:b594468129 . _:b594468371 . _:b46911371 . _:b594468552 . _:b594469530 . _:b594468370 . _:b594469541 . _:b594469608 . _:b594468648 . _:b594468381 . _:b594468904 . _:b594468479 . _:b594468820 . _:b594469540 . _:b594468380 . . . _:b46911164 "The coupling of antibodies, particularly monoclonal antibodies, to create immunoliposomes represents one of the more versatile ligands that can be affixed to liposome surfaces (Bendas, 2001; Puri et al., >>2009<<). One of the advantages of using monoclonal antibodies is their stability and higher binding avidity because of the presence of two binding sites on the molecule. Since lipid assemblies are usually dynamic structures, surface-coupled" . _:b594469543 . _:b594468383 . _:b594469583 . . _:b594469542 . _:b46911191 "Generally, large unmodified liposomes are eliminated more rapidly than small, neutral, or positively charged liposomes (Oku and Namba, 1994; Laverman et al., 1999; Ulrich, >>2002<<). Nevertheless, the presence of high electrostatic charge can still promote the interaction of liposomes with biomolecules that can serve as opsonins (Laverman et al., 1999; Ishida et al., 2001a). Previous investigation has revealed that" . . _:b594468382 . . _:b594468328 . _:b594469537 . _:b594469082 . _:b594468377 . _:b594469167 . _:b594469536 . _:b594468314 . _:b594468376 . . . _:b594469539 . . . . _:b594468379 . _:b594469381 "2"^^ . _:b594469538 . . _:b594469482 . _:b594468378 . _:b594469380 "2"^^ . _:b594469549 . _:b594468389 . _:b594469155 . _:b594469921 . . _:b594469548 . _:b594469383 "2"^^ . _:b594468388 . _:b594469382 "2"^^ . _:b594469551 . _:b594468391 . _:b594469377 "2"^^ . _:b594469550 . _:b594468390 . _:b594469440 . . _:b594469376 "2"^^ . _:b594469545 . . _:b594468385 . _:b594469379 "2"^^ . _:b46911264 . _:b594469544 . . _:b46911153 "This not only reduces the elimination of drugs by prolonging blood circulation and providing accumulation at pathological sites, but also attenuates side effects (Torchilin et al., >>1992<<; Northfelt et al., 1996; Ishida et al., 2001b)." . _:b594468384 . _:b594469378 "2"^^ . _:b594469547 . _:b594468387 . _:b594469389 "2"^^ . _:b594469546 . _:b594469449 . _:b594468386 . . _:b594469378 . _:b594469388 "2"^^ . _:b46911277 . _:b594469557 . _:b594468397 . . . _:b594469391 "2"^^ . _:b594469556 . _:b594469394 . . _:b594468396 . _:b594469390 "2"^^ . _:b594469559 . _:b594468399 . . _:b594469558 . _:b594469385 "2"^^ . _:b594468398 . _:b594468467 . . _:b594469384 "2"^^ . _:b594469553 . _:b46911126 . . _:b594468393 . _:b594468510 . _:b594469387 "2"^^ . _:b46911127 . _:b594469552 . _:b594468392 . _:b594469386 "2"^^ . _:b594469555 . _:b594469816 . . _:b46911228 "In addition, this response may also be due to doxorubicin-mediated macrophage death and the inhibition of B-cell proliferation and/or the death of proliferated B-cells (Ishida et al., 2006b; Szebeni and Moghimi, >>2009<<)." . _:b594468395 . _:b594469397 "2"^^ . _:b594469554 . _:b594468394 . _:b46911304 "Recent studies have investigated the use of cationic thermosensitive liposomes (CTSL) for tumor targeting (Dicheva et al., 2013, >>2014<<), with promising results showing doxorubicin-encapsulated CTSLs having three-fold higher accumulation at the target site compared to the thermosensitive liposomal formulation (Dicheva et al., 2014)." . _:b594469159 . . _:b594469396 "2"^^ . _:b594469565 . . _:b594468405 . . . _:b594469564 . _:b594469399 "2"^^ . . _:b594469884 . _:b594468404 . _:b594469398 "2"^^ . _:b46911132 . _:b594469567 . _:b594468407 . . . _:b46911133 . _:b594469566 . _:b594469393 "2"^^ . _:b594468406 . _:b594469392 "2"^^ . _:b46911134 . _:b594469561 . _:b594469382 . _:b594468401 . _:b594469391 . _:b594469395 "2"^^ . _:b46911135 . _:b594469560 . _:b594468444 . . . _:b594468400 . _:b594469290 . _:b594469394 "2"^^ . _:b46911128 . _:b594469563 . _:b594468403 . _:b594468637 . . _:b46911129 . _:b594469562 . _:b594469405 "2"^^ . . _:b594468402 . . _:b594469404 "2"^^ . _:b46911130 . _:b594469573 . . _:b594468413 . _:b594469407 "2"^^ . _:b46911131 . _:b594469572 . _:b594468412 . _:b594469406 "2"^^ . _:b46911140 . _:b594469575 . _:b594468415 . _:b594469793 . _:b594469401 "2"^^ . _:b46911141 . _:b594469574 . _:b594468414 . . _:b46911142 . _:b594469569 . _:b594469400 "2"^^ . . _:b594468409 . . _:b594469403 "2"^^ . _:b46911143 . _:b594469568 . _:b594468408 . . _:b594468584 . _:b594469402 "2"^^ . _:b46911136 . _:b594469571 . _:b594469827 . _:b594468411 . _:b594469413 "2"^^ . _:b46911137 . _:b594469570 . _:b594468410 . . _:b594468553 . _:b46911138 . _:b594469581 . _:b594469412 "2"^^ . _:b594468785 . _:b594468421 . _:b594469415 "2"^^ . _:b46911139 . _:b594469580 . _:b594468420 . _:b594469414 "2"^^ . _:b46911148 . _:b594469583 . _:b594468423 . _:b594468880 . _:b594468651 . _:b46911149 . _:b594469582 . _:b594469409 "2"^^ . _:b594469413 . _:b594468422 . . . . _:b46911150 . _:b594469577 . _:b594469408 "2"^^ . _:b46911137 "large drug payloads, and a wide range of physicochemical and biophysical properties that can be modified to control their biological characteristics (Koning and Storm, 2003; Metselaar and Storm, 2005; Ding et al., 2006; Hua and Wu, >>2013<<). Liposomal formulations are characterized by properties such as particle size, charge, number of lamellae, lipid composition, and surface modification with polymers and ligands\u2014these all govern their stability in vitro and in vivo (Hua" . _:b594468417 . . . _:b594469411 "2"^^ . _:b46911151 . _:b594469576 . _:b594468416 . _:b594469410 "2"^^ . _:b46911144 . _:b594469579 . . . _:b594468419 . _:b594468355 . _:b594469421 "2"^^ . _:b594469578 . _:b46911145 . _:b594468418 . _:b594469760 . _:b594469420 "2"^^ . _:b46911146 . _:b594469589 . _:b594469457 . _:b594468429 . _:b594469109 . _:b594469423 "2"^^ . _:b46911179 . _:b46911147 . _:b594469588 . _:b46911306 "successful, with issues surrounding therapeutic efficacy (e.g., location of diseased tissue and accessibility for remote triggers) and potential toxicity of particularly synthetic components of the drug delivery system (Bibi et al., >>2012<<; Allen and Cullis, 2013)." . . . _:b594468428 . _:b594469422 "2"^^ . _:b46911156 . _:b594469591 . _:b594468431 . _:b594469417 "2"^^ . _:b46911312 . _:b46911157 . _:b594469590 . _:b594468430 . _:b594469416 "2"^^ . _:b46911158 . _:b594469585 . _:b594468425 . . . _:b46911159 . _:b594469584 . _:b594469419 "2"^^ . . _:b594468424 . _:b594469386 . _:b46911152 . _:b594469587 . _:b594469418 "2"^^ . _:b594469682 . _:b594468427 . _:b594468270 . _:b46911153 . _:b594469586 . _:b594469429 "2"^^ . _:b594468426 . . _:b594469939 . _:b46911232 "CARPA is an immediate, non-IgE-mediated hypersensitivity reaction that involves symptoms such as anaphylaxis, facial flushing, facial swelling, headache, chills, and cardiopulmonary distress (Szebeni, >>2005<<\u2014the latter of which may limit the clinical use of potentially reactogenic liposomes in cardiac patients (Szebeni and Barenholz, 2009)." . _:b594469428 "2"^^ . _:b46911154 . _:b594469597 . _:b594468437 . . . _:b594469431 "2"^^ . _:b46911310 . _:b46911155 . _:b594469596 . _:b594468778 . _:b594468436 . . _:b594469430 "2"^^ . _:b46911164 . _:b594469599 . _:b594468439 . _:b594469425 "2"^^ . _:b46911165 . _:b594469598 . _:b594468438 . . _:b46911393 . _:b46911166 . _:b594469593 . _:b594469424 "2"^^ . _:b594468433 . . _:b594468393 . _:b594468596 . _:b46911167 . _:b594469592 . _:b594469427 "2"^^ . . _:b594468432 . _:b594468985 . _:b594469426 "2"^^ . _:b46911160 . _:b594469595 . _:b594468435 . . _:b46911161 . _:b594469594 . _:b594469437 "2"^^ . _:b594468429 . . _:b594468434 . . _:b46911162 . _:b594469661 . _:b594469605 . _:b594469436 "2"^^ . _:b594468431 . _:b594468445 . _:b594469439 "2"^^ . _:b46911163 . _:b594469604 . _:b594468444 . _:b46911284 . _:b594468663 . _:b46911172 . _:b594469607 . _:b594469438 "2"^^ . _:b594468447 . _:b594469433 "2"^^ . _:b46911173 . _:b594469606 . _:b594468446 . _:b594469432 "2"^^ . _:b46911174 . _:b594469601 . _:b594468441 . _:b46911138 "formulations are characterized by properties such as particle size, charge, number of lamellae, lipid composition, and surface modification with polymers and ligands\u2014these all govern their stability in vitro and in vivo (Hua and Wu, >>2013<<; Monteiro et al., 2014). Encapsulation within liposomes protects compounds from early inactivation, degradation and dilution in the circulation (Ulrich, 2002)." . _:b594469278 . _:b594469435 "2"^^ . _:b46911175 . _:b594469600 . _:b594468440 . _:b594469221 . _:b594469321 . _:b594469434 "2"^^ . _:b594469603 . _:b46911168 . _:b594469054 . _:b594468443 . _:b594469445 "2"^^ . _:b46911169 . _:b594469602 . . _:b594468442 . _:b46911287 "large, charged structures, such as DNA and RNA, based on electrostatic interaction between the positively charged phospholipids [e.g., dioleoylphosphatidylethanolamine (DOPE)] and negatively charged nucleic acids (Felgner et al., >>1987<<; Campbell et al., 2002, 2009; Kunstfeld et al., 2003; Wu et al., 2007)." . . _:b594469444 "2"^^ . _:b46911170 . _:b594469613 . _:b594469460 . _:b594468621 . _:b594468453 . _:b46911367 "2012VerteporfinMolecular degenerationFDA Approved in 2000CationicChang and Yeh, 2012; Allen and Cullis, 2013; Gross et al., 2013AmikacinLung infectionPhase II/IIIConventionalChang and Yeh, 2012; Clancy et al., 2013; Olivier et al., >>2014< . _:b594469447 "2"^^ . _:b46911171 . _:b594469612 . . _:b594468452 . _:b594469446 "2"^^ . _:b46911180 . _:b594469615 . _:b594468455 . _:b594469451 . _:b594469441 "2"^^ . _:b46911181 . _:b594469614 . . _:b594468454 . _:b594469440 "2"^^ . _:b46911182 . _:b594469609 . _:b594468449 . . _:b46911183 . _:b594469608 . _:b594469443 "2"^^ . . . _:b594468448 . . _:b594469442 "2"^^ . _:b46911176 . _:b594469611 . _:b594468451 . . _:b46911177 . _:b594469610 . _:b594469453 "2"^^ . . _:b594468450 . _:b594469352 . _:b594469452 "2"^^ . _:b46911178 . _:b594469621 . _:b594468461 . . _:b594469455 "2"^^ . _:b46911179 . _:b594469620 . _:b594468460 . _:b594469238 . _:b594469454 "2"^^ . _:b46911188 . _:b594469623 . _:b594468463 . . _:b594469449 "2"^^ . _:b46911189 . _:b594469622 . _:b594468462 . . _:b594468278 . _:b46911190 . _:b594469617 . _:b594469448 "2"^^ . . _:b594469887 . _:b594468457 . _:b594468245 . _:b594469451 "2"^^ . _:b46911191 . _:b594469616 . _:b594468456 . _:b594468931 . _:b594469450 "2"^^ . _:b46911184 . _:b594469619 . _:b594468459 . _:b594469461 "2"^^ . _:b46911185 . _:b594469618 . . _:b594468458 . _:b594468188 . _:b594469460 "2"^^ . _:b46911186 . _:b594469629 . . _:b594469240 . _:b594468469 . . _:b594469463 "2"^^ . _:b46911187 . _:b594469628 . _:b594468376 . _:b46911312 "A number of studies have shown effective diagnostic imaging and therapeutic delivery of encapsulated drugs in vivo with theranostic nanosystems, especially in various cancers (Charron et al., >>2015<<; Cole and Holland, 2015)." . _:b594468468 . _:b594468542 . _:b594469462 "2"^^ . _:b46911196 . _:b594469631 . _:b594468471 . _:b594468174 . _:b594469457 "2"^^ . _:b46911197 . _:b594469630 . _:b594468470 . _:b594469456 "2"^^ . _:b46911198 . _:b594469625 . _:b594468465 . . _:b46911247 "More recent strategies to improve on conventional or stealth liposomal systems involve active targeting, charged lipids, triggered release, and multi-functional formulations (Puri et al., >>2009<<; Allen and Cullis, 2013; Bozzuto and Molinari, 2015)." . . _:b46911199 . _:b594469624 . _:b594469459 "2"^^ . _:b594468464 . _:b594469458 "2"^^ . _:b46911192 . _:b594469627 . _:b594469560 . _:b594468467 . _:b46911238 "Liposome size, morphology, charge, lipid composition, bilayer packaging, surface characteristics, and administered lipid dose all regulate complement activation (Szebeni and Moghimi, >>2009<<). Specific liposomal characteristics that enhance the propensity for complement activation include a positive or negative surface charge, increasing size, lack of liposomal homogeneity, endotoxin contamination, presence of aggregates," . _:b594468509 . _:b594469469 "2"^^ . _:b46911193 . _:b594469626 . _:b594469592 . . _:b594469376 . _:b594468466 . . . _:b594469125 . _:b46911194 . _:b594469468 "2"^^ . _:b594468477 . _:b594469124 . _:b46911195 . _:b594469471 "2"^^ . _:b594468476 . _:b594469127 . _:b46911204 . _:b594469470 "2"^^ . . _:b594468832 . _:b594468479 . . _:b594468673 . _:b46911205 . _:b594469465 "2"^^ . _:b594469126 . _:b594469643 . _:b46911360 "IICationicChang and Yeh, 2012; Awada et al., 2014Paclitaxel EndoTAG-1Pancreatic cancerPhase IICationicL\u00F6hr et al., 2012Mitoxantrone LEM-ETUAcute myeloid leukemia, multiple sclerosis, and prostate cancerPhase ICationicImmordino et al., >>2006<<; Chang and Yeh, 2012VerteporfinMolecular degenerationFDA Approved in 2000CationicChang and Yeh, 2012; Allen and Cullis, 2013; Gross et al., 2013AmikacinLung infectionPhase II/IIIConventionalChang and Yeh, 2012; Clancy et al., 2013;" . _:b46911206 "The width of the tight junctional regions between endothelial cells in vivo has been reported to range from 12 to 20 nm (Antohe et al., >>2004<<), however exposure to inflammatory mediators increases permeability of the microvasculature, with the formation of gaps of up to 1 \u03BCm (Antohe et al., 2004)." . _:b594468478 . . _:b46911206 . _:b594469464 "2"^^ . _:b594469121 . _:b594468473 . _:b594469120 . _:b46911207 . _:b594469596 . _:b594469467 "2"^^ . . _:b594468472 . _:b594469123 . _:b46911200 . _:b594469466 "2"^^ . _:b594468938 . _:b594468676 . _:b594468475 . _:b594469122 . _:b46911201 . _:b594469477 "2"^^ . . _:b594469915 . _:b594468474 . _:b594469133 . _:b46911202 . _:b594469664 . _:b594469476 "2"^^ . _:b594469064 . _:b594468485 . . . _:b46911203 . _:b594469479 "2"^^ . _:b594469132 . . _:b594468484 . . _:b46911173 "Primary organs associated with the RES include the liver, spleen, kidney, lungs, bone marrow, and lymph nodes (Senior, >>1987<<). The liver exhibits the largest capacity for liposomal uptake followed by the spleen, which can accumulate liposomes up to 10-fold higher than other RES organs (Chrai et al., 2002). The ability of the RES to sequester liposomes from the" . _:b594469135 . _:b46911212 . _:b594469478 "2"^^ . _:b46911319 _:b46911392 . . _:b46911319 _:b46911393 . _:b594468487 . _:b594469134 . _:b46911213 . _:b594469473 "2"^^ . _:b594468486 . _:b594468907 . . . _:b46911214 . _:b594469472 "2"^^ . _:b594469129 . _:b46911319 _:b46911384 . _:b46911319 _:b46911385 . _:b594468481 . _:b46911319 _:b46911386 . _:b46911319 _:b46911387 . _:b46911215 . _:b594469475 "2"^^ . _:b594469128 . _:b46911319 _:b46911388 . . _:b46911319 _:b46911389 . _:b594468480 . _:b46911319 _:b46911390 . . . _:b46911319 _:b46911391 . _:b46911208 . _:b594469474 "2"^^ . _:b594469131 . _:b46911319 _:b46911376 . _:b46911319 _:b46911377 . _:b594468483 . _:b46911319 _:b46911378 . _:b46911319 _:b46911379 . _:b46911209 . _:b594469485 "2"^^ . _:b594469130 . _:b46911319 _:b46911380 . _:b594469809 . _:b46911319 _:b46911381 . _:b594468482 . _:b46911319 _:b46911382 . _:b46911319 _:b46911383 . _:b46911210 . _:b594469484 "2"^^ . _:b594469141 . _:b46911319 _:b46911368 . _:b594468368 . _:b594468493 . _:b46911319 _:b46911369 . _:b46911319 _:b46911370 . _:b594468540 . _:b46911319 _:b46911371 . _:b46911211 . _:b594469487 "2"^^ . _:b594469140 . _:b46911319 _:b46911372 . . _:b46911319 _:b46911373 . _:b594468492 . . _:b46911319 _:b46911374 . _:b46911319 _:b46911375 . _:b46911220 . _:b594469486 "2"^^ . _:b594469143 . . _:b46911319 _:b46911360 . . . _:b46911319 _:b46911361 . _:b594468495 . _:b46911319 _:b46911362 . _:b46911196 "with other circulating structures (e.g., red blood cells and lipoproteins) that can cause the depletion of high phase transition temperature lipids and their replacement with less physiologically stable components (Willis and Forssen, >>1998<<; Laverman et al., 1999; Ulrich, 2002). Integrating cholesterol into small (approximately 100 nm), electrostatically neutral liposomes has been shown to prolong circulation time in the range of several hours (Geng et al., 2014)." . _:b46911319 _:b46911363 . _:b46911221 . _:b594469481 "2"^^ . _:b594469142 . . _:b46911319 _:b46911364 . _:b46911319 _:b46911365 . _:b594468494 . _:b594468496 . _:b46911319 _:b46911366 . _:b46911319 _:b46911367 . _:b46911222 . _:b594469480 "2"^^ . _:b594469137 . . _:b594469395 . _:b594468489 . . _:b594469136 . _:b46911223 . _:b594469483 "2"^^ . . _:b594468488 . . _:b594469139 . _:b46911216 . _:b594469482 "2"^^ . _:b594468491 . . _:b46911264 "studies have demonstrated enhanced uptake and efficacy of ligand-targeted liposomes in diseased tissue in comparison to non-targeted liposomes in vivo (Vingerhoeds et al., 1994; Puri et al., 2009; Allen and Cullis, 2013; Kraft et al., >>2014<<). For example, attachment of folate to liposomes showed enhanced biodistribution of liposomes in folate-expressing tumors in a murine model (Gabizon et al., 2003)." . _:b594468616 . _:b46911217 . _:b594469493 "2"^^ . _:b594469138 . . _:b594468490 . . _:b594469149 . _:b46911218 . _:b594469620 . _:b594469492 "2"^^ . _:b594468501 . _:b594469148 . _:b46911219 . _:b594469495 "2"^^ . _:b594469249 . _:b594468500 . . . . . _:b594469151 . _:b46911228 . _:b594469494 "2"^^ . _:b594468503 . _:b594469150 . _:b46911229 . _:b594469489 "2"^^ . _:b594468502 . _:b594468709 . _:b46911230 . _:b594469488 "2"^^ . _:b594469145 . _:b594468873 . . _:b594468497 . . _:b46911231 . _:b594469491 "2"^^ . _:b594469144 . _:b594468496 . . _:b46911224 . _:b594469490 "2"^^ . _:b594469147 . _:b594469124 . _:b594468725 . _:b594468499 . _:b594469146 . _:b46911225 . _:b594469890 . _:b594469501 "2"^^ . . _:b594468969 . _:b594468498 . _:b594469157 . _:b46911226 . _:b594469500 "2"^^ . . . _:b594468509 . _:b594469156 . _:b46911227 . _:b594469503 "2"^^ . _:b594468739 . _:b594468508 . _:b594469159 . _:b594469502 "2"^^ . _:b594468924 . _:b594469723 . _:b594468511 . . _:b594469497 "2"^^ . _:b594469158 . _:b594468510 . _:b594469153 . _:b594469496 "2"^^ . _:b594469328 . _:b594468505 . . _:b594469152 . _:b594469499 "2"^^ . _:b594468504 . _:b594469096 . _:b594469155 . _:b594469498 "2"^^ . _:b594468507 . _:b46911227 "In addition, this response may also be due to doxorubicin-mediated macrophage death and the inhibition of B-cell proliferation and/or the death of proliferated B-cells (Ishida et al., 2006b; Szebeni and Moghimi, 2009)." . . _:b594469154 . _:b594469509 "2"^^ . _:b594468506 . _:b594469165 . _:b594469508 "2"^^ . _:b594468517 . _:b594468921 . _:b594468593 . _:b46911415 "Then we can determine whether therapeutic efficacy in preclinical animal studies translate to success in humans (Allen and Cullis, >>2004<<, 2013; Narang et al., 2013)." . _:b594469511 "2"^^ . _:b594469164 . . _:b594468516 . _:b594469381 . _:b594469033 . _:b594469510 "2"^^ . _:b594469167 . . _:b594468519 . . _:b594469505 "2"^^ . _:b594469166 . . _:b594468518 . _:b594469161 . _:b594469867 . _:b594469504 "2"^^ . . _:b594468513 . _:b594469899 . _:b594469160 . _:b594469507 "2"^^ . _:b594468512 . _:b594469163 . _:b594469506 "2"^^ . _:b594468515 . _:b594469162 . _:b594469517 "2"^^ . _:b594468514 . . _:b594469173 . _:b594469516 "2"^^ . _:b594468140 . . _:b594468525 . _:b594468417 . _:b594469519 "2"^^ . _:b594469172 . _:b594468524 . _:b594469175 . _:b594469518 "2"^^ . . _:b594468527 . _:b594469174 . _:b594469513 "2"^^ . _:b594468526 . _:b594469804 . _:b594469169 . _:b594469512 "2"^^ . _:b46911319 _:b46911352 . . _:b46911319 _:b46911353 . _:b594468521 . _:b46911319 _:b46911354 . _:b594469095 . _:b46911319 _:b46911355 . _:b594469515 "2"^^ . _:b594469168 . _:b46911319 _:b46911356 . _:b46911319 _:b46911357 . _:b594468520 . _:b46911319 _:b46911358 . _:b594469519 . _:b594468800 . _:b46911319 _:b46911359 . _:b594469514 "2"^^ . _:b594469171 . _:b46911319 _:b46911344 . _:b594469366 . _:b46911319 _:b46911345 . _:b594468523 . _:b46911319 _:b46911346 . . _:b46911319 _:b46911347 . _:b46911402 . _:b594469525 "2"^^ . _:b594469170 . _:b46911319 _:b46911348 . _:b46911319 _:b46911349 . _:b46911321 "PLD has also been found to be an effective alternative to conventional doxorubicin in patients with pre-existing cardiac dysfunction (Schmitt et al., >>2012<<). When doxorubicin is incorporated in PEGylated liposomes, it minimizes the uptake and clearance by the RES, which prolongs the serum and plasma half-life. This allows the PLD to accumulate in the tumor tissue, rather than in non-target" . _:b594468522 . _:b46911319 _:b46911350 . _:b46911319 _:b46911351 . _:b594469524 "2"^^ . _:b594469181 . _:b46911319 _:b46911336 . _:b46911319 _:b46911337 . _:b594468533 . _:b46911319 _:b46911338 . _:b46911319 _:b46911339 . _:b46911305 . _:b594469527 "2"^^ . _:b594469180 . _:b46911319 _:b46911340 . _:b46911319 _:b46911341 . _:b594468532 . _:b46911319 _:b46911342 . _:b594469692 . _:b46911319 _:b46911343 . _:b46911304 . _:b594469526 "2"^^ . _:b594469183 . . _:b46911319 _:b46911328 . _:b46911319 _:b46911329 . _:b594468535 . _:b46911319 _:b46911330 . _:b46911319 _:b46911331 . _:b594469521 "2"^^ . _:b594469182 . _:b46911319 _:b46911332 . _:b46911319 _:b46911333 . _:b594468534 . _:b46911319 _:b46911334 . _:b46911319 _:b46911335 . _:b594469520 "2"^^ . _:b594469177 . _:b594468326 . . . _:b46911319 _:b46911320 . . _:b46911319 _:b46911321 . _:b594468370 . _:b594468529 . _:b46911319 _:b46911322 . _:b594469584 . _:b46911319 _:b46911323 . _:b594469523 "2"^^ . _:b594469176 . _:b46911319 _:b46911324 . _:b46911300 "magnetic, and light) and local triggers specific to the target site (e.g., enzymes and pH), through the use of specific lipid compositions and coatings (Guo and Szoka, 2003; Andresen et al., 2004; Ponce et al., 2006; Bibi et al., >>2012<<). Of these strategies, the use of an external hyperthermic trigger to release therapeutic compounds from liposomal formulations (e.g., ThermoDox\u00AE) appears to be the most promising to date (Needham et al., 2000)." . . _:b46911319 _:b46911325 . _:b594468528 . _:b46911319 _:b46911326 . _:b46911319 _:b46911327 . _:b594469522 "2"^^ . _:b594469257 . _:b594469179 . _:b594468531 . . _:b594469178 . _:b594469533 "2"^^ . _:b594469565 . _:b594468530 . . _:b594469532 "2"^^ . _:b594469189 . _:b594468541 . _:b594469092 . _:b594469188 . _:b594469535 "2"^^ . _:b594468540 . _:b594468562 . _:b594469534 "2"^^ . _:b594469191 . . _:b594468543 . . _:b594469024 . _:b594469529 "2"^^ . _:b594469190 . _:b594468542 . . _:b594469528 "2"^^ . _:b594469185 . _:b594468537 . _:b46911187 "Opsonization of liposomes by serum proteins depends on a variety of factors including size, surface charge and stability (Cullis et al., >>1998<<; Ishida et al., 2001a)." . _:b594469184 . _:b594469531 "2"^^ . _:b594468536 . . _:b594469187 . _:b594469530 "2"^^ . _:b594468539 . _:b594468578 . . _:b594469541 "2"^^ . _:b594469462 . _:b594469186 . _:b594468538 . . _:b594469540 "2"^^ . _:b594469197 . _:b594468549 . . _:b594469543 "2"^^ . _:b594469196 . . . _:b594468548 . _:b594469199 . _:b594469542 "2"^^ . _:b594469429 . . _:b594468551 . _:b594468201 . _:b594469537 "2"^^ . _:b594469198 . . _:b594468550 . _:b594469193 . _:b594469536 "2"^^ . _:b594469571 . _:b594468545 . _:b594469192 . _:b46911324 "Finally, PLD avoids the high plasma peak levels of free drug, which has been correlated with cardiotoxicity (Lyass et al., >>2000<<). In addition to receiving FDA approval for usage of PLD in 1995, combination therapies of PLD and other drugs (such as bortezomib for the treatment of relapsed or refractory multiple myeloma) have recently received FDA approval (Ning et" . _:b594469539 "2"^^ . _:b594469065 . _:b594468544 . . _:b594468889 . _:b594469195 . _:b594469538 "2"^^ . _:b594468547 . _:b594469194 . _:b594469549 "2"^^ . _:b594468546 . . . _:b594469205 . _:b594469548 "2"^^ . _:b594469195 . _:b594469528 . _:b594468557 . _:b594468665 . _:b594469529 . _:b594469475 . _:b594469530 . _:b594469551 "2"^^ . _:b594469204 . _:b594469531 . _:b594469532 . . _:b594468556 . _:b594469533 . _:b594469534 . _:b594469550 "2"^^ . _:b594469207 . _:b594469535 . _:b594469520 . _:b594469702 . _:b594469668 . _:b594468559 . _:b594469521 . _:b594469522 . _:b594469545 "2"^^ . _:b594469206 . _:b594469523 . _:b594469524 . _:b594468558 . _:b594469525 . _:b594469526 . _:b594469544 "2"^^ . _:b594469201 . _:b594469527 . _:b594469512 . _:b46911200 "Liposomes that have evaded both the RES and opsonization are subjected to the EPR effect (Sawant and Torchilin, >>2012<<; Nehoff et al., 2014). The EPR effect refers to the increased permeability of the vasculature that supplies pathological tissues (e.g., tumors and conditions involving inflammation)." . _:b594468553 . _:b594469513 . _:b46911258 "The notion that ligand-targeted liposomes have a therapeutic advantage over non-targeted liposomes is still subject to debate, with conflicting results in the literature (Ferrari, >>2005<<; Puri et al., 2009; Riehemann et al., 2009)." . _:b594469630 . _:b594469514 . _:b594469547 "2"^^ . _:b594469200 . _:b594468843 . _:b594469515 . _:b594469516 . _:b594468552 . _:b594469517 . _:b594469518 . _:b594469546 "2"^^ . _:b594469203 . _:b594469519 . _:b594469504 . _:b594468555 . _:b594469505 . _:b594468206 . _:b594469557 "2"^^ . _:b594469202 . _:b594469506 . _:b594469507 . _:b594468380 . _:b594468554 . _:b594469508 . _:b594469509 . _:b594469405 . _:b594469510 . _:b594469556 "2"^^ . _:b594469213 . _:b594469511 . _:b46911398 "Similar obstacles are faced by other nano-delivery systems for translation into the clinic (Allen and Cullis, 2004, 2013; Zhang et al., 2008; Sawant and Torchilin, >>2012<<; Narang et al., 2013)." . _:b594469560 . . _:b594468565 . . _:b594469561 . _:b594469562 . _:b594469559 "2"^^ . _:b594469212 . _:b594469563 . _:b594469564 . _:b594468564 . _:b594469565 . _:b594469817 . . _:b594469558 "2"^^ . _:b594469215 . _:b594469566 . . _:b594469567 . _:b594469552 . _:b594468567 . _:b594469553 . _:b594469554 . _:b594469553 "2"^^ . _:b594469214 . _:b594469555 . _:b594469556 . _:b594468566 . _:b594469557 . . _:b594469552 "2"^^ . _:b594469209 . _:b594469558 . _:b594469559 . _:b594469544 . _:b594468561 . . _:b594469545 . . _:b594469546 . _:b594469555 "2"^^ . _:b594469208 . _:b594469547 . _:b594469548 . _:b594468560 . . _:b594468821 . _:b594469549 . _:b594469550 . _:b594469554 "2"^^ . _:b594469211 . _:b594469551 . _:b594469536 . _:b594468563 . . _:b594469537 . _:b594469538 . _:b594469565 "2"^^ . _:b594469210 . _:b594469539 . _:b594469540 . _:b594468562 . . _:b594469541 . _:b594469542 . _:b594469564 "2"^^ . _:b594469221 . _:b594469543 . _:b594469592 . _:b594469145 . _:b594468573 . _:b594469593 . _:b594469594 . _:b594469808 . _:b594469567 "2"^^ . _:b594469220 . . _:b594469591 . _:b594469595 . _:b594469596 . _:b594468572 . . _:b594469550 . _:b594469597 . _:b594468337 . _:b594468198 . _:b594469598 . _:b594469566 "2"^^ . _:b594469223 . _:b594469599 . _:b594469229 . . _:b594468575 . _:b594469584 . _:b594469585 . _:b594469586 . _:b594469561 "2"^^ . _:b594469222 . _:b594469587 . _:b594469588 . _:b594468574 . _:b594469589 . _:b594469590 . _:b594469700 . _:b594469560 "2"^^ . _:b594469217 . _:b46911243 _:b46911304 . _:b594469591 . _:b46911243 _:b46911305 . _:b594468569 . _:b594469576 . _:b46911243 _:b46911306 . _:b594469577 . _:b46911243 _:b46911307 . _:b594469563 "2"^^ . _:b594469216 . _:b594469578 . _:b46911243 _:b46911308 . _:b594469579 . . _:b46911243 _:b46911309 . _:b594468568 . _:b594469580 . _:b46911243 _:b46911310 . _:b594469581 . _:b46911243 _:b46911311 . _:b594469562 "2"^^ . _:b594469219 . _:b594469582 . _:b46911243 _:b46911296 . _:b594469583 . _:b46911243 _:b46911297 . _:b594468571 . _:b594469568 . _:b46911243 _:b46911298 . _:b594469569 . _:b46911243 _:b46911299 . _:b594469573 "2"^^ . _:b594469218 . _:b594469570 . _:b46911243 _:b46911300 . _:b594469358 . _:b594469571 . _:b46911243 _:b46911301 . _:b594469383 . _:b594468570 . _:b594469572 . . _:b594469573 . . _:b46911243 _:b46911302 . _:b46911243 _:b46911303 . _:b594469572 "2"^^ . _:b594469229 . _:b594469574 . _:b594469575 . _:b594469639 . _:b594469624 . _:b46911332 . _:b594468581 . _:b594469625 . . _:b46911270 "via antigen binding, but rather the result of the marked difference in pharmacodynamics of the targeted liposomal formulation in vivo, by mediating intracellular drug delivery to HER2-overexpressing cancer cells (Kirpotin et al., >>2006<<). Therefore, it is likely that attachment of targeting moieties enhances therapeutic efficacy by increasing receptor-mediated uptake of drug-encapsulated liposomes into target cells, subsequent to the accumulation of the nanocarriers in" . _:b594469575 "2"^^ . _:b594469228 . _:b594469626 . _:b594469627 . _:b594468762 . _:b594469628 . _:b594468580 . _:b594469629 . _:b594469630 . _:b594469574 "2"^^ . _:b594469231 . _:b46911243 _:b46911312 . _:b594469631 . _:b46911243 _:b46911313 . _:b594468583 . _:b594469616 . _:b46911243 _:b46911314 . _:b594469617 . . _:b46911243 _:b46911315 . _:b594469569 "2"^^ . _:b594469230 . _:b594469618 . _:b46911243 _:b46911316 . _:b594469619 . _:b46911243 _:b46911317 . _:b594468582 . _:b594469620 . _:b46911243 _:b46911318 . _:b594469621 . . _:b594469622 . _:b594469568 "2"^^ . _:b594469225 . _:b594469623 . _:b594468974 . _:b594469608 . _:b594469018 . _:b594468577 . _:b594469609 . _:b594469610 . _:b594469571 "2"^^ . _:b594469224 . _:b594469611 . _:b594469612 . _:b594468576 . _:b594469613 . _:b594469614 . _:b594469570 "2"^^ . _:b594469261 . _:b594469227 . _:b594469615 . _:b594469600 . _:b594469947 . _:b594469476 . _:b594468579 . _:b594469601 . _:b594469602 . _:b594469581 "2"^^ . _:b594469226 . _:b594469603 . . _:b594469604 . _:b46911368 "Allen and Cullis, 2013; Gross et al., 2013AmikacinLung infectionPhase II/IIIConventionalChang and Yeh, 2012; Clancy et al., 2013; Olivier et al., 2014VincristineNon-Hodgkin lymphomaFDA Approved in 2012ConventionalAllen and Cullis, >>2013<<; Wang et al., 2015TretinoinAcute promyelocytic leukemia and hormone-refractory prostate cancerPhase IIConventionalOzpolat et al., 2003; Immordino et al., 2006Irinotecan SN-38Metastatic colorectal cancerPhase I/IIConventionalZhang et al.," . _:b594468578 . _:b594469605 . . _:b594469580 "2"^^ . _:b594469237 . . _:b594469606 . _:b594469607 . . _:b594468589 . _:b594469400 . . _:b594469401 . _:b594469402 . _:b46911208 "Pore sizes ranging from 0.2 to 1.2 \u03BCm have been observed, though the size and number of pores are dependent upon the microenvironment of the pathological site (Klimuk et al., >>1999<<; Antohe et al., 2004; Hua, 2013)." . _:b594469583 "2"^^ . _:b594469236 . _:b594469403 . _:b594469404 . _:b594468588 . . _:b594469405 . _:b594469406 . _:b594469582 "2"^^ . _:b594469239 . _:b594469407 . _:b594469540 . _:b594469392 . _:b594468591 . _:b594469393 . _:b594469394 . _:b594469577 "2"^^ . _:b594469238 . _:b594469395 . . _:b594468590 . _:b594469396 . _:b594468670 . _:b594469397 . _:b594469398 . _:b594469576 "2"^^ . _:b594469233 . . _:b594469399 . _:b594469384 . _:b594468585 . _:b594469385 . _:b594469386 . _:b594469579 "2"^^ . _:b594469232 . _:b46911243 _:b46911244 . _:b594469387 . _:b46911243 _:b46911245 . _:b46911162 . _:b594468584 . _:b594469388 . _:b46911243 _:b46911246 . _:b594469389 . _:b46911243 _:b46911247 . _:b594469578 "2"^^ . _:b594469235 . _:b594469390 . . _:b594469391 . _:b594469376 . _:b594468587 . _:b594469377 . _:b594469378 . _:b594469736 . _:b594469589 "2"^^ . _:b594469234 . . _:b594469379 . _:b594469380 . _:b594468586 . _:b594469381 . . _:b594469382 . _:b594469588 "2"^^ . _:b594469245 . _:b46911243 _:b46911256 . _:b594469383 . _:b46911243 _:b46911257 . _:b594468597 . _:b594469432 . _:b46911243 _:b46911258 . _:b594469433 . _:b46911243 _:b46911259 . _:b594469591 "2"^^ . _:b594469244 . _:b594469434 . . _:b594469435 . _:b46911243 _:b46911260 . _:b46911243 _:b46911261 . . _:b594468596 . _:b594469436 . _:b46911243 _:b46911262 . _:b594469437 . _:b46911243 _:b46911263 . _:b594469590 "2"^^ . _:b594469247 . _:b594469438 . . _:b46911243 _:b46911248 . _:b594469439 . _:b46911243 _:b46911249 . _:b594468599 . _:b594469424 . _:b46911243 _:b46911250 . _:b594469527 . _:b594469425 . . _:b594469585 "2"^^ . _:b594469246 . _:b594469426 . _:b46911243 _:b46911251 . _:b46911243 _:b46911252 . _:b594469427 . _:b46911243 _:b46911253 . _:b594468598 . _:b594469428 . _:b46911243 _:b46911254 . . _:b594469429 . _:b46911243 _:b46911255 . _:b594469584 "2"^^ . _:b594469276 . _:b594469241 . _:b594469430 . _:b46911243 _:b46911272 . _:b46911171 . _:b594469431 . _:b46911243 _:b46911273 . _:b594468593 . _:b594469416 . _:b46911243 _:b46911274 . _:b594469417 . _:b46911243 _:b46911275 . _:b594469587 "2"^^ . _:b594469240 . . _:b594468661 . _:b594469418 . _:b46911243 _:b46911276 . _:b594469419 . _:b46911243 _:b46911277 . _:b594468592 . _:b594469420 . . _:b46911243 _:b46911278 . _:b594469421 . _:b46911243 _:b46911279 . _:b594469586 "2"^^ . _:b594469243 . . _:b594469422 . . _:b46911243 _:b46911264 . _:b594469423 . _:b46911243 _:b46911265 . _:b594468595 . _:b594469408 . _:b46911243 _:b46911266 . _:b594469409 . _:b46911243 _:b46911267 . _:b594469597 "2"^^ . _:b594469242 . _:b594469013 . _:b594469410 . _:b46911243 _:b46911268 . _:b594468980 . _:b594469411 . _:b46911243 _:b46911269 . _:b594468594 . _:b594469412 . _:b46911243 _:b46911270 . _:b594469413 . _:b46911243 _:b46911271 . _:b594469596 "2"^^ . _:b594469253 . _:b594469414 . _:b46911243 _:b46911288 . _:b594469415 . _:b46911243 _:b46911289 . _:b594468605 . _:b594469464 . _:b46911243 _:b46911290 . _:b46911351 . _:b594469465 . _:b46911243 _:b46911291 . _:b594469599 "2"^^ . _:b594469252 . _:b594468719 . _:b594469466 . _:b46911243 _:b46911292 . _:b594469467 . _:b46911243 _:b46911293 . _:b594469091 . _:b594468604 . _:b594469468 . _:b46911243 _:b46911294 . _:b594469469 . _:b46911243 _:b46911295 . _:b594469598 "2"^^ . _:b594469255 . _:b594469470 . . _:b46911243 _:b46911280 . _:b594469471 . _:b46911243 _:b46911281 . _:b594468607 . _:b594469456 . _:b46911243 _:b46911282 . _:b594469457 . _:b46911243 _:b46911283 . _:b594469593 "2"^^ . _:b594469254 . _:b594469458 . _:b46911243 _:b46911284 . _:b594469459 . _:b46911243 _:b46911285 . _:b594468606 . _:b594469460 . _:b46911243 _:b46911286 . _:b46911237 "be noted that the sensitivity of different species to liposomal CARPA shows substantial variation, with some species (dogs and pigs) also showing tachyphylaxis (tolerance induction) following additional doses (Szebeni et al., 1999, >>2007<<). Therefore, desensitization protocols using empty liposomes may be used to prevent CARPA, as well as pre-administration of complement inhibitors (e.g., soluble C receptor type 1, anti-C5 antibody, and indomethacin) (Szebeni and" . _:b594469461 . _:b46911243 _:b46911287 . _:b594469592 "2"^^ . _:b594469249 . _:b594469462 . _:b594469463 . _:b594469448 . _:b46911342 "It is embedded in a cationic liposome and is in Phase II trials to treat advanced triple-negative breast cancer (Awada et al., >>2014<<) and pancreatic cancer (L\u00F6hr et al., 2012)." . _:b594468601 . _:b594469449 . . . _:b594469595 "2"^^ . _:b594469248 . . _:b594469450 . _:b594469451 . _:b594469452 . _:b46911315 . _:b594468600 . _:b594469453 . _:b594469454 . _:b594469594 "2"^^ . _:b594469251 . _:b594469455 . . _:b46911314 . _:b594468603 . _:b594469440 . _:b594469441 . _:b594468866 . _:b594469442 . _:b594469605 "2"^^ . _:b594469250 . . _:b594469443 . _:b594469444 . _:b594468602 . _:b594469445 . . _:b594469446 . _:b594469604 "2"^^ . _:b594469261 . _:b594469447 . _:b46911399 "Similar obstacles are faced by other nano-delivery systems for translation into the clinic (Allen and Cullis, 2004, 2013; Zhang et al., 2008; Sawant and Torchilin, 2012; Narang et al., >>2013<<). Limitations in pharmaceutical development are centered on quality assurance and cost. Quality assurance involves issues surrounding the manufacturing process and stability of the formulation, with nano-delivery systems being affected by" . _:b594469496 . _:b594468101 . . _:b594469497 . _:b594469498 . _:b594469607 "2"^^ . _:b594469260 . _:b594469499 . _:b594468825 . . _:b594469500 . _:b594468100 . _:b594469501 . _:b46911356 . _:b594469502 . _:b594469606 "2"^^ . _:b594469263 . _:b594469503 . _:b594469488 . _:b594468103 . _:b594468251 . _:b594469489 . _:b594469490 . _:b594469601 "2"^^ . _:b594469262 . _:b594469491 . _:b594469492 . _:b594468102 . _:b594469493 . _:b594469494 . _:b594469600 "2"^^ . _:b594469257 . _:b594469495 . _:b594469480 . _:b594468097 . _:b594469481 . _:b594469219 . _:b594469482 . _:b594469603 "2"^^ . _:b594469256 . . _:b594469483 . _:b594469484 . _:b594468096 . _:b594469485 . _:b594469486 . _:b594469602 "2"^^ . _:b594469259 . _:b594469487 . _:b594469472 . _:b594468099 . _:b594468555 . _:b594469473 . _:b594468435 . _:b594469474 . _:b594469613 "2"^^ . _:b594469258 . _:b594469475 . _:b594469476 . _:b594468098 . _:b594469477 . . _:b594469612 "2"^^ . _:b594469269 . _:b594469102 . _:b594469478 . _:b594469479 . _:b594469784 . _:b594468936 . _:b594468109 . _:b594469785 . _:b594469786 . _:b594469615 "2"^^ . _:b594469268 . _:b594469787 . _:b594469788 . _:b594469090 . _:b594468108 . . _:b594469789 . . . _:b594469790 . _:b594469614 "2"^^ . _:b594469271 . _:b594468413 . _:b594469791 . _:b594468112 . _:b594468111 . _:b594469776 . . _:b594469777 . _:b594468524 . _:b594469609 "2"^^ . _:b594469270 . _:b594469778 . _:b594469779 . _:b594469861 . _:b594469780 . _:b594468110 . _:b594469781 . _:b594469782 . _:b594469608 "2"^^ . _:b594469265 . _:b594469783 . _:b594469768 . _:b594468148 . _:b594468105 . . . _:b594469769 . _:b594468332 . _:b594469611 "2"^^ . _:b594469264 . _:b594469770 . . _:b594468772 . _:b594469771 . _:b594469772 . _:b594468104 . _:b594469773 . _:b594469774 . _:b594469610 "2"^^ . _:b594469267 . _:b594469775 . _:b594469760 . _:b594468107 . _:b594469761 . _:b594469762 . _:b594469621 "2"^^ . _:b594469266 . . _:b594469869 . _:b594469763 . _:b594469764 . _:b594469248 . _:b594468106 . . _:b594469765 . _:b594469766 . _:b594469620 "2"^^ . _:b594469277 . _:b594469767 . _:b594468944 . _:b594469816 . _:b594468117 . _:b594469817 . _:b594469818 . _:b594469623 "2"^^ . _:b594469276 . . _:b594469819 . . _:b594469820 . _:b594468116 . _:b594469821 . _:b594469822 . _:b594469622 "2"^^ . _:b594469279 . _:b594468989 . _:b594469823 . . _:b594469808 . _:b594468119 . _:b594469809 . _:b594469443 . _:b594469032 . _:b594469810 . _:b594469617 "2"^^ . _:b594469278 . . _:b594469811 . _:b46911287 . _:b594469812 . _:b594468118 . _:b594469813 . _:b594469814 . _:b594469616 "2"^^ . _:b594469273 . _:b594468706 . . _:b594469815 . _:b594469800 . _:b594468113 . _:b594469801 . _:b594469341 . _:b594469802 . _:b594469619 "2"^^ . _:b594469272 . _:b594468333 . _:b594469803 . _:b594469804 . _:b594468112 . _:b594469805 . _:b594469806 . _:b46911290 "based on electrostatic interaction between the positively charged phospholipids [e.g., dioleoylphosphatidylethanolamine (DOPE)] and negatively charged nucleic acids (Felgner et al., 1987; Campbell et al., 2002, 2009; Kunstfeld et al., >>2003<<; Wu et al., 2007). Such liposomes have also been demonstrated to have greater interaction with tumor vessels due to the overexpression of negatively charged functional groups on the angiogenic endothelial cell membrane (Ran et al., 2002)." . _:b594469618 "2"^^ . _:b594469275 . _:b594469807 . _:b594469792 . _:b594469848 . _:b594468115 . _:b594469793 . . _:b594469629 "2"^^ . _:b594469274 . _:b594469794 . . _:b594468940 . _:b594469795 . . _:b594469796 . _:b594468114 . _:b594469797 . _:b46911380 "Cullis, 2013Cytarabine or cytosine arabinosideNeoplastic meningitis and lymphomatous meningitisFDA ApprovedConventionalChang and Yeh, 2012; Jahn et al., 2015Morphine sulfatePain ManagementFDA Approved in 2004ConventionalChang and Yeh, >>2012<<; Allen and Cullis, 2013LurtotecanOvarian cancer, head, and neck cancerPhase I/IIConventionalDark et al., 2005; Chang and Yeh, 2012VinorelbineNewly diagnosed or relapsed solid tumorsPhase IConventionalAllen and Cullis," . _:b594469798 . _:b594469789 . _:b594469628 "2"^^ . _:b594469285 . _:b594469799 . . _:b594468125 . _:b594469848 . _:b594469849 . _:b594469850 . _:b594469631 "2"^^ . _:b594469284 . _:b594468518 . . _:b594468855 . _:b594469851 . . _:b594469852 . _:b594468124 . _:b594468258 . _:b594469853 . _:b594469854 . _:b594469630 "2"^^ . _:b594469287 . _:b594469855 . _:b594469840 . _:b594468127 . . _:b594469841 . _:b594469842 . _:b594469625 "2"^^ . _:b594469286 . _:b594469843 . _:b594469844 . _:b594468126 . _:b594469845 . _:b594468547 . _:b594469846 . _:b594469624 "2"^^ . _:b594469281 . _:b594469847 . _:b594469832 . _:b594468121 . . _:b594469833 . _:b594469834 . _:b594469627 "2"^^ . _:b594469280 . _:b594469835 . _:b594469836 . _:b594468120 . . _:b594469837 . _:b594469838 . _:b594469626 "2"^^ . _:b594469283 . _:b594469839 . _:b594469824 . _:b594468123 . _:b594469825 . _:b594469192 . _:b594468755 . _:b594469826 . _:b594469637 "2"^^ . _:b594469282 . _:b594468531 . _:b594469827 . _:b594469828 . _:b594468122 . _:b594469829 . _:b594468970 . _:b594469830 . _:b594469897 . _:b594469636 "2"^^ . _:b594469293 . _:b594469831 . _:b594469880 . _:b594468133 . . . _:b594469881 . _:b594469882 . _:b594469639 "2"^^ . _:b594469292 . _:b594469883 . _:b594469884 . _:b594468132 . . _:b594469885 . . _:b594469638 "2"^^ . _:b594469295 . _:b594469886 . _:b594469887 . _:b594469872 . _:b594468135 . _:b594468541 . _:b594468737 . _:b594468603 . _:b594469873 . . _:b594469633 "2"^^ . _:b594469294 . _:b594469874 . _:b594469875 . _:b594469876 . _:b594469416 . _:b594468134 . _:b594469877 . _:b594469026 . _:b594469878 . _:b594469632 "2"^^ . _:b594469289 . _:b594469879 . _:b594469864 . _:b594468594 . _:b594468129 . _:b594469865 . _:b594469866 . _:b594469635 "2"^^ . _:b594469288 . _:b594469867 . _:b594469868 . _:b594468128 . _:b594469869 . _:b46911140 "Encapsulation within liposomes protects compounds from early inactivation, degradation and dilution in the circulation (Ulrich, >>2002<<). Liposomes are generally considered to be pharmacologically inactive with minimal toxicity, as they tend to be composed of natural phospholipids (Koning and Storm, 2003; Metselaar and Storm, 2005; Ding et al., 2006; Hua and Wu, 2013);" . _:b594468448 . _:b594469634 "2"^^ . _:b594469291 . _:b594469870 . _:b594469871 . _:b594469856 . _:b594468131 . . _:b594469338 . _:b594469857 . _:b594468454 . _:b594469799 . _:b594469645 "2"^^ . _:b594469290 . _:b594469079 . _:b594469858 . _:b594469859 . . _:b594469860 . _:b594468130 . _:b594469861 . _:b594469769 . . _:b594469644 "2"^^ . _:b594469301 . _:b594469862 . _:b594469863 . _:b594469656 . _:b594468994 . _:b594468141 . _:b594469657 . _:b594469658 . _:b594469647 "2"^^ . _:b594469300 . _:b594469141 . _:b594469659 . _:b46911280 "systems can influence the electrostatic interaction of the nanocarriers with components in the gastrointestinal (GI) tract following oral administration, and theoretically should confer selectivity to diseased tissue (Hua et al., >>2015<<). Cationic nano-delivery systems have been shown to adhere to the mucosal surface within inflamed GI tissue, due to the interaction between the positively charged nanocarrier and the negatively charged intestinal mucosa (Coco et al.," . _:b594469660 . _:b594468140 . _:b594469661 . _:b594469662 . _:b594469646 "2"^^ . _:b594469303 . _:b594469663 . _:b594469648 . _:b594468860 . _:b594468143 . _:b594469649 . _:b594469650 . _:b594469641 "2"^^ . _:b594469302 . _:b594469651 . _:b594469652 . _:b594468142 . _:b594469653 . _:b46911144 "(Koning and Storm, 2003; Metselaar and Storm, 2005; Ding et al., 2006; Hua and Wu, 2013); however increasing number of studies have shown that liposomes are not as immunologically inert as once suggested (Szebeni and Moghimi, >>2009<<). Despite the success of liposomal formulations in vivo, their translation into the clinic has progressed incrementally." . _:b594469654 . _:b594469640 "2"^^ . _:b594469297 . _:b594469069 . _:b594469655 . . _:b594468137 . _:b594469640 . _:b594468446 . _:b594469641 . _:b594469642 . _:b594469643 "2"^^ . _:b594469296 . _:b594469643 . _:b594469773 . _:b594468091 . _:b594468136 . . _:b594469644 . _:b594469645 . _:b594469646 . _:b594469642 "2"^^ . _:b594469299 . _:b594468406 . _:b594469647 . _:b594469632 . _:b594468139 . _:b594469633 . _:b594469634 . _:b594469653 "2"^^ . _:b594469298 . . _:b594469635 . _:b594469636 . _:b594468138 . _:b594469637 . _:b46911226 "Generally higher doses (15 \u03BCmol phospholipid/kg) are administered clinically, which may account for this absence of the ABC phenomenon (Lyass et al., >>2000<<). In addition, this response may also be due to doxorubicin-mediated macrophage death and the inhibition of B-cell proliferation and/or the death of proliferated B-cells (Ishida et al., 2006b; Szebeni and Moghimi, 2009)." . _:b594469638 . _:b594469652 "2"^^ . _:b594469309 . . _:b594469639 . _:b594469688 . _:b594468149 . _:b594469689 . _:b594469690 . _:b594469655 "2"^^ . _:b594469308 . _:b594469691 . _:b594469692 . _:b594468148 . . _:b594469693 . _:b594469694 . _:b594469654 "2"^^ . _:b594469311 . _:b594469695 . _:b594469680 . _:b594468151 . _:b594468213 . . _:b594469681 . _:b594469682 . _:b594469649 "2"^^ . _:b594469310 . . _:b594469683 . . _:b594469684 . _:b594468150 . _:b594469685 . _:b594469686 . _:b594469648 "2"^^ . _:b594469305 . _:b594469687 . _:b594468652 . _:b594469672 . _:b594468145 . _:b594469673 . . _:b594469651 "2"^^ . _:b594469627 . _:b594469304 . _:b594469674 . _:b594469675 . _:b594469676 . _:b594468144 . _:b594469677 . _:b594469678 . _:b594469650 "2"^^ . _:b594469307 . _:b594469679 . _:b594469664 . _:b594468147 . _:b594469665 . _:b46911225 . _:b594468991 . _:b594469666 . _:b594469661 "2"^^ . _:b594469306 . _:b594469667 . _:b594469668 . _:b594468146 . _:b594469669 . _:b594469670 . _:b594469660 "2"^^ . _:b594469317 . _:b594469671 . . _:b594468157 . _:b594469720 . _:b594469721 . _:b594469722 . _:b594469663 "2"^^ . _:b594469316 . . _:b594469723 . _:b594469724 . _:b594468156 . . _:b594469725 . _:b594469726 . _:b594469662 "2"^^ . _:b594469437 . _:b594469319 . . _:b594469727 . _:b594469712 . _:b46911205 . _:b594468159 . . _:b594469713 . _:b594469714 . _:b594469657 "2"^^ . _:b594469318 . _:b594469715 . _:b594468771 . _:b594469716 . _:b594468158 . _:b594469717 . _:b594469718 . _:b594469656 "2"^^ . _:b594469313 . _:b594469719 . _:b594469856 . _:b594469704 . _:b594468153 . _:b594469705 . _:b594469706 . _:b594469659 "2"^^ . _:b594469312 . _:b594469707 . _:b594469708 . _:b46911210 . _:b594468152 . . _:b594469709 . . _:b594469658 "2"^^ . _:b594469315 . _:b594469710 . . _:b594469711 . _:b594469696 . _:b594468155 . . _:b594469697 . . _:b594469698 . _:b594469669 "2"^^ . _:b594469314 . _:b594469699 . _:b594469700 . _:b594468154 . _:b594469701 . _:b594469702 . _:b594469668 "2"^^ . _:b594469325 . _:b594469703 . _:b594469752 . _:b594468165 . _:b594469753 . _:b46911183 . _:b594469754 . _:b594469671 "2"^^ . _:b594469633 . _:b594469324 . _:b594469755 . _:b594469756 . _:b594468164 . . _:b594469757 . _:b594469758 . _:b594469670 "2"^^ . _:b594469327 . _:b594468930 . _:b594469759 . _:b46911158 . _:b594469744 . _:b594468167 . _:b594469745 . _:b46911271 "of targeting moieties enhances therapeutic efficacy by increasing receptor-mediated uptake of drug-encapsulated liposomes into target cells, subsequent to the accumulation of the nanocarriers in the diseased tissues (Kirpotin et al., >>2006<<; Puri et al., 2009)." . _:b594469746 . _:b594469836 . _:b594469665 "2"^^ . _:b594469326 . . _:b594469747 . _:b594468412 . _:b594468166 . _:b594469748 . . _:b594469749 . _:b594469750 . _:b594469664 "2"^^ . _:b594469321 . . _:b594469751 . . _:b594468161 . _:b594469736 . _:b594469737 . . _:b594469738 . _:b594469667 "2"^^ . _:b594469320 . _:b594469739 . _:b594469740 . _:b594468160 . _:b594469741 . _:b594469163 . _:b594469742 . _:b594469666 "2"^^ . _:b594469384 . _:b594469323 . . _:b594469743 . _:b594469728 . _:b594468163 . _:b594468305 . _:b594469729 . _:b594469730 . _:b594469677 "2"^^ . _:b594469322 . _:b594469731 . _:b594469732 . _:b594468162 . _:b594469733 . _:b594469734 . _:b594469676 "2"^^ . _:b594469333 . _:b594469173 . . _:b594469735 . _:b594468610 . _:b594469016 . _:b594468579 . _:b594468173 . _:b594468419 . _:b594469017 . _:b594469018 . _:b594469679 "2"^^ . _:b594469332 . _:b594469019 . _:b594469020 . _:b594468172 . _:b594469021 . _:b594468766 . _:b594469022 . _:b594469683 . _:b594469678 "2"^^ . _:b594469335 . _:b594469023 . _:b594469008 . _:b46911179 "In addition, administration of Doxil\u00AE in mice was reported to interfere with the clearance of bacteria from the blood, which was suggested to be due to macrophage suppression (Storm et al., >>1998<<; Szebeni and Barenholz, 2009)." . _:b594468175 . _:b594469009 . _:b594469078 . _:b594469010 . _:b594469864 . _:b594469673 "2"^^ . _:b594469334 . _:b594469011 . _:b594469012 . _:b594468174 . . _:b594469013 . . _:b594469672 "2"^^ . _:b594469329 . _:b594469014 . _:b594469015 . _:b594469801 . _:b594468191 . _:b594469000 . _:b594468169 . _:b594469001 . _:b594469002 . _:b594469675 "2"^^ . _:b594469328 . _:b594468165 . _:b594469003 . _:b594469004 . _:b594468913 . _:b594468168 . _:b594469005 . _:b594469006 . _:b594469674 "2"^^ . _:b594469574 . _:b594469331 . . _:b594469007 . _:b594468992 . _:b594468171 . _:b594468993 . _:b594469835 . _:b594468994 . _:b594469685 "2"^^ . _:b594469330 . _:b594468995 . _:b594468997 . _:b594468996 . _:b594468170 . _:b594468997 . _:b594468998 . _:b594469684 "2"^^ . _:b594469341 . . _:b594468999 . _:b594469048 . _:b594468181 . _:b594469049 . _:b594469056 . _:b594469050 . _:b594469687 "2"^^ . _:b594469340 . _:b594469051 . . _:b594469323 . _:b594468180 . _:b594469052 . . _:b594469053 . _:b594469054 . _:b594469686 "2"^^ . _:b594469343 . _:b594469055 . _:b46911141 "Liposomes are generally considered to be pharmacologically inactive with minimal toxicity, as they tend to be composed of natural phospholipids (Koning and Storm, >>2003<<; Metselaar and Storm, 2005; Ding et al., 2006; Hua and Wu, 2013); however increasing number of studies have shown that liposomes are not as immunologically inert as once suggested (Szebeni and Moghimi, 2009)." . _:b594469040 . _:b594468183 . _:b594469041 . _:b594469778 . _:b594469042 . _:b594469681 "2"^^ . _:b594469342 . _:b594469043 . _:b594469044 . _:b594468182 . _:b46911243 "experimental use of liposomes for biomedical applications" . _:b594469045 . . _:b594469046 . _:b594469680 "2"^^ . _:b594469337 . _:b594469047 . _:b594469032 . _:b594468177 . _:b594469033 . _:b594469034 . _:b594469683 "2"^^ . _:b594469336 . _:b594469035 . _:b594469036 . _:b594468176 . . _:b594468862 . _:b594469037 . _:b594469038 . _:b594469682 "2"^^ . _:b594469339 . _:b594469039 . . _:b594469024 . . _:b594468179 . _:b594469025 . _:b594469026 . _:b594469693 "2"^^ . _:b594469338 . _:b594469027 . _:b594469028 . _:b594468178 . _:b594469029 . _:b594469030 . _:b594469692 "2"^^ . _:b594469349 . _:b594469031 . . _:b594468189 . _:b594469080 . _:b594469081 . _:b594469082 . _:b594469695 "2"^^ . _:b594469348 . _:b594469083 . _:b594469084 . _:b594468188 . _:b594469085 . _:b46911325 . _:b594469314 . . _:b594469694 "2"^^ . _:b594469351 . _:b594469086 . _:b594469087 . _:b594469072 . _:b594468191 . _:b594469073 . _:b594469074 . _:b594469689 "2"^^ . _:b594469350 . _:b594469075 . _:b594469076 . _:b594468190 . _:b594469077 . _:b594469078 . _:b594469688 "2"^^ . _:b594469345 . _:b594469079 . _:b594469064 . _:b594468185 . . _:b46911320 . _:b594469065 . _:b594469066 . _:b594469691 "2"^^ . _:b594469344 . _:b594468320 . _:b594469255 . _:b594469067 . _:b594469068 . _:b46911382 . _:b594468184 . _:b594469069 . _:b594469070 . _:b594469690 "2"^^ . _:b594469347 . _:b594469071 . _:b594469056 . _:b46911392 "IIIPEGylatedYarmolenko et al., 2010Thermosensitive doxorubicinChest wall recurrences of breast cancerPhase IPEGylatedYarmolenko et al., 2010IrinotecanAdvanced refractory solid tumors and colorectal cancerPhase IPEGylatedChang et al., >>2015< . _:b594469057 . _:b594469058 . _:b594469701 "2"^^ . _:b594469346 . _:b594469059 . _:b594469060 . _:b594468186 . _:b594469061 . _:b46911336 "drugs include a reduced toxicity by increased vasculature permeability/accumulation at the target tissue and an ability to encapsulate drugs of different lipophilicities while protecting them from biodegradation (Immordino et al., >>2006<<; Chang and Yeh, 2012; Allen and Cullis, 2013)." . _:b594469062 . _:b594469700 "2"^^ . _:b594469357 . _:b594469339 . _:b594469063 . _:b594469112 . _:b594468197 . _:b594469113 . _:b594469114 . _:b594469703 "2"^^ . _:b594469356 . _:b594469115 . _:b594469116 . _:b594468196 . _:b594469117 . _:b594468822 . _:b594469118 . _:b594469702 "2"^^ . _:b594469359 . _:b594469119 . _:b594469104 . _:b594468199 . _:b594469105 . . _:b594469697 "2"^^ . _:b594469358 . _:b594469106 . _:b594469107 . . _:b594468198 . _:b594469108 . _:b594469109 . _:b594469110 . _:b594469696 "2"^^ . _:b594469353 . _:b594469111 . _:b594469178 . _:b594469096 . _:b594468193 . _:b594469097 . _:b594469098 . _:b594469699 "2"^^ . _:b594469352 . _:b594469099 . _:b594468752 . . _:b594469100 . _:b46911216 "As a result, the circulation time of the second dose of PEGylated liposomes was significantly reduced, and liposome accumulation in the liver and spleen increased (Dams et al., >>2000<<). Subsequent investigations have verified these findings, with a maximum clearance of liposomes 4\u20137 days after the initial dose in rats and 10 days in mice (Ishida et al., 2003, 2006b)." . _:b594468192 . _:b594469101 . _:b594469102 . _:b46911209 "Pore sizes ranging from 0.2 to 1.2 \u03BCm have been observed, though the size and number of pores are dependent upon the microenvironment of the pathological site (Klimuk et al., 1999; Antohe et al., >>2004<<; Hua, 2013)." . _:b594469698 "2"^^ . _:b594469355 . _:b594469103 . _:b594469088 . _:b594468195 . _:b594469089 . _:b594469090 . _:b594469709 "2"^^ . _:b594469354 . _:b594469091 . . _:b594468194 . _:b594469092 . . _:b594469093 . _:b594468557 . . _:b594468425 . _:b594469708 "2"^^ . _:b594469365 . _:b594469094 . _:b594469095 . _:b46911151 "However, the delivery system was prone to rapid elimination from the bloodstream, therefore limiting its therapeutic efficacy (Gabizon et al., 1991, >>1994<<). This rapid clearance was due to opsonization of plasma components and uptake by fixed macrophages of the reticuloendothelial system (RES), mainly in the liver and spleen (Hua and Wu, 2013)." . _:b594468888 . _:b594468205 . . _:b46911161 "for site-specific delivery of drugs to designated cell types or organs in vivo, which selectively express or over-express specific ligands (e.g., receptors or cell adhesion molecules) at the site of disease (Willis and Forssen, >>1998<<; Hua, 2013). Many types of ligands are available, such as antibodies, peptides/proteins and carbohydrates (Figure 1)." . _:b594468889 . . _:b594469711 "2"^^ . _:b594469364 . _:b594468890 . _:b594468891 . _:b594468892 . _:b594468204 . _:b594468893 . _:b594469502 . . _:b594469710 "2"^^ . _:b594469367 . _:b594468894 . _:b594468895 . _:b594468880 . _:b594468207 . _:b594468881 . _:b594468882 . _:b594469705 "2"^^ . _:b594469366 . _:b594468883 . . _:b594468206 . _:b594468884 . . _:b594468885 . _:b594468886 . _:b594469704 "2"^^ . _:b594469361 . _:b46911394 _:b46911404 . _:b594468887 . _:b46911394 _:b46911405 . _:b594468201 . _:b594468872 . _:b46911394 _:b46911406 . _:b594468873 . _:b46911394 _:b46911407 . _:b594469707 "2"^^ . _:b594469499 . _:b594469360 . _:b594468874 . _:b46911394 _:b46911400 . _:b46911308 "targeting with one or more targeting ligands, response to triggers to control drug release, delivery of a combination of therapeutics (e.g., siRNA and small molecule drugs), and biomarker and imaging capabilities (Zhang et al., >>2011<<; Allen and Cullis, 2013; Charron et al., 2015; Cole and Holland, 2015). In particular, theranostic nanoparticles have generated much interest as it is both a therapeutic and diagnostic tool all-in-one (Figure 1)." . _:b594468875 . . _:b46911394 _:b46911401 . _:b594468200 . _:b594468876 . _:b46911394 _:b46911402 . _:b594468877 . . _:b46911394 _:b46911403 . _:b594469706 "2"^^ . _:b594469363 . _:b594468878 . _:b46911394 _:b46911396 . _:b594468879 . _:b46911394 _:b46911397 . _:b594468203 . _:b594468864 . _:b46911394 _:b46911398 . _:b594468865 . _:b46911394 _:b46911399 . _:b594469717 "2"^^ . _:b594469362 . _:b594468866 . _:b594468867 . _:b594469829 . _:b594468868 . _:b594468202 . _:b594468869 . _:b46911394 _:b46911395 . _:b594469716 "2"^^ . _:b594469373 . _:b594469086 . _:b594468870 . _:b594468192 . . _:b594468871 . . _:b594468213 . _:b594468920 . . _:b594468921 . _:b594468922 . _:b594469719 "2"^^ . _:b594469372 . _:b46911394 _:b46911416 . _:b594468923 . _:b46911394 _:b46911417 . _:b594468212 . _:b594468924 . . _:b594468925 . _:b594468926 . _:b594469718 "2"^^ . _:b594469375 . _:b46911394 _:b46911412 . _:b594468927 . _:b46911394 _:b46911413 . _:b46911320 "In fact, the first FDA approved nano-drug, doxorubicin, is delivered using PEGylated liposomes (Ning et al., >>2007<<). Often used in combination with other medicines, PLD treats various types of cancer including AIDS-related Kaposi's sarcoma, leukemia, and ovarian, breast, bone, lung, and brain cancers. PLD has also been found to be an effective" . _:b594468215 . _:b594468912 . _:b46911394 _:b46911414 . _:b594468913 . _:b46911394 _:b46911415 . _:b594469713 "2"^^ . _:b594469374 . _:b594468914 . _:b46911394 _:b46911408 . _:b594469225 . _:b594468915 . _:b46911394 _:b46911409 . _:b594468214 . _:b594468916 . _:b46911394 _:b46911410 . _:b594469060 . _:b594468917 . _:b46911394 _:b46911411 . _:b594469712 "2"^^ . _:b594469369 . _:b594468918 . _:b594468919 . _:b594468904 . _:b594468209 . _:b594468905 . _:b594469083 . _:b594468906 . _:b594469715 "2"^^ . _:b594469368 . _:b594468907 . . _:b594468208 . _:b594468908 . . _:b594468909 . _:b594468910 . _:b594469714 "2"^^ . _:b594469371 . . _:b594468911 . _:b594468896 . _:b594468211 . _:b594468897 . _:b594468898 . _:b594469725 "2"^^ . _:b594469370 . _:b594468899 . _:b594468900 . _:b594468210 . _:b594468901 . _:b594469311 . _:b594468902 . _:b594469724 "2"^^ . _:b594468869 . _:b594468903 . _:b594469794 . . _:b594468221 . _:b594468952 . _:b594468953 . _:b594468954 . _:b594469727 "2"^^ . _:b594468868 . _:b594468955 . _:b594468956 . _:b594469859 . _:b594468220 . _:b594468957 . _:b594468958 . _:b594469726 "2"^^ . _:b594468871 . _:b594468959 . _:b594468944 . _:b594468223 . _:b594468945 . _:b594468946 . _:b594469721 "2"^^ . _:b594468870 . . _:b594468947 . _:b594468948 . _:b594468222 . _:b594468949 . . _:b594469807 . _:b594469720 "2"^^ . _:b594468865 . _:b594468315 . _:b594468950 . _:b594468951 . _:b594468936 . _:b594468217 . . _:b594468937 . _:b594468938 . _:b594469723 "2"^^ . _:b594468864 . _:b594468939 . _:b594468940 . _:b594468216 . _:b594468941 . _:b594468942 . _:b594469722 "2"^^ . _:b594468867 . _:b594468943 . _:b594469254 . _:b594468928 . _:b594469641 . _:b594468219 . _:b594468929 . _:b594468930 . _:b594469733 "2"^^ . _:b594468866 . _:b594468931 . _:b594468932 . _:b594468218 . _:b594468933 . _:b594468948 . _:b594468934 . _:b594469732 "2"^^ . _:b594468877 . _:b594468125 . _:b594468935 . . _:b594468229 . _:b594468984 . _:b594468985 . _:b594468986 . _:b594469735 "2"^^ . _:b594468876 . _:b594468987 . . _:b594468228 . _:b594468988 . . _:b594468989 . _:b594468990 . _:b594469734 "2"^^ . _:b594468879 . _:b594468991 . _:b594468976 . _:b594468231 . _:b594468977 . . _:b594469729 "2"^^ . _:b594468878 . _:b594468978 . _:b594468979 . _:b594468980 . _:b594468230 . _:b594468981 . _:b594468982 . _:b46911379 "and solid tumorsFDA Approved in 1996ConventionalChang and Yeh, 2012; Allen and Cullis, 2013Cytarabine or cytosine arabinosideNeoplastic meningitis and lymphomatous meningitisFDA ApprovedConventionalChang and Yeh, 2012; Jahn et al., >>2015< "2"^^ . _:b594468873 . _:b594468504 . _:b594468983 . _:b594468505 . _:b594469806 . _:b594468225 . _:b594468968 . _:b594468506 . _:b594468969 . _:b594468507 . _:b594469876 . _:b594469731 "2"^^ . _:b594468872 . _:b594468970 . _:b594468508 . _:b594468971 . _:b594468509 . _:b594468224 . _:b594468972 . _:b594468510 . _:b594468973 . _:b594468511 . _:b594469730 "2"^^ . _:b594468875 . _:b594468974 . _:b594468496 . _:b594468751 . _:b594468975 . _:b594468497 . _:b46911282 "Colonic mucins carry a negative charge since their carbohydrates are substituted with numerous sulfate and sialic acid residues (Larsson et al., >>2009<<; Antoni et al., 2014)." . _:b594468227 . _:b594468960 . . _:b594468961 . _:b594468498 . . _:b594469741 "2"^^ . _:b594468874 . _:b594468962 . _:b594468499 . _:b594468500 . _:b46911366 "2006; Chang and Yeh, 2012VerteporfinMolecular degenerationFDA Approved in 2000CationicChang and Yeh, 2012; Allen and Cullis, 2013; Gross et al., 2013AmikacinLung infectionPhase II/IIIConventionalChang and Yeh, 2012; Clancy et al., >>2013<<; Olivier et al., 2014VincristineNon-Hodgkin lymphomaFDA Approved in 2012ConventionalAllen and Cullis, 2013; Wang et al., 2015TretinoinAcute promyelocytic leukemia and hormone-refractory prostate cancerPhase IIConventionalOzpolat et al.," . _:b594468963 . _:b594468501 . _:b594468226 . _:b594468964 . . _:b594468965 . _:b594468502 . _:b594468503 . _:b594469740 "2"^^ . _:b594468885 . _:b594468966 . _:b594468488 . _:b594468967 . _:b594468489 . _:b594469950 . _:b594468237 . _:b594469272 . _:b594468490 . _:b594469273 . . _:b594469743 "2"^^ . _:b594468884 . _:b594469274 . _:b594468491 . _:b594468492 . _:b594469275 . _:b594468493 . _:b594468236 . _:b594469276 . . _:b594469729 . _:b594469277 . _:b594468494 . _:b594468589 . _:b594469742 "2"^^ . _:b594468887 . _:b594469278 . _:b594468495 . _:b594468480 . _:b594469279 . _:b594468481 . _:b594468239 . _:b594469264 . _:b594468482 . _:b594469265 . _:b594468483 . _:b594469737 "2"^^ . _:b594468886 . _:b594469266 . _:b594468484 . _:b594469267 . _:b594468485 . _:b594468238 . _:b594469268 . _:b594468486 . _:b594469002 . _:b594469269 . _:b594468487 . _:b46911203 "This allows liposomes to extravasate and accumulate by passive targeting (Hashizume et al., >>2000<<). For example, inflammation results in a dramatic change in blood vessel permeability as the capillary vasculature undergoes structural remodeling to allow leukocyte diapedesis into the peripheral tissue (Klimuk et al., 1999; Hua, 2013)." . _:b594469736 "2"^^ . _:b594468881 . _:b594469270 . _:b594468536 . _:b594469271 . _:b594468537 . _:b594469161 . _:b594468233 . _:b594469256 . _:b594468300 . _:b594469257 . _:b594468538 . _:b594468539 . _:b594469739 "2"^^ . _:b594468880 . _:b594469258 . _:b594468540 . _:b594469259 . _:b594468541 . _:b594468232 . _:b594469260 . _:b594468542 . _:b594469877 . _:b594469268 . _:b594469261 . . _:b594469738 "2"^^ . _:b594469658 . _:b594468883 . _:b594469262 . _:b594468543 . _:b594468528 . _:b594469263 . . _:b594468235 . _:b594469248 . _:b594468529 . _:b594468530 . _:b594469249 . _:b594468531 . _:b594469749 "2"^^ . _:b594468882 . _:b594469250 . _:b594468532 . _:b594469251 . _:b594468533 . _:b594468234 . _:b594469252 . _:b594468550 . _:b594469253 . _:b594468534 . _:b594468535 . _:b594469748 "2"^^ . _:b594468893 . _:b594469254 . . _:b594469255 . _:b594468520 . . _:b594468245 . _:b594469304 . _:b594468521 . . _:b594469305 . _:b594468522 . . _:b594469751 "2"^^ . _:b594468892 . _:b594469306 . _:b594468523 . _:b594468524 . _:b594469307 . . _:b594468244 . _:b594469308 . _:b594468525 . . _:b594468526 . _:b594469309 . _:b594468527 . _:b594469750 "2"^^ . _:b594468895 . _:b594469310 . . _:b594469311 . _:b594468512 . . _:b594468247 . _:b594469296 . _:b594468513 . _:b594468514 . _:b594468830 . _:b594469297 . . _:b594469745 "2"^^ . _:b594468894 . _:b594469298 . _:b594468515 . . _:b594468516 . _:b594469299 . . _:b594468246 . _:b594469300 . _:b594468517 . . _:b594469301 . _:b594468518 . _:b594468519 . _:b46911132 "Hydrophobic molecules are inserted into the bilayer membrane, and hydrophilic molecules can be entrapped in the aqueous center (Koning and Storm, 2003; Metselaar and Storm, 2005; Ding et al., 2006; Hua and Wu, >>2013<<; Figure 1)." . _:b594469744 "2"^^ . _:b594468889 . _:b594469302 . _:b594468568 . _:b594469303 . _:b594468569 . _:b594468241 . _:b594469288 . _:b594468516 . _:b46911286 "In particular, high amounts of eosinophil cationic protein and transferrin have been observed in inflamed colon sections in patients with inflammatory bowel disease (IBD) (Carlson et al., 1999; Peterson et al., 2002; Tirosh et al., >>2009<<). Cationic nano-delivery systems are also able to effectively transport large, charged structures, such as DNA and RNA, based on electrostatic interaction between the positively charged phospholipids [e.g.," . _:b594469289 . _:b594468570 . _:b594468571 . _:b594469747 "2"^^ . _:b594468888 . _:b594469290 . _:b594468572 . _:b594469291 . _:b594468573 . _:b594469094 . _:b594468240 . _:b594469292 . _:b594468574 . _:b594469293 . _:b594468575 . _:b594469746 "2"^^ . _:b594468891 . _:b594469294 . _:b594468560 . _:b594469295 . _:b594468561 . _:b594468243 . _:b594469280 . . _:b594468972 . _:b594469281 . _:b594468562 . _:b594468563 . _:b594469757 "2"^^ . _:b594469272 . _:b594468890 . _:b594469282 . _:b594468564 . _:b594469283 . _:b594468565 . _:b594468242 . _:b594469284 . _:b594468566 . _:b594469285 . _:b594468567 . _:b594469756 "2"^^ . _:b594468901 . _:b594469286 . _:b594468552 . _:b594469287 . _:b594468553 . _:b594468253 . _:b594469336 . _:b594468554 . _:b46911388 . _:b594469512 . _:b594469337 . _:b594468555 . _:b594469791 . _:b594469759 "2"^^ . _:b594468900 . _:b594469338 . _:b594468556 . _:b594468886 . _:b594469339 . . _:b594468252 . _:b594469340 . _:b594468557 . _:b594468558 . _:b46911389 . _:b594469341 . . _:b594469758 "2"^^ . _:b594468903 . _:b594469342 . _:b594468559 . _:b594468544 . _:b594469343 . _:b594468545 . _:b594468255 . _:b594469328 . . _:b594469329 . _:b594468546 . _:b594468547 . _:b594469753 "2"^^ . _:b594468902 . _:b594469330 . _:b594468548 . _:b594469331 . _:b594468549 . _:b594468875 . _:b594468254 . _:b594469332 . _:b594468550 . _:b594469333 . _:b594468551 . _:b594469752 "2"^^ . _:b594468897 . _:b594469334 . _:b594468600 . _:b594469335 . . _:b594468249 . _:b594469320 . _:b594468601 . _:b594468602 . _:b594468705 . _:b594469321 . _:b594468603 . _:b594469755 "2"^^ . _:b594468896 . _:b594469322 . _:b594468604 . _:b594469323 . _:b594468605 . _:b594468248 . _:b594469324 . _:b594468606 . _:b594469325 . _:b594468334 . _:b594469754 "2"^^ . _:b594468899 . _:b594469326 . _:b594468607 . . _:b594468592 . _:b594469327 . . _:b594468251 . _:b594469312 . _:b594468593 . . _:b594469313 . _:b594468594 . _:b594468595 . _:b594469765 "2"^^ . _:b594468898 . _:b594469314 . _:b594468596 . _:b594469315 . _:b594468597 . _:b594468250 . _:b594469316 . _:b594468598 . _:b594469317 . _:b594468599 . _:b594469764 "2"^^ . _:b594468909 . _:b594469318 . _:b594468584 . _:b594469319 . _:b594468585 . _:b594469853 . _:b594468261 . _:b594469368 . _:b594468586 . _:b46911330 "Liposomal amphotericin B for anti-fungal prophylaxis (Chandrasekar, 2008), daunorubicin for the treatment of leukemia and solid tumors (Chang and Yeh, 2012), verteporfin to treat macular degeneration (Chang and Yeh, >>2012<<), cytarabine or cytosine arabinoside to treat neoplastic meningitis and lymphomatous meningitis (Chang and Yeh, 2012; Jahn et al., 2015), and morphine sulfate for pain management are currently on the market (Chang and Yeh, 2012)." . _:b594469369 . _:b594468587 . _:b594469767 "2"^^ . _:b594468908 . _:b594469370 . _:b594468588 . _:b594469371 . . _:b594468260 . _:b594469372 . _:b594468589 . _:b594468590 . . _:b594469373 . _:b594468591 . _:b594469766 "2"^^ . _:b594468911 . _:b594469374 . _:b594468576 . _:b594469375 . _:b594468577 . _:b594468263 . _:b594469360 . _:b594468578 . _:b594469361 . _:b594468579 . _:b594469761 "2"^^ . _:b594468910 . _:b594469362 . _:b594468580 . _:b594469363 . . _:b594468262 . _:b594469364 . _:b594468581 . _:b594468582 . _:b594469365 . _:b594468583 . _:b594469760 "2"^^ . _:b594468905 . _:b594469366 . _:b594468376 . . _:b594469367 . _:b594468377 . _:b594468257 . _:b594469352 . _:b594468378 . _:b594469785 . _:b594469353 . _:b594468379 . _:b594469763 "2"^^ . _:b594468904 . _:b594469354 . _:b594468380 . _:b594469355 . _:b594468381 . _:b594468256 . _:b594469356 . _:b594468382 . _:b594469357 . _:b594468383 . _:b594469762 "2"^^ . _:b594468907 . _:b594469358 . _:b594468368 . _:b594469359 . . _:b594468259 . _:b594469344 . _:b594468369 . _:b594468370 . _:b594469345 . _:b594468371 . _:b594469773 "2"^^ . _:b594468906 . _:b594469346 . _:b594468372 . _:b594469021 . _:b594469347 . _:b594468261 . _:b594468258 . _:b594469348 . _:b594468373 . _:b594468612 . _:b594469349 . _:b594468374 . _:b594468375 . _:b594469772 "2"^^ . _:b594468917 . _:b594469350 . . _:b594469351 . _:b594468360 . . _:b594468269 . _:b594469144 . _:b594468361 . _:b594468482 . _:b594469145 . _:b594468362 . _:b594468683 . _:b594469775 "2"^^ . _:b594468916 . _:b594469146 . _:b594468363 . _:b594468364 . _:b594469147 . . _:b594468268 . _:b594469148 . _:b594468365 . _:b594468288 . _:b594469149 . _:b594468366 . _:b594468367 . _:b594469774 "2"^^ . _:b594468919 . _:b594469150 . _:b594468352 . _:b594469151 . . _:b594468271 . . _:b594469136 . _:b594468353 . _:b594468354 . _:b594469137 . _:b594468355 . _:b594469769 "2"^^ . _:b594468918 . _:b594469138 . _:b594468356 . _:b594469139 . _:b594468357 . _:b594468270 . _:b594469140 . _:b594468358 . _:b594469141 . _:b594468359 . _:b594469768 "2"^^ . _:b594468913 . _:b594469142 . _:b594468408 . _:b594469143 . _:b594468409 . _:b594468265 . _:b594469128 . _:b594468410 . _:b594469129 . _:b594468411 . _:b594469771 "2"^^ . _:b594468912 . _:b594469130 . _:b594468412 . _:b594469131 . _:b594468413 . _:b594468264 . _:b594469132 . _:b594468546 . _:b594469133 . _:b594468414 . _:b594468415 . _:b594469770 "2"^^ . _:b594469067 . _:b594468915 . _:b594469134 . _:b594468400 . _:b594469135 . _:b594468401 . _:b594468267 . _:b594469120 . . _:b594469121 . _:b594468402 . _:b594468403 . _:b594469843 . _:b594469781 "2"^^ . _:b594468914 . _:b594469122 . _:b594468404 . _:b46911413 "Given the complexities of incorporating nanotechnology into biomedical applications, there will likely be multiple patents associated with any given technology and the need for cross-licensing arrangements (Murday et al., >>2009<<). It will be important to simplify the pathway from invention to commercialization through new IP practices and protocols, so as to reduce the time and expense required for negotiating collaboration and licensing agreements (Murday et al." . _:b594469123 . _:b594468405 . _:b594468266 . _:b594469124 . . _:b594469125 . _:b594468406 . _:b594468443 . _:b594469780 "2"^^ . _:b594468925 . _:b594469126 . _:b594468407 . _:b594468375 . _:b594468392 . _:b594469127 . . _:b594468277 . _:b594469176 . _:b594468393 . _:b594468394 . _:b594469177 . _:b594468395 . _:b594469783 "2"^^ . _:b594468924 . _:b594469178 . _:b594468396 . _:b594469179 . _:b594468397 . _:b594469844 . _:b594468276 . _:b594468421 . _:b594469180 . _:b594468398 . _:b594469181 . _:b594468399 . _:b594469782 "2"^^ . _:b594468927 . _:b594469182 . _:b594468384 . _:b594469183 . _:b594468385 . _:b46911207 "cells in vivo has been reported to range from 12 to 20 nm (Antohe et al., 2004), however exposure to inflammatory mediators increases permeability of the microvasculature, with the formation of gaps of up to 1 \u03BCm (Antohe et al., >>2004<<). Pore sizes ranging from 0.2 to 1.2 \u03BCm have been observed, though the size and number of pores are dependent upon the microenvironment of the pathological site (Klimuk et al., 1999; Antohe et al., 2004; Hua, 2013)." . _:b594468279 . _:b594469168 . _:b594468386 . _:b594469169 . _:b594468387 . _:b594469777 "2"^^ . _:b594468926 . _:b594469170 . _:b594468388 . _:b594469171 . _:b594468209 . _:b594468278 . _:b594469172 . _:b594468389 . . _:b594468390 . _:b594469173 . _:b594468391 . _:b594469776 "2"^^ . _:b594468921 . _:b594469174 . _:b594468440 . _:b594469175 . _:b594468441 . _:b594468273 . _:b594469160 . _:b594468442 . _:b594469161 . _:b594468443 . _:b46911268 "with both targeted and non-targeted liposomes achieving similarly high levels of tumor tissue accumulation (7\u20138% injected dose/g tumor tissue) in HER2-overexpressing breast cancer xenografts models (Kirpotin et al., 1997, >>2006<<). However, doxorubicin-loaded anti-HER2 immunoliposomes produced significantly superior therapeutic results in comparison to all other control groups, including free doxorubicin, non-targeted liposomal doxorubicin and recombinant" . _:b594469779 "2"^^ . _:b594468920 . _:b594469162 . . _:b594469163 . _:b594468444 . _:b594468445 . _:b594468272 . _:b594469164 . _:b594468446 . _:b594469706 . _:b594468909 . _:b594469165 . _:b594468284 . _:b594469778 "2"^^ . _:b594468923 . _:b594469166 . _:b594468447 . . _:b594468432 . _:b594469167 . _:b594468628 . _:b594468275 . _:b594469152 . _:b594468433 . . _:b594469153 . _:b594468434 . . _:b594469789 "2"^^ . _:b594468922 . _:b594469154 . _:b594468435 . . _:b594468436 . _:b594469155 . _:b594468437 . _:b594469544 . _:b594468274 . _:b594469156 . _:b594468438 . _:b594469157 . _:b594468439 . _:b594469788 "2"^^ . _:b594468933 . _:b594469158 . _:b594468424 . _:b594469159 . _:b594468425 . _:b594468285 . _:b594469208 . _:b594468426 . _:b594469209 . . _:b594469791 "2"^^ . _:b594468932 . _:b594469210 . _:b594468427 . _:b594468428 . _:b594469211 . . _:b594468284 . _:b594469212 . _:b594468429 . . _:b594468430 . _:b594469213 . _:b594468431 . _:b594469790 "2"^^ . _:b594468935 . _:b594469214 . _:b594468078 . _:b594469215 . _:b594468416 . _:b594468417 . _:b594468287 . _:b594469200 . _:b594468418 . _:b594469463 . _:b594469201 . _:b594468419 . _:b594469785 "2"^^ . _:b594469220 . _:b594468934 . _:b594469202 . . _:b594469203 . _:b594468420 . _:b594468421 . _:b46911286 . _:b594469604 . _:b594468286 . _:b594469204 . _:b594468422 . _:b594469205 . _:b594468423 . _:b594469784 "2"^^ . _:b594468929 . _:b594469206 . _:b594468472 . _:b594469207 . _:b594468473 . _:b594468281 . _:b594469192 . _:b594468474 . _:b594469193 . _:b594468475 . _:b594469787 "2"^^ . _:b594468928 . _:b594469194 . _:b594468476 . _:b594469195 . _:b594468289 . _:b594468280 . _:b594469196 . _:b594468477 . . _:b594469197 . _:b594468478 . . _:b594469786 "2"^^ . _:b594468931 . _:b594469198 . _:b594468479 . _:b594468464 . _:b594469199 . _:b594468465 . _:b594468283 . _:b594469184 . . _:b594469185 . _:b594468466 . _:b594468467 . _:b594469797 "2"^^ . _:b594468930 . _:b594469186 . _:b594468468 . _:b594469187 . _:b594468469 . _:b594468282 . _:b594469188 . _:b594468470 . _:b594469743 . _:b594469189 . _:b594468471 . _:b594469796 "2"^^ . _:b594468941 . _:b594469190 . _:b594468456 . _:b594469191 . _:b594468457 . _:b594468293 . _:b594469240 . . _:b594469241 . _:b594468458 . . _:b594469799 "2"^^ . _:b594468940 . _:b594468720 . _:b594469242 . _:b594468459 . _:b594468460 . _:b594469243 . _:b594468461 . _:b594468292 . _:b594469244 . . _:b594469245 . _:b594468462 . . _:b594469798 "2"^^ . _:b594468943 . _:b594469246 . _:b594468463 . _:b594468448 . _:b594469247 . _:b594468449 . _:b594468295 . _:b594469232 . _:b594468450 . _:b594469233 . _:b594468451 . _:b594469793 "2"^^ . _:b594468942 . _:b594469234 . _:b594468452 . _:b594469235 . _:b594468294 . _:b594469236 . _:b594468453 . . _:b594468871 . _:b594469237 . _:b594468454 . _:b594468455 . _:b594469792 "2"^^ . _:b594468937 . _:b594469238 . _:b594468760 . _:b594469239 . _:b594468289 . _:b594469224 . _:b594468761 . _:b594468762 . _:b594469225 . _:b594468763 . _:b46911404 "formulation processes, which inevitably pose problems for large scale good manufacturing (cGMP) production, increases the cost of production, and makes the evaluation of such products more difficult (Teli et al., 2010; Tinkle et al., >>2014<<). Increasing the number of physicochemical variables in a nanoformulation system also makes it more complicated to assess the pharmacokinetics, pharmacodynamics and toxicology of a formulation following administration (Teli et al., 2010;" . _:b594469795 "2"^^ . _:b594469202 . _:b594468936 . _:b594469226 . _:b594468764 . _:b594469227 . _:b594468288 . _:b594469228 . _:b594468765 . _:b594468766 . _:b594469229 . _:b594468330 . _:b594469794 "2"^^ . _:b594468939 . _:b594469230 . _:b594468767 . _:b594468752 . _:b594469231 . _:b594468291 . _:b594469216 . _:b594468753 . _:b594468754 . _:b594469217 . _:b594468755 . _:b594469805 "2"^^ . _:b594468938 . _:b594469218 . _:b594468756 . _:b594469219 . _:b594468290 . _:b594469220 . _:b594468757 . _:b594468758 . _:b46911401 . _:b594469221 . . _:b594469804 "2"^^ . _:b594468949 . _:b594469222 . _:b594468759 . _:b594468744 . _:b594469223 . _:b594468301 . _:b594468745 . . _:b594468746 . _:b594468747 . _:b594469807 "2"^^ . _:b594468948 . _:b594468748 . _:b594468300 . _:b594468749 . . _:b594468750 . _:b594468751 . _:b594469806 "2"^^ . _:b594469697 . _:b594468951 . . _:b594468736 . _:b594468303 . _:b594468737 . _:b594468738 . _:b594468739 . _:b594469801 "2"^^ . _:b594468950 . _:b594468740 . _:b594468302 . _:b594469164 . _:b594468741 . _:b594468459 . _:b594468742 . _:b594468743 . _:b594469800 "2"^^ . _:b594468945 . _:b594468792 . _:b594468297 . _:b594469587 . _:b594468793 . _:b594468794 . _:b594468795 . _:b594469803 "2"^^ . _:b594468944 . _:b594468796 . _:b594468296 . _:b594468797 . _:b594468798 . _:b594468799 . _:b594469802 "2"^^ . _:b594468947 . . _:b594468784 . _:b594468299 . _:b594468785 . _:b594468786 . _:b594468452 . _:b594469813 "2"^^ . _:b594469655 . _:b594468946 . _:b594468787 . _:b594468601 . _:b594468788 . _:b594468298 . _:b594468789 . _:b594468790 . _:b594468791 . _:b594469812 "2"^^ . _:b594468957 . _:b594468776 . _:b594468309 . _:b594468777 . _:b594468778 . _:b594468779 . _:b594469815 "2"^^ . _:b594468956 . _:b594468780 . _:b594468308 . _:b594468781 . . _:b594468782 . . _:b594469814 "2"^^ . _:b594468959 . _:b594468783 . . _:b594469372 . _:b594468768 . _:b594468311 . _:b594468769 . . _:b594468770 . _:b594468771 . _:b594469809 "2"^^ . _:b594468958 . _:b594468882 . . _:b594469828 . _:b594468772 . _:b594468310 . _:b46911379 . _:b594468773 . _:b594468774 . _:b594468775 . _:b594469808 "2"^^ . _:b594468953 . . _:b594468824 . _:b594468305 . _:b594468825 . _:b594468826 . _:b594468827 . _:b594469811 "2"^^ . _:b594468952 . _:b594468828 . _:b594468304 . _:b594468829 . . _:b594468830 . _:b594468831 . _:b594469810 "2"^^ . _:b594468955 . . _:b594468816 . _:b594468307 . _:b594468817 . _:b594468296 . _:b594468818 . _:b594468819 . _:b594469821 "2"^^ . _:b594468954 . _:b594468820 . _:b594468306 . _:b594469035 . _:b594468761 . _:b594468821 . _:b594468822 . _:b594468923 . _:b594468823 . _:b594469820 "2"^^ . _:b594468965 . _:b594468808 . _:b594468317 . _:b594468809 . . _:b594468810 . _:b594468811 . _:b46911239 . _:b594469823 "2"^^ . _:b594468964 . _:b594468812 . _:b594468316 . _:b594468813 . _:b594468814 . _:b594468815 . _:b594469822 "2"^^ . _:b594468967 . _:b594468381 . _:b594468728 . _:b594468800 . _:b594468522 . _:b594468319 . _:b594469680 . _:b594468801 . _:b594468802 . _:b594469309 . _:b594468803 . _:b594469817 "2"^^ . _:b594468966 . _:b594468391 . _:b594468804 . _:b594468318 . _:b594468805 . _:b594468806 . _:b594468807 . _:b594469816 "2"^^ . _:b594468961 . _:b594468856 . _:b594468313 . _:b594468857 . . _:b594469296 . _:b594468858 . _:b594468859 . _:b594469819 "2"^^ . _:b594468960 . _:b594468860 . _:b594468312 . _:b594468861 . _:b594468862 . _:b594468863 . _:b594469818 "2"^^ . _:b594468963 . . _:b594468848 . _:b594468315 . _:b594469572 . _:b594468849 . . _:b594468850 . _:b594468851 . _:b594469829 "2"^^ . _:b594468962 . . _:b594468852 . _:b594468314 . _:b594469034 . _:b594468853 . _:b594468513 . _:b594468854 . _:b594468855 . _:b594469828 "2"^^ . _:b594468973 . _:b594468840 . _:b594468325 . _:b594468841 . _:b594468842 . _:b594468843 . _:b594469831 "2"^^ . _:b594468972 . _:b594468844 . _:b594469364 . _:b594468324 . _:b594468845 . _:b594468846 . _:b594468847 . _:b594469830 "2"^^ . _:b594468975 . _:b594468832 . _:b594468327 . _:b594468833 . _:b594468834 . _:b594468835 . _:b594469943 . _:b594469825 "2"^^ . _:b594468974 . . _:b594468836 . _:b594468326 . _:b594468837 . _:b594468838 . _:b594468839 . _:b594469824 "2"^^ . _:b594468969 . _:b594468632 . _:b594468321 . _:b594468633 . _:b594468634 . _:b594468635 . _:b594469827 "2"^^ . _:b594468968 . _:b594468322 . _:b594468636 . . _:b594468320 . _:b594468637 . _:b594468638 . _:b594468639 . _:b594469826 "2"^^ . _:b594468971 . _:b594468088 . _:b594468624 . _:b594468323 . _:b46911296 "Another approach to improve therapeutic efficacy of liposomal formulations has been to use triggering modalities for site-specific release of therapeutics from liposomes (Bibi et al., >>2012<<). Strategies that have been utilized include remote triggers (e.g., temperature, ultrasound, magnetic, and light) and local triggers specific to the target site (e.g., enzymes and pH), through the use of specific lipid compositions and" . _:b594468625 . _:b594468626 . _:b594468627 . _:b594469837 "2"^^ . _:b594468970 . _:b594468628 . _:b594468322 . _:b594468629 . . _:b594468717 . _:b594468630 . . _:b594468631 . _:b594469836 "2"^^ . _:b594468981 . _:b594468616 . _:b594468333 . _:b594468617 . _:b594468618 . _:b594468619 . _:b594469839 "2"^^ . _:b594469157 . _:b594468980 . _:b594468620 . _:b594468332 . _:b594468621 . . _:b594468622 . _:b594469213 . _:b594468623 . _:b594469838 "2"^^ . _:b594468983 . _:b594468608 . _:b594468335 . . _:b594468609 . _:b594468610 . _:b594468611 . _:b594469833 "2"^^ . _:b594469758 . _:b594468982 . _:b594468612 . _:b594468334 . _:b594468613 . _:b594468614 . _:b594468615 . _:b594469832 "2"^^ . _:b594468977 . _:b594468664 . _:b594468329 . _:b594468665 . _:b594468666 . . _:b594468667 . _:b594469835 "2"^^ . _:b594468976 . _:b594468668 . _:b46911414 "will be important to simplify the pathway from invention to commercialization through new IP practices and protocols, so as to reduce the time and expense required for negotiating collaboration and licensing agreements (Murday et al., >>2009<<)." . _:b594468328 . _:b594468669 . . _:b594468670 . . _:b594469834 "2"^^ . _:b594468979 . _:b594468671 . _:b594468656 . _:b594468331 . _:b594468657 . . _:b594468658 . _:b594468659 . _:b594469845 "2"^^ . _:b594468978 . . _:b46911131 "Hydrophobic molecules are inserted into the bilayer membrane, and hydrophilic molecules can be entrapped in the aqueous center (Koning and Storm, 2003; Metselaar and Storm, 2005; Ding et al., >>2006<<; Hua and Wu, 2013; Figure 1)." . _:b594468660 . _:b594468330 . _:b594468661 . _:b594468662 . _:b594468663 . _:b594469844 "2"^^ . _:b594468989 . . _:b594468648 . . _:b594468341 . _:b594468649 . _:b594468650 . _:b46911223 "Increasing the phospholipid dose has been suggested to cause PEG-reactive B cells to become apoptotic, reducing anti-PEG IgM production and thus abating the ABC phenomenon (Ishida et al., 2006b; Ishida and Kiwada, 2008)." . _:b594468084 . _:b594469847 "2"^^ . _:b594469129 . _:b594468988 . _:b594468651 . . _:b594468652 . _:b594468340 . _:b594468653 . . _:b594468654 . _:b594468319 . _:b594469846 "2"^^ . _:b594468991 . _:b594468847 . _:b594468655 . _:b594468640 . _:b594468343 . _:b594468641 . . _:b594468642 . _:b594468643 . _:b594469919 . _:b594469841 "2"^^ . _:b594468990 . _:b594468971 . . _:b594468644 . _:b594468342 . _:b594468645 . _:b594468646 . _:b594468647 . _:b594469840 "2"^^ . _:b594469450 . _:b594468985 . . _:b594468696 . _:b594469385 . _:b594468337 . _:b594468697 . _:b594468698 . _:b594468255 . _:b594469843 "2"^^ . _:b594468984 . _:b594468699 . . _:b594468700 . . . . _:b594468336 . _:b46911325 "to receiving FDA approval for usage of PLD in 1995, combination therapies of PLD and other drugs (such as bortezomib for the treatment of relapsed or refractory multiple myeloma) have recently received FDA approval (Ning et al., >>2007<<). Another type of PEGylated liposome currently in Phase I trials is PEPO2, an irinotecan-encapsulated liposomal formulation used to treat advanced refractory solid tumors (Chang et al., 2015)." . _:b594468701 . _:b594468702 . _:b594468703 . _:b46911301 . _:b594469842 "2"^^ . _:b594468987 . . _:b594468688 . _:b594468339 . _:b594468689 . _:b594468690 . _:b594468691 . _:b594469853 "2"^^ . _:b594468986 . _:b594468692 . _:b594468338 . _:b594468693 . _:b594468694 . _:b594468695 . _:b594469852 "2"^^ . _:b594469452 . _:b594468997 . . _:b594468680 . _:b594468349 . _:b594468987 . _:b594468681 . _:b594468682 . _:b594468683 . _:b594469855 "2"^^ . _:b594468996 . _:b594468394 . _:b594468684 . _:b594468348 . _:b594468685 . _:b594468686 . . _:b594469854 "2"^^ . _:b594468999 . _:b594468687 . . _:b594468631 . . _:b594468672 . . _:b594468351 . _:b594468673 . . _:b594468674 . _:b46911386 "et al., 2005; Chang and Yeh, 2012VinorelbineNewly diagnosed or relapsed solid tumorsPhase IConventionalAllen and Cullis, 2013TopotecanAdvanced solid tumorsPhase 1/IIConventionalSeiden et al., 2004; Allen and Cullis, >>2013< . _:b594469849 "2"^^ . _:b594468998 . _:b594468675 . _:b594468676 . _:b594468350 . _:b594468677 . . _:b594468678 . _:b594468679 . _:b594469848 "2"^^ . _:b594468993 . _:b594468728 . _:b594468345 . _:b594468729 . . _:b594468367 . _:b46911267 . _:b594468730 . _:b594468731 . _:b594469851 "2"^^ . _:b594468992 . _:b594468732 . _:b46911288 . _:b594468344 . _:b594468733 . . _:b594468734 . _:b594468087 . _:b594468735 . _:b594469850 "2"^^ . _:b594468995 . _:b594468720 . _:b594468347 . _:b594468721 . _:b594468722 . _:b594468723 . _:b594469861 "2"^^ . _:b594468994 . . _:b594468724 . _:b594468346 . _:b594468725 . . _:b594468726 . _:b594468727 . _:b594469860 "2"^^ . _:b594469005 . _:b594468712 . _:b594468713 . _:b594468714 . _:b594468715 . _:b594469863 "2"^^ . _:b594469004 . _:b46911126 _:b46911144 . _:b594468716 . _:b594468717 . _:b594468718 . _:b594468719 . _:b594469862 "2"^^ . _:b594469007 . _:b46911126 _:b46911140 . _:b594468704 . _:b46911126 _:b46911141 . _:b594468705 . . _:b46911126 _:b46911142 . _:b594468706 . _:b46911126 _:b46911143 . _:b594469857 "2"^^ . _:b594469006 . _:b594468707 . . _:b46911126 _:b46911136 . _:b594468708 . _:b46911126 _:b46911137 . _:b594468709 . _:b46911126 _:b46911138 . _:b594468710 . _:b46911126 _:b46911139 . _:b594469856 "2"^^ . _:b594469001 . _:b594468711 . _:b46911126 _:b46911132 . _:b594469674 . _:b46911126 _:b46911133 . _:b46911126 _:b46911134 . _:b46911126 _:b46911135 . _:b594469859 "2"^^ . _:b594469000 . _:b594468117 . _:b46911126 _:b46911128 . . . _:b46911126 _:b46911129 . _:b46911126 _:b46911130 . . _:b594469858 "2"^^ . _:b594469552 . _:b594469003 . _:b46911126 _:b46911131 . . . . _:b46911126 _:b46911127 . _:b594469869 "2"^^ . _:b594469002 . . . _:b594468497 . _:b594468899 . _:b594469013 . _:b594469868 "2"^^ . . _:b46911376 "I/IIConventionalWetzler et al., 2013Amphotericin BAnti-fungal prophylaxisFDA approved in 1997ConventionalChandrasekar, 2008; Allen and Cullis, 2013DaunorubicinLeukemia and solid tumorsFDA Approved in 1996ConventionalChang and Yeh, >>2012<<; Allen and Cullis, 2013Cytarabine or cytosine arabinosideNeoplastic meningitis and lymphomatous meningitisFDA ApprovedConventionalChang and Yeh, 2012; Jahn et al., 2015Morphine sulfatePain ManagementFDA Approved in 2004ConventionalChang" . _:b594469012 . _:b594469871 "2"^^ . . . _:b594469015 . _:b594469870 "2"^^ . . . _:b594468223 . . _:b594469014 . _:b594469865 "2"^^ . _:b594469747 . _:b594468942 . _:b594469009 . _:b594469864 "2"^^ . _:b594469187 . . . . _:b594469008 . _:b594469867 "2"^^ . . . _:b594468901 . _:b594469011 . _:b594469866 "2"^^ . _:b594469010 . _:b594469877 "2"^^ . _:b594469216 . _:b46911310 "response to triggers to control drug release, delivery of a combination of therapeutics (e.g., siRNA and small molecule drugs), and biomarker and imaging capabilities (Zhang et al., 2011; Allen and Cullis, 2013; Charron et al., >>2015<<; Cole and Holland, 2015). In particular, theranostic nanoparticles have generated much interest as it is both a therapeutic and diagnostic tool all-in-one (Figure 1)." . _:b594469021 . _:b594469876 "2"^^ . . . . _:b594469879 "2"^^ . _:b594469020 . . _:b46911267 "the nanoparticles, with both targeted and non-targeted liposomes achieving similarly high levels of tumor tissue accumulation (7\u20138% injected dose/g tumor tissue) in HER2-overexpressing breast cancer xenografts models (Kirpotin et al., >>1997<<, 2006). However, doxorubicin-loaded anti-HER2 immunoliposomes produced significantly superior therapeutic results in comparison to all other control groups, including free doxorubicin, non-targeted liposomal doxorubicin and recombinant" . . _:b594469878 "2"^^ . _:b594469023 . _:b594469580 . . _:b46911246 . _:b594468252 . _:b594469873 "2"^^ . _:b594469022 . . . . _:b594469872 "2"^^ . _:b594469017 . . _:b594469875 "2"^^ . _:b594469016 . . _:b594469019 . _:b594469874 "2"^^ . . _:b594468571 . . _:b594469934 . _:b594468430 . _:b594469885 "2"^^ . _:b594469018 . . _:b594469884 "2"^^ . _:b594469029 . _:b594468611 . _:b594469887 "2"^^ . _:b594469028 . _:b594469031 . _:b594469886 "2"^^ . _:b594469274 . _:b594469030 . _:b594469881 "2"^^ . . . _:b594468768 . _:b594469025 . _:b594469880 "2"^^ . _:b594468088 . _:b594468089 . _:b594468090 . _:b594468091 . _:b594469883 "2"^^ . _:b594469024 . _:b594468849 . _:b594468092 . _:b594468093 . _:b594468094 . _:b594468095 . _:b594469882 "2"^^ . _:b594469027 . _:b594468126 . _:b594468080 . . _:b594468081 . _:b594468082 . _:b594468083 . _:b594469026 . _:b594468869 "2"^^ . _:b594468084 . _:b594468085 . _:b594468086 . _:b594468087 . _:b594469037 . _:b594468868 "2"^^ . . _:b594469036 . _:b594468871 "2"^^ . _:b594468075 . . _:b594468076 . _:b594468077 . _:b594468078 . _:b594468079 . _:b594469039 . _:b594468870 "2"^^ . _:b594468865 "2"^^ . _:b594469038 . . _:b594468121 . _:b594469913 . _:b594469033 . _:b594468864 "2"^^ . . . _:b594468867 "2"^^ . _:b594469032 . . _:b594468866 "2"^^ . _:b594469035 . . _:b594468877 "2"^^ . _:b594469034 . _:b594468221 . _:b594468876 "2"^^ . _:b594469045 . . _:b594468879 "2"^^ . _:b594469044 . _:b46911260 "The notion that ligand-targeted liposomes have a therapeutic advantage over non-targeted liposomes is still subject to debate, with conflicting results in the literature (Ferrari, 2005; Puri et al., 2009; Riehemann et al., >>2009<<). A number of studies have demonstrated enhanced uptake and efficacy of ligand-targeted liposomes in diseased tissue in comparison to non-targeted liposomes in vivo (Vingerhoeds et al., 1994; Puri et al., 2009; Allen and Cullis, 2013;" . . _:b594468878 "2"^^ . _:b594469047 . _:b594468873 "2"^^ . _:b594469046 . _:b594468674 . _:b594469638 . _:b594468872 "2"^^ . _:b594469041 . _:b46911282 . _:b594468875 "2"^^ . _:b594469040 . _:b594468874 "2"^^ . _:b594469043 . _:b594468928 . . . _:b594468885 "2"^^ . _:b594469042 . . _:b594469053 . _:b594468884 "2"^^ . . . . _:b594469468 . _:b594468887 "2"^^ . _:b594469052 . _:b46911256 . _:b46911142 . _:b594468886 "2"^^ . _:b594469564 . _:b594469055 . . _:b594468881 "2"^^ . _:b594469054 . _:b594469435 . . _:b594468903 . . _:b594468880 "2"^^ . _:b594469049 . _:b46911168 _:b46911236 . _:b46911168 _:b46911237 . _:b46911168 _:b46911238 . _:b46911168 _:b46911239 . _:b594469048 . _:b594468883 "2"^^ . _:b46911168 _:b46911232 . _:b46911168 _:b46911233 . _:b594469892 . _:b594468874 . _:b46911168 _:b46911234 . _:b46911168 _:b46911235 . _:b594469051 . _:b594468882 "2"^^ . _:b46911145 _:b46911146 . _:b46911145 _:b46911147 . _:b594469050 . _:b594468893 "2"^^ . _:b46911145 _:b46911148 . _:b46911168 _:b46911240 . _:b46911168 _:b46911241 . _:b46911145 _:b46911149 . _:b46911168 _:b46911242 . _:b46911136 . _:b46911145 _:b46911150 . _:b46911145 _:b46911151 . _:b594469061 . _:b594468892 "2"^^ . _:b46911145 _:b46911152 . _:b46911145 _:b46911153 . _:b594468669 . _:b594468082 . _:b46911145 _:b46911154 . . _:b594469060 . _:b594468895 "2"^^ . _:b46911145 _:b46911155 . _:b46911145 _:b46911156 . . _:b46911145 _:b46911157 . _:b46911145 _:b46911158 . . _:b46911145 _:b46911159 . _:b594469063 . _:b594468894 "2"^^ . _:b46911145 _:b46911160 . _:b594469623 . _:b46911145 _:b46911161 . _:b594469714 . _:b46911145 _:b46911162 . _:b46911145 _:b46911163 . _:b594469062 . _:b594468889 "2"^^ . _:b594468813 . . _:b46911145 _:b46911164 . _:b46911145 _:b46911165 . _:b46911341 "(Zhang et al., 2004; Suenaga et al., 2015) and a liposomal-based all-trans-retinoic acid (ATRA) in Phase II that contains the drug tretinoin to treat acute promyelocytic leukemia and hormone-refractory prostate cancer (Ozpolat et al., >>2003<<). One type of conventional liposomal formation is EndoTAG-1, which carries paclitaxel." . _:b46911145 _:b46911166 . _:b46911148 . _:b46911145 _:b46911167 . _:b594469057 . _:b594468888 "2"^^ . _:b46911168 _:b46911204 . _:b46911168 _:b46911205 . _:b46911168 _:b46911206 . _:b46911168 _:b46911207 . _:b46911405 . _:b594469056 . _:b594468891 "2"^^ . _:b46911168 _:b46911200 . . _:b46911168 _:b46911201 . _:b46911168 _:b46911202 . _:b46911168 _:b46911203 . _:b594469059 . _:b594468890 "2"^^ . _:b594468527 . _:b46911168 _:b46911212 . _:b46911168 _:b46911213 . _:b46911168 _:b46911214 . _:b46911168 _:b46911215 . _:b46911403 . _:b594469058 . _:b594468901 "2"^^ . _:b46911168 _:b46911208 . _:b46911168 _:b46911209 . _:b46911168 _:b46911210 . _:b46911168 _:b46911211 . _:b594469069 . _:b594468900 "2"^^ . _:b46911168 _:b46911220 . _:b46911168 _:b46911221 . _:b46911168 _:b46911222 . _:b46911168 _:b46911223 . _:b46911328 "Liposomal amphotericin B for anti-fungal prophylaxis (Chandrasekar, >>2008<<), daunorubicin for the treatment of leukemia and solid tumors (Chang and Yeh, 2012), verteporfin to treat macular degeneration (Chang and Yeh, 2012), cytarabine or cytosine arabinoside to treat neoplastic meningitis and lymphomatous" . _:b594469068 . _:b594468903 "2"^^ . . _:b46911168 _:b46911216 . _:b46911168 _:b46911217 . _:b46911168 _:b46911218 . _:b46911168 _:b46911219 . _:b594469071 . _:b594468902 "2"^^ . . _:b46911168 _:b46911228 . _:b46911168 _:b46911229 . _:b46911210 "Pore sizes ranging from 0.2 to 1.2 \u03BCm have been observed, though the size and number of pores are dependent upon the microenvironment of the pathological site (Klimuk et al., 1999; Antohe et al., 2004; Hua, >>2013<<). Importantly, all types of liposomal delivery systems are subjected to the EPR effect, with PEGylated liposomes having an advantage due to having reduced RES clearance and extended circulation time (Sawant and Torchilin, 2012)." . _:b594468559 . _:b46911168 _:b46911230 . _:b46911168 _:b46911231 . _:b594469070 . _:b594468897 "2"^^ . _:b46911168 _:b46911224 . . . _:b46911168 _:b46911225 . _:b46911168 _:b46911226 . . _:b46911168 _:b46911227 . _:b594469065 . _:b594468896 "2"^^ . _:b594468248 . _:b594469575 . _:b46911168 _:b46911172 . _:b594468249 . _:b46911168 _:b46911173 . _:b594468250 . _:b46911168 _:b46911174 . . _:b594468251 . _:b594469064 . _:b594468899 "2"^^ . _:b46911168 _:b46911175 . _:b594468252 . _:b594468253 . _:b594468679 . _:b594468180 . _:b594468276 . _:b46911168 _:b46911169 . _:b594468254 . _:b46911168 _:b46911170 . _:b594468255 . _:b594469067 . _:b594468898 "2"^^ . _:b594468492 . _:b46911168 _:b46911171 . _:b594468240 . _:b46911168 _:b46911180 . _:b594468241 . _:b46911168 _:b46911181 . _:b594468242 . _:b46911168 _:b46911182 . _:b594468243 . _:b594469066 . _:b594468909 "2"^^ . _:b46911168 _:b46911183 . _:b594468244 . _:b46911168 _:b46911176 . _:b594468245 . _:b46911168 _:b46911177 . _:b594468246 . _:b46911168 _:b46911178 . _:b594468247 . _:b594469077 . _:b594468908 "2"^^ . _:b46911168 _:b46911179 . _:b594468232 . _:b46911168 _:b46911188 . _:b594468233 . _:b46911168 _:b46911189 . _:b594468234 . . _:b46911168 _:b46911190 . _:b594468235 . _:b594469076 . _:b594468911 "2"^^ . _:b46911168 _:b46911191 . _:b594468236 . _:b46911197 "structures (e.g., red blood cells and lipoproteins) that can cause the depletion of high phase transition temperature lipids and their replacement with less physiologically stable components (Willis and Forssen, 1998; Laverman et al., >>1999<<; Ulrich, 2002). Integrating cholesterol into small (approximately 100 nm), electrostatically neutral liposomes has been shown to prolong circulation time in the range of several hours (Geng et al., 2014)." . _:b46911168 _:b46911184 . . _:b594468237 . _:b46911259 "The notion that ligand-targeted liposomes have a therapeutic advantage over non-targeted liposomes is still subject to debate, with conflicting results in the literature (Ferrari, 2005; Puri et al., >>2009<<; Riehemann et al., 2009)." . _:b46911168 _:b46911185 . _:b594468238 . _:b46911168 _:b46911186 . _:b594468239 . _:b594469079 . _:b594468910 "2"^^ . _:b46911168 _:b46911187 . _:b594468224 . _:b46911168 _:b46911196 . _:b594468225 . _:b46911168 _:b46911197 . . _:b594468226 . _:b46911168 _:b46911198 . _:b594468227 . _:b594469078 . _:b594468905 "2"^^ . _:b46911168 _:b46911199 . _:b594468228 . _:b46911168 _:b46911192 . . _:b594468229 . _:b46911168 _:b46911193 . _:b594468230 . _:b46911168 _:b46911194 . _:b594468231 . _:b594469073 . _:b594468904 "2"^^ . _:b46911168 _:b46911195 . _:b594468280 . _:b594468281 . _:b594468282 . _:b594468283 . _:b46911361 "2012; Awada et al., 2014Paclitaxel EndoTAG-1Pancreatic cancerPhase IICationicL\u00F6hr et al., 2012Mitoxantrone LEM-ETUAcute myeloid leukemia, multiple sclerosis, and prostate cancerPhase ICationicImmordino et al., 2006; Chang and Yeh, >>2012< . _:b594468907 "2"^^ . _:b594468291 . _:b594468284 . _:b594468285 . _:b594469198 . _:b594468286 . _:b594468287 . _:b594469075 . _:b594468906 "2"^^ . _:b594468272 . . _:b594468273 . _:b594468274 . _:b46911131 . _:b594469022 . _:b594468275 . _:b594469074 . _:b594468917 "2"^^ . _:b594468276 . . _:b594468277 . _:b594468278 . _:b46911128 . _:b594468279 . _:b594469085 . _:b594468916 "2"^^ . _:b594468264 . _:b594468265 . . _:b594468266 . _:b594468233 . _:b594468267 . _:b594469084 . _:b594468919 "2"^^ . _:b594468268 . _:b594468269 . _:b594468270 . _:b594468271 . _:b594469624 . _:b594469087 . _:b594468918 "2"^^ . . . . . _:b594469918 . _:b594468301 . _:b594468256 . _:b594468257 . _:b594468975 . _:b594468258 . _:b594469472 . _:b594468259 . _:b594469086 . _:b594468913 "2"^^ . . _:b594468260 . _:b594468504 . _:b594468261 . _:b46911168 . . . _:b594468262 . _:b594468263 . _:b594469081 . _:b594468912 "2"^^ . _:b594468312 . _:b594468313 . _:b46911397 "Similar obstacles are faced by other nano-delivery systems for translation into the clinic (Allen and Cullis, 2004, 2013; Zhang et al., >>2008<<; Sawant and Torchilin, 2012; Narang et al., 2013)." . _:b594468314 . _:b594468810 . _:b594468748 . _:b594468315 . _:b594469080 . _:b594468915 "2"^^ . _:b594468316 . . _:b594468317 . _:b594469726 . _:b594468318 . . . _:b594468319 . _:b594469083 . _:b594468914 "2"^^ . _:b594468304 . _:b594468305 . . _:b594468306 . _:b594468307 . _:b594469082 . _:b594468925 "2"^^ . . _:b594468308 . _:b594468309 . _:b46911339 "These include irinotecan SN-38 in Phase I/II to treat colorectal cancer (Zhang et al., >>2004<<; Suenaga et al., 2015) and a liposomal-based all-trans-retinoic acid (ATRA) in Phase II that contains the drug tretinoin to treat acute promyelocytic leukemia and hormone-refractory prostate cancer (Ozpolat et al., 2003)." . _:b594468310 . . _:b594468311 . _:b594469093 . _:b594468924 "2"^^ . _:b594468296 . _:b594469039 . _:b594468297 . _:b594468298 . _:b594468990 . . _:b594468299 . _:b594469092 . _:b594468927 "2"^^ . _:b594468300 . _:b594468301 . _:b594468302 . _:b594468481 . _:b594468190 . _:b594468303 . _:b594469095 . _:b594468926 "2"^^ . _:b594468288 . _:b594469663 . _:b594468289 . _:b594468290 . _:b594468291 . _:b594469094 . _:b594468921 "2"^^ . _:b594468292 . . _:b594468293 . _:b594468294 . _:b594468295 . _:b594469089 . _:b594468920 "2"^^ . _:b594468263 . _:b594468344 . _:b594468979 . _:b594468345 . _:b594468346 . _:b594468347 . _:b594469088 . _:b594468923 "2"^^ . _:b594468824 . _:b594468348 . _:b594469717 . _:b594468349 . _:b594468350 . . _:b594468351 . _:b594469091 . _:b594468922 "2"^^ . _:b594468336 . _:b594468337 . _:b594468338 . _:b594468339 . _:b594469090 . _:b594468933 "2"^^ . _:b594468340 . _:b594468341 . . _:b594468342 . _:b594468343 . _:b594469101 . _:b594468932 "2"^^ . _:b594468328 . _:b594468329 . _:b46911256 "following parenteral administration (e.g., intravenous and intraperitoneal injection) (Torchilin, 1994; Vingerhoeds et al., 1994; Willis and Forssen, 1998; Noble et al., 2004; Deshpande et al., 2013; Hua and Cabot, 2013; Rip et al., >>2014<<; Hua et al., 2015). Targeting ligands are used to increase the specificity of delivery of encapsulated cargo to and retain it in diseased tissues and cells, with minimal deposition in non-target sites." . _:b594468330 . _:b594468331 . _:b594469100 . _:b594468935 "2"^^ . _:b594468332 . . _:b594468333 . . . _:b594468334 . . _:b594468335 . _:b594469103 . _:b594468934 "2"^^ . . _:b594468320 . _:b594468321 . _:b594468322 . _:b594468323 . _:b594469102 . _:b594468929 "2"^^ . _:b594468324 . _:b594468325 . _:b594468326 . _:b594468327 . _:b594469097 . _:b594468928 "2"^^ . . _:b594468120 . _:b594468675 . _:b594468121 . _:b594468122 . _:b594468123 . _:b594469096 . _:b594468931 "2"^^ . _:b594468124 . _:b594468125 . _:b594468126 . _:b594468127 . _:b594469166 . _:b594469099 . _:b594468930 "2"^^ . . _:b594468112 . _:b594468113 . _:b594468114 . _:b594468115 . _:b594469098 . _:b594468941 "2"^^ . _:b594468116 . _:b594468117 . _:b594468118 . _:b594468119 . _:b594469109 . _:b594468940 "2"^^ . _:b594468104 . _:b594468105 . _:b594469111 . . _:b594469912 . _:b594468106 . _:b594469913 . _:b594468107 . _:b594469108 . _:b594468943 "2"^^ . _:b46911126 . _:b594469914 . _:b594468108 . . _:b594469915 . _:b594468109 . _:b594468957 . _:b594468582 . _:b594469916 . _:b594468110 . _:b46911145 . _:b594469917 . _:b594468111 . _:b594469111 . _:b594468942 "2"^^ . _:b594469918 . _:b594468096 . _:b46911239 "Formulation strategies to minimize the immunogenicity of liposomes have included methylation of the anionic charge localized on the phosphate oxygen of mPEG-phospholipid conjugate (Moghimi et al., >>2006<<) or the use of other non-ionic lipopolymers and lipid conjugates, such as mPEG-substituted synthetic ceramides (Webb et al., 1998; Szebeni and Moghimi, 2009)." . _:b594469143 . _:b594469919 . _:b594468097 . _:b594469904 . _:b594468098 . _:b594469905 . _:b594468099 . _:b594469110 . _:b594468937 "2"^^ . _:b594469906 . _:b594468100 . _:b594469907 . _:b594468101 . _:b594469122 . _:b594469908 . _:b594468102 . _:b594469909 . _:b594468103 . _:b594469105 . _:b594468936 "2"^^ . _:b594469910 . _:b594468152 . _:b594469911 . _:b594468153 . _:b594468850 . _:b594469896 . _:b594468154 . _:b46911150 . _:b594469897 . _:b594468155 . _:b594469104 . _:b594468939 "2"^^ . _:b594469898 . _:b594468156 . _:b594469899 . _:b594468157 . _:b594469900 . _:b594468158 . _:b594469901 . _:b594468159 . _:b594469107 . _:b594468938 "2"^^ . _:b594469902 . _:b594468144 . _:b594469903 . _:b594468145 . _:b594469888 . _:b594468146 . _:b594469889 . _:b594468147 . _:b46911370 "lymphomaFDA Approved in 2012ConventionalAllen and Cullis, 2013; Wang et al., 2015TretinoinAcute promyelocytic leukemia and hormone-refractory prostate cancerPhase IIConventionalOzpolat et al., 2003; Immordino et al., >>2006< . _:b594468949 "2"^^ . _:b594469890 . _:b594468148 . _:b594469891 . _:b594468149 . _:b46911146 . _:b594469892 . _:b594468150 . _:b594468442 . . _:b594469893 . _:b594468151 . _:b594469117 . _:b594468948 "2"^^ . _:b594469894 . _:b594468136 . _:b594469895 . _:b594468137 . _:b46911305 "targeting (Dicheva et al., 2013, 2014), with promising results showing doxorubicin-encapsulated CTSLs having three-fold higher accumulation at the target site compared to the thermosensitive liposomal formulation (Dicheva et al., >>2014<<). Translation of these drug delivery systems into the clinic has not yet been successful, with issues surrounding therapeutic efficacy (e.g., location of diseased tissue and accessibility for remote triggers) and potential toxicity of" . _:b594469944 . _:b594468138 . _:b594469945 . _:b594468139 . _:b594469554 . _:b594469116 . _:b594468951 "2"^^ . _:b594469946 . _:b594468140 . _:b594469947 . _:b594468141 . _:b594469948 . _:b594468142 . _:b594469617 . _:b594468846 . _:b594469949 . _:b594468143 . _:b594469119 . _:b594468950 "2"^^ . . _:b594469950 . _:b594468128 . _:b46911400 . . _:b594468129 . . _:b594469936 . _:b594468130 . _:b594469937 . _:b594468131 . _:b594469118 . _:b594468945 "2"^^ . _:b594469938 . _:b594468132 . _:b594469939 . _:b594468133 . _:b594468515 . _:b594469940 . _:b594468134 . _:b594469941 . _:b594468135 . _:b594469113 . _:b594468944 "2"^^ . _:b594469942 . _:b594468184 . _:b594469247 . _:b594469943 . _:b594468185 . _:b594469928 . _:b594468186 . _:b594469929 . _:b594468187 . _:b594469112 . _:b594468947 "2"^^ . _:b594469930 . _:b594468188 . _:b594469931 . _:b594468189 . . _:b594469932 . _:b594468190 . _:b594469933 . _:b594468191 . _:b594469115 . _:b594468946 "2"^^ . _:b594469934 . _:b594468176 . _:b594469935 . _:b594468177 . _:b594469920 . _:b594468178 . _:b594469921 . _:b594468179 . _:b594469114 . _:b594468957 "2"^^ . _:b594468937 . _:b594468514 . _:b594469922 . _:b594468180 . _:b46911399 . _:b594469917 . _:b594469923 . _:b594468181 . _:b594469924 . _:b594468182 . _:b594468168 . _:b594469925 . _:b594468183 . _:b594468956 "2"^^ . . _:b594469926 . _:b594468168 . . _:b594469927 . . _:b594468169 . _:b594468170 . . _:b594468171 . _:b594468959 "2"^^ . _:b594468708 . . . _:b46911319 . _:b594468172 . _:b594468173 . _:b594468174 . _:b594469879 . _:b594468175 . _:b594468958 "2"^^ . _:b594468160 . _:b594468161 . _:b594468162 . _:b594468163 . _:b594468953 "2"^^ . _:b594468164 . _:b594468475 . _:b594468165 . _:b594468166 . _:b594468167 . _:b594468952 "2"^^ . . _:b594468216 . _:b594468217 . . . _:b594468218 . _:b594469434 . _:b594468219 . _:b594468955 "2"^^ . _:b594468220 . _:b594468221 . _:b594469916 . _:b594468222 . . _:b594468223 . _:b594469703 . _:b594468954 "2"^^ . _:b594468208 . _:b594468209 . _:b594468210 . _:b594468211 . _:b594468965 "2"^^ . . _:b594468212 . _:b594468213 . _:b594468214 . _:b594468215 . _:b594468964 "2"^^ . _:b594468200 . _:b594468201 . _:b594469020 . _:b594468202 . _:b594469115 . _:b594468203 . _:b594468967 "2"^^ . _:b594468204 . _:b46911417 . _:b594468199 . . _:b594468205 . _:b594468206 . _:b594468798 . _:b594468207 . _:b594468966 "2"^^ . _:b594468192 . _:b46911243 . _:b594468193 . _:b594468194 . . _:b594468195 . _:b594468961 "2"^^ . _:b594468196 . _:b594468197 . _:b594468198 . . _:b594468199 . _:b594469761 . _:b594468960 "2"^^ . _:b594468456 . . _:b594468963 "2"^^ . _:b594468767 . _:b594468389 . _:b594468962 "2"^^ . _:b594469667 . _:b594468973 "2"^^ . . _:b594468972 "2"^^ . _:b594468975 "2"^^ . _:b46911146 "Research on the clinical potential of conventional liposomes began in the 1980s, whereby liposomal delivery proved useful for improving the therapeutic index of encapsulated drugs, such as doxorubicin and amphotericin (Gabizon et al., >>1982<<; Koning and Storm, 2003; Metselaar and Storm, 2005; Ding et al., 2006; Hua and Wu, 2013)." . _:b594468974 "2"^^ . _:b46911134 "Furthermore, the large aqueous center and biocompatible lipid exterior permits the delivery of a variety of macromolecules, such as DNA, proteins and imaging agents (Ulrich, 2002; Monteiro et al., >>2014<<). As a drug delivery system, liposomes offer several advantages including biocompatibility, capacity for self-assembly, ability to carry large drug payloads, and a wide range of physicochemical and biophysical properties that can be" . . _:b594469646 . _:b594469180 . _:b594468969 "2"^^ . _:b46911411 . _:b594468962 . _:b594468968 "2"^^ . . _:b594469212 . _:b594468912 . _:b594468971 "2"^^ . . _:b594468970 "2"^^ . . _:b594468225 . _:b594468981 "2"^^ . _:b46911260 . _:b594468980 "2"^^ . _:b594469777 . . _:b594468983 "2"^^ . . . _:b594468982 "2"^^ . _:b594469000 . _:b594468222 . _:b594468736 . _:b594468977 "2"^^ . . . _:b594468976 "2"^^ . _:b594469852 . _:b594468979 "2"^^ . _:b594468978 "2"^^ . _:b594469597 . _:b594468150 . _:b594468989 "2"^^ . . . _:b594468988 "2"^^ . _:b594468806 . _:b594468991 "2"^^ . _:b594468990 "2"^^ . _:b594469673 . _:b594468985 "2"^^ . . _:b594469340 . _:b594469819 . . _:b594468984 "2"^^ . _:b594469942 . _:b594468987 "2"^^ . . _:b594468986 "2"^^ . _:b594468997 "2"^^ . . _:b594468996 "2"^^ . _:b594469910 . . . _:b594468999 "2"^^ . _:b594468646 . . _:b594468998 "2"^^ . _:b594469901 . _:b46911190 "Generally, large unmodified liposomes are eliminated more rapidly than small, neutral, or positively charged liposomes (Oku and Namba, 1994; Laverman et al., >>1999<<; Ulrich, 2002)." . _:b594468993 "2"^^ . _:b594469838 . _:b594468992 "2"^^ . . _:b594469725 . _:b594468995 "2"^^ . . _:b594468145 . _:b594468994 "2"^^ . _:b594469005 "2"^^ . . _:b46911259 . _:b594469004 "2"^^ . _:b594468491 . _:b594468986 . . _:b46911181 "Conjugation of PEG polymers to the liposomal membrane is a key strategy for improving circulation times and preventing removal by the RES through steric stabilization (Oku and Namba, 1994; Ishida et al., 2001a). PEGylation creates a local surface concentration of highly hydrated groups, which sterically inhibits both electrostatic and hydrophobic reactions with plasma proteins and/or cells and thereby reduces liposomal uptake by the RES (Ishida" . _:b594469007 "2"^^ . . . _:b594469006 "2"^^ . . _:b46911262 . . . _:b594469001 "2"^^ . . . _:b46911394 . _:b594469000 "2"^^ . . _:b594468079 . _:b594469139 . . . _:b594469003 "2"^^ . . _:b594469002 "2"^^ . _:b594469013 "2"^^ . _:b594469012 "2"^^ . . _:b594468202 . . _:b594469015 "2"^^ . _:b594469616 . . . _:b594469014 "2"^^ . . . _:b594469009 "2"^^ . . _:b594469008 "2"^^ . . _:b594469011 "2"^^ . . _:b594469010 "2"^^ . . _:b594468365 . _:b594469021 "2"^^ . _:b594469380 . _:b594469781 . _:b594469020 "2"^^ . _:b594468366 . _:b594469023 "2"^^ . _:b594469689 . . . . _:b594469022 "2"^^ . _:b594469017 "2"^^ . _:b46911247 . . _:b46911234 "This pseudoallergy is thought to be partly due to the activation of the complement system with the subsequent generation of C3 split-products (e.g., C3d) (Dempsey et al., 1996) and anaphylatoxins C3a and C5a (Szebeni, >>2005<<; Szebeni and Moghimi, 2009)." . _:b594468638 . _:b594469016 "2"^^ . _:b594469868 . _:b594468947 . . _:b594469019 "2"^^ . . _:b594469903 . _:b594469018 "2"^^ . _:b594469029 "2"^^ . _:b594468137 . _:b594468385 . _:b594468842 . _:b46911126 "introduction" . _:b594469028 "2"^^ . . _:b594469031 "2"^^ . . _:b594469030 "2"^^ . . _:b594469025 "2"^^ . . _:b594469024 "2"^^ . _:b594469027 "2"^^ . . _:b594469026 "2"^^ . _:b46911218 "Subsequent investigations have verified these findings, with a maximum clearance of liposomes 4\u20137 days after the initial dose in rats and 10 days in mice (Ishida et al., 2003, 2006b)." . _:b46911255 "and particularly following parenteral administration (e.g., intravenous and intraperitoneal injection) (Torchilin, 1994; Vingerhoeds et al., 1994; Willis and Forssen, 1998; Noble et al., 2004; Deshpande et al., 2013; Hua and Cabot, >>2013<<; Rip et al., 2014; Hua et al., 2015). Targeting ligands are used to increase the specificity of delivery of encapsulated cargo to and retain it in diseased tissues and cells, with minimal deposition in non-target sites." . _:b594469037 "2"^^ . . _:b594469036 "2"^^ . . _:b594469039 "2"^^ . . . _:b594469038 "2"^^ . _:b594468625 . . _:b594469014 . _:b594469033 "2"^^ . _:b594469881 . _:b594469032 "2"^^ . _:b594469035 "2"^^ . . . _:b594469034 "2"^^ . _:b594469045 "2"^^ . . _:b594469720 . . _:b594469044 "2"^^ . . . . _:b594469047 "2"^^ . _:b594469046 "2"^^ . _:b594469907 . . _:b594469041 "2"^^ . . _:b594469040 "2"^^ . _:b46911272 . _:b594469043 "2"^^ . . _:b594469721 . _:b594469042 "2"^^ . _:b46911316 . _:b594468885 . _:b594469053 "2"^^ . _:b46911275 . _:b594469052 "2"^^ . . _:b594468961 . _:b594469055 "2"^^ . . _:b594469471 . _:b594469355 . _:b594468488 . _:b594469054 "2"^^ . _:b46911278 . _:b594469710 . . _:b594469049 "2"^^ . _:b594469048 "2"^^ . _:b594469051 "2"^^ . _:b594468539 . . . _:b594469050 "2"^^ . _:b46911269 . . _:b594469061 "2"^^ . . _:b594469060 "2"^^ . . _:b594469063 "2"^^ . _:b594468560 . _:b594469062 "2"^^ . _:b46911194 "Previous investigation has revealed that large, charged liposomes are cleared within minutes by the liver and less than an hour by the spleen (Senior, >>1987<<; Chrai et al., 2002)." . . _:b594469057 "2"^^ . . _:b594469056 "2"^^ . . _:b46911266 "antibodies to the surface of loperamide-encapsulated liposomes, demonstrated increased efficacy and localization of the targeted nanoparticles to peripheral inflammatory tissue in a rodent model of musculoskeletal pain (Hua and Cabot, >>2013<<). Conversely, there are studies that have shown no difference in the biodistribution and target tissue accumulation of ligand-targeted liposomes compared with non-targeted liposomes." . _:b594469059 "2"^^ . . _:b594468627 . . _:b594468537 . _:b594469058 "2"^^ . _:b594469069 "2"^^ . . _:b594468388 . _:b594469068 "2"^^ . _:b594468077 . _:b594468865 . _:b594469071 "2"^^ . _:b594468076 . . _:b594469070 "2"^^ . _:b594469704 . _:b594469388 . _:b594469359 . _:b594468079 . _:b46911129 "therapeutic compounds, overcoming obstacles to cellular and tissue uptake, and improving biodistribution of compounds to target sites in vivo (Koning and Storm, 2003; Metselaar and Storm, 2005; Ding et al., 2006; Hua and Wu, >>2013<<). Liposomes are defined as phospholipid vesicles consisting of one or more concentric lipid bilayers enclosing discrete aqueous spaces." . _:b594469065 "2"^^ . _:b594468078 . _:b594469226 . _:b594469064 "2"^^ . . _:b594468604 . _:b594469067 "2"^^ . _:b594468102 . _:b594469066 "2"^^ . . . . _:b594468075 . . _:b594469077 "2"^^ . _:b46911168 "biological challenges facing liposomal drug delivery systems" . _:b594469911 . _:b594469076 "2"^^ . _:b594468085 . _:b594468856 . _:b594469079 "2"^^ . . _:b594469581 . _:b594468084 . _:b594469345 . _:b594469078 "2"^^ . _:b594468087 . _:b594469073 "2"^^ . _:b46911265 . _:b594468086 . _:b594469442 . _:b594469072 "2"^^ . _:b594468081 . _:b594469075 "2"^^ . . _:b594468080 . . . _:b594469074 "2"^^ . . . _:b594469949 . _:b594468083 . . _:b594469085 "2"^^ . . _:b594469370 . _:b594468082 . _:b594469084 "2"^^ . _:b46911214 . _:b594468093 . _:b594468893 . . . _:b594469087 "2"^^ . _:b594468092 . . _:b594469086 "2"^^ . _:b594468095 . _:b46911254 "applications, and particularly following parenteral administration (e.g., intravenous and intraperitoneal injection) (Torchilin, 1994; Vingerhoeds et al., 1994; Willis and Forssen, 1998; Noble et al., 2004; Deshpande et al., >>2013<<; Hua and Cabot, 2013; Rip et al., 2014; Hua et al., 2015)." . _:b594469081 "2"^^ . . _:b594468094 . _:b594469080 "2"^^ . _:b594469342 . _:b594468089 . . _:b594469063 . _:b594469349 . _:b594469083 "2"^^ . . _:b594468088 . _:b594469082 "2"^^ . _:b594468091 . _:b594469093 "2"^^ . _:b594468090 . . _:b594468624 . _:b594469092 "2"^^ . _:b594469524 . _:b594468149 . . _:b594469095 "2"^^ . _:b594469094 "2"^^ . _:b594469089 "2"^^ . . _:b46911289 . _:b594469088 "2"^^ . _:b594469091 "2"^^ . _:b594469228 . . _:b594469090 "2"^^ . _:b594469101 "2"^^ . _:b594469543 . _:b594469390 . _:b594468119 . _:b594469100 "2"^^ . _:b594469103 "2"^^ . _:b594468093 . . _:b594469102 "2"^^ . _:b594469110 . _:b594468159 . _:b594469097 "2"^^ . _:b46911227 . . _:b594469096 "2"^^ . . _:b594468595 . _:b594469099 "2"^^ . _:b594468439 . . _:b594469098 "2"^^ . _:b46911220 . . _:b594469109 "2"^^ . _:b46911223 . _:b594469108 "2"^^ . . . _:b594469111 "2"^^ . . _:b594469927 . _:b594469110 "2"^^ . _:b594468348 . _:b594469615 . _:b594468735 . _:b594469105 "2"^^ . . _:b594468096 . _:b594469104 "2"^^ . _:b46911218 . _:b594469107 "2"^^ . _:b46911407 "affect the biocompatibility, biodistribution and toxicology profile of liposomal formulations, and will require further evaluation to understand the interaction of the nanoparticles with biological tissues and cells (Allen and Cullis, >>2004<<, 2013; Zhang et al., 2008; Sawant and Torchilin, 2012; Narang et al., 2013; Tinkle et al., 2014)." . _:b594469106 "2"^^ . . _:b594469117 "2"^^ . _:b594469893 . _:b594469116 "2"^^ . _:b594468200 . _:b594468468 . _:b594469119 "2"^^ . _:b594469184 . _:b594469118 "2"^^ . . . _:b594468563 . _:b594469113 "2"^^ . _:b594469330 . _:b46911200 . _:b594469112 "2"^^ . _:b594468240 . . _:b594468839 . _:b594469115 "2"^^ . _:b594469490 . _:b594469114 "2"^^ . _:b594469015 . _:b594468451 . _:b594469410 . _:b594469333 . . _:b594469125 "2"^^ . _:b594469124 "2"^^ . _:b594469750 . _:b594469127 "2"^^ . _:b594469207 . . _:b594469126 "2"^^ . _:b46911211 . _:b594469121 "2"^^ . _:b594468919 . . _:b594469409 . _:b594469120 "2"^^ . _:b594469123 "2"^^ . . _:b594469122 "2"^^ . _:b594468214 . _:b594469133 "2"^^ . . _:b594468321 . . _:b594469132 "2"^^ . _:b594468984 . _:b594469135 "2"^^ . _:b594469134 "2"^^ . . . _:b46911364 . _:b594469129 "2"^^ . . . _:b594468982 . _:b594469128 "2"^^ . _:b594469131 "2"^^ . _:b594469130 "2"^^ . . _:b594468617 . _:b594469141 "2"^^ . . _:b594469140 "2"^^ . . _:b594468373 . _:b594469557 . . _:b594469143 "2"^^ . _:b594468396 . . _:b594468973 . _:b594469043 . _:b594469142 "2"^^ . _:b594469137 "2"^^ . . _:b594469136 "2"^^ . _:b594469139 "2"^^ . _:b594469455 . _:b594469660 . _:b594469138 "2"^^ . _:b594469147 . _:b46911353 "With non-cross resistance properties and an enhanced cellular uptake and retention, annamycin's efficacy and anti-tumor activity is enhanced with the use of a targeted liposomal-based delivery system (Zou et al., >>1994<<). These and more liposomal-based drugs that are FDA approved or currently in clinical trials are summarized in Table 1." . . _:b594469149 "2"^^ . _:b594469148 "2"^^ . _:b594468841 . _:b594469151 "2"^^ . _:b46911170 . _:b594469150 "2"^^ . _:b594469145 "2"^^ . . . _:b594469112 . _:b594469144 "2"^^ . . . . . _:b594469147 "2"^^ . _:b594469146 "2"^^ . _:b594469894 . _:b594469157 "2"^^ . . _:b594468861 . _:b46911202 . _:b594469156 "2"^^ . _:b594469159 "2"^^ . _:b46911201 . . _:b594468884 . _:b594469158 "2"^^ . _:b46911143 "Liposomes are generally considered to be pharmacologically inactive with minimal toxicity, as they tend to be composed of natural phospholipids (Koning and Storm, 2003; Metselaar and Storm, 2005; Ding et al., 2006; Hua and Wu, >>2013<<); however increasing number of studies have shown that liposomes are not as immunologically inert as once suggested (Szebeni and Moghimi, 2009)." . _:b594469153 "2"^^ . _:b594469126 . _:b594469152 "2"^^ . _:b594469144 . . _:b594469027 . _:b594469155 "2"^^ . . . _:b594468253 . _:b594469154 "2"^^ . _:b46911180 . _:b594469165 "2"^^ . _:b594468329 . . . _:b594469164 "2"^^ . _:b594469946 . . _:b594469167 "2"^^ . _:b594469166 "2"^^ . _:b594469161 "2"^^ . _:b46911184 . _:b46911322 . . _:b594469160 "2"^^ . . _:b46911362 "et al., 2012Mitoxantrone LEM-ETUAcute myeloid leukemia, multiple sclerosis, and prostate cancerPhase ICationicImmordino et al., 2006; Chang and Yeh, 2012VerteporfinMolecular degenerationFDA Approved in 2000CationicChang and Yeh, >>2012<<; Allen and Cullis, 2013; Gross et al., 2013AmikacinLung infectionPhase II/IIIConventionalChang and Yeh, 2012; Clancy et al., 2013; Olivier et al., 2014VincristineNon-Hodgkin lymphomaFDA Approved in 2012ConventionalAllen and Cullis, 2013;" . _:b46911323 . . _:b46911139 "by properties such as particle size, charge, number of lamellae, lipid composition, and surface modification with polymers and ligands\u2014these all govern their stability in vitro and in vivo (Hua and Wu, 2013; Monteiro et al., >>2014<<). Encapsulation within liposomes protects compounds from early inactivation, degradation and dilution in the circulation (Ulrich, 2002)." . _:b594469163 "2"^^ . _:b594468657 . _:b594469162 "2"^^ . _:b594469173 "2"^^ . . _:b594469172 "2"^^ . _:b594469788 . _:b46911216 . . _:b594469175 "2"^^ . _:b594469174 "2"^^ . _:b594469315 . . _:b594469447 . _:b594469306 . _:b594469169 "2"^^ . . _:b46911178 . . _:b594469168 "2"^^ . _:b594469171 "2"^^ . _:b594469105 . . _:b594468197 . _:b594468918 . _:b594469170 "2"^^ . _:b46911224 "Increasing the phospholipid dose has been suggested to cause PEG-reactive B cells to become apoptotic, reducing anti-PEG IgM production and thus abating the ABC phenomenon (Ishida et al., 2006b; Ishida and Kiwada, >>2008<<). The ABC phenomenon has not been reported to occur in patients receiving PLD, even after multiple-dosing regimens (Laverman et al., 2001). Generally higher doses (15 \u03BCmol phospholipid/kg) are administered clinically, which may account" . _:b46911314 "For example, Han et al. (>>2014<<) conjugated ECl-GLuc to nickel-chelating liposomes (ECl-GLuc-liposome), and demonstrated significant bioluminescence imaging and targeted drug delivery in both SKOv3 cells in vitro and in ErbB2-overexpressing metastatic ovarian tumors in" . _:b594469181 "2"^^ . _:b594468172 . _:b594469180 "2"^^ . . _:b594469787 . . _:b594469183 "2"^^ . _:b594468713 . _:b46911335 "For example, liposomal amphotericin B is in a prospective Phase II trial to test the safety and tolerability of high doses (Giannella et al., >>2015<<). Advantages of these marketed drugs include a reduced toxicity by increased vasculature permeability/accumulation at the target tissue and an ability to encapsulate drugs of different lipophilicities while protecting them from" . _:b594468156 . . _:b594469182 "2"^^ . . _:b594469176 . _:b594469177 "2"^^ . _:b594469486 . _:b46911261 "A number of studies have demonstrated enhanced uptake and efficacy of ligand-targeted liposomes in diseased tissue in comparison to non-targeted liposomes in vivo (Vingerhoeds et al., >>1994<<; Puri et al., 2009; Allen and Cullis, 2013; Kraft et al., 2014)." . _:b46911375 "et al., 2004; Suenaga et al., 2015AnnamycinAcute lymphoblastic leukemiaPhase I/IIConventionalWetzler et al., 2013Amphotericin BAnti-fungal prophylaxisFDA approved in 1997ConventionalChandrasekar, 2008; Allen and Cullis, >>2013< "2"^^ . _:b594468967 . _:b594469179 "2"^^ . . _:b46911189 . _:b594469312 . _:b594469178 "2"^^ . _:b594469556 . . . _:b594469189 "2"^^ . _:b594469188 "2"^^ . . . _:b594469191 "2"^^ . _:b594468453 . _:b594469190 "2"^^ . _:b594468883 . _:b594468963 . _:b594469185 "2"^^ . _:b594469184 "2"^^ . _:b46911273 . . _:b594469187 "2"^^ . _:b46911139 . _:b594469782 . _:b594469186 "2"^^ . _:b594469197 "2"^^ . _:b594469196 "2"^^ . _:b594469199 "2"^^ . . _:b46911215 . _:b594469198 "2"^^ . . . _:b594469193 "2"^^ . _:b594468377 . _:b594468556 . _:b594469192 "2"^^ . _:b594468166 . _:b46911212 . _:b594469195 "2"^^ . _:b594469194 "2"^^ . _:b594469205 "2"^^ . _:b46911385 "and neck cancerPhase I/IIConventionalDark et al., 2005; Chang and Yeh, 2012VinorelbineNewly diagnosed or relapsed solid tumorsPhase IConventionalAllen and Cullis, 2013TopotecanAdvanced solid tumorsPhase 1/IIConventionalSeiden et al., >>2004<<; Allen and Cullis, 2013NystatinFungal InfectionsPhase I/IIConventionalOffner et al., 2004DoxorubicinLeukemia, breast cancer, bone cancer, lung cancer, brain cancerFDA Approved in 1995PEGylatedNing et al., 2007Doxorubicin and" . . _:b594469204 "2"^^ . _:b594469553 . _:b594469862 . _:b594469207 "2"^^ . . _:b594468292 . _:b594469011 . _:b594469206 "2"^^ . _:b594469201 "2"^^ . . _:b594469200 "2"^^ . _:b594469670 . _:b594468357 "3"^^ . _:b594468672 . . _:b594469203 "2"^^ . _:b594468356 "3"^^ . _:b594469202 "2"^^ . _:b594468359 "3"^^ . _:b594468878 . _:b594468308 . _:b594469213 "2"^^ . _:b594468363 . _:b594468591 . _:b594468358 "3"^^ . . _:b594469212 "2"^^ . _:b594468353 "3"^^ . . _:b594469215 "2"^^ . _:b594469818 . . _:b594468352 "3"^^ . . _:b594469214 "2"^^ . _:b594468355 "3"^^ . _:b594469209 "2"^^ . _:b594469845 . _:b594468354 "3"^^ . _:b594468316 . _:b594469208 "2"^^ . _:b594468939 . . _:b594468365 "3"^^ . _:b594469211 "2"^^ . _:b594468868 . . _:b594468364 "3"^^ . . _:b594469325 . _:b594469210 "2"^^ . . _:b594468786 . . _:b594468367 "3"^^ . _:b594469221 "2"^^ . _:b594468161 . _:b594468217 . _:b594468366 "3"^^ . _:b594469220 "2"^^ . _:b46911163 "The coupling of antibodies, particularly monoclonal antibodies, to create immunoliposomes represents one of the more versatile ligands that can be affixed to liposome surfaces (Bendas, >>2001<<; Puri et al., 2009)." . _:b594468361 "3"^^ . . . _:b594469223 "2"^^ . _:b594468331 . _:b594468360 "3"^^ . _:b594469222 "2"^^ . _:b594469811 . _:b594468363 "3"^^ . _:b46911134 . _:b594469217 "2"^^ . _:b594468362 "3"^^ . . _:b594469216 "2"^^ . _:b594468373 "3"^^ . _:b594469354 . _:b594468477 . _:b594469219 "2"^^ . . _:b594468372 "3"^^ . _:b594468402 . _:b594469218 "2"^^ . _:b594468375 "3"^^ . _:b594469229 "2"^^ . _:b594468374 "3"^^ . _:b594469228 "2"^^ . _:b594468369 "3"^^ . _:b594469231 "2"^^ . _:b594468368 "3"^^ . _:b594469051 . . _:b594469230 "2"^^ . _:b594468371 "3"^^ . _:b594469225 "2"^^ . _:b594469004 . _:b594468586 . _:b594468370 "3"^^ . _:b594469224 "2"^^ . . _:b594468381 "3"^^ . . . . _:b46911374 "cancerPhase I/IIConventionalZhang et al., 2004; Suenaga et al., 2015AnnamycinAcute lymphoblastic leukemiaPhase I/IIConventionalWetzler et al., 2013Amphotericin BAnti-fungal prophylaxisFDA approved in 1997ConventionalChandrasekar, >>2008<<; Allen and Cullis, 2013DaunorubicinLeukemia and solid tumorsFDA Approved in 1996ConventionalChang and Yeh, 2012; Allen and Cullis, 2013Cytarabine or cytosine arabinosideNeoplastic meningitis and lymphomatous meningitisFDA" . _:b594469227 "2"^^ . _:b594468380 "3"^^ . . _:b594469226 "2"^^ . . . _:b594468383 "3"^^ . . . _:b594469237 "2"^^ . . _:b594468382 "3"^^ . _:b594469236 "2"^^ . _:b594468569 . _:b594468377 "3"^^ . _:b594469239 "2"^^ . _:b594468376 "3"^^ . _:b594469238 "2"^^ . _:b594468379 "3"^^ . _:b594469233 "2"^^ . _:b594468378 "3"^^ . _:b46911174 "Pore diameters in these capillaries can range from 100 to 800 nm, which is large enough for the extravasation and subsequent removal of most drug-loaded liposomes (50\u20131000 nm in size) (Sapra and Allen, >>2003<<). Liposomes are cleared in the RES by resident macrophages via direct interactions with the phagocytic cells (Chrai et al., 2002). Uptake of liposomes by the RES is typically secondary to vesicle opsonization\u2014that is, the adsorption of" . _:b594469232 "2"^^ . _:b594468389 "3"^^ . . . _:b594469235 "2"^^ . _:b594468388 "3"^^ . . _:b594469234 "2"^^ . _:b594468391 "3"^^ . _:b594469204 . _:b594468715 . _:b594469245 "2"^^ . _:b594468290 . _:b594468390 "3"^^ . _:b594469244 "2"^^ . . _:b594469470 . _:b594468385 "3"^^ . _:b594469247 "2"^^ . _:b594469933 . _:b594468384 "3"^^ . _:b594469246 "2"^^ . . _:b594468387 "3"^^ . . _:b594468246 . _:b594468414 . _:b594469241 "2"^^ . _:b594468264 . _:b594468386 "3"^^ . _:b594469149 . _:b594469240 "2"^^ . _:b594469049 . _:b594468397 "3"^^ . _:b594469243 "2"^^ . _:b594468396 "3"^^ . _:b46911170 "While these obstacles must be circumvented for optimal liposome function, other factors such as the enhanced permeability and retention (EPR) effect can be exploited to enhance drug delivery (Sawant and Torchilin, >>2012<<)." . _:b594469242 "2"^^ . _:b594468399 "3"^^ . . _:b594469253 "2"^^ . _:b594468398 "3"^^ . _:b594469252 "2"^^ . _:b594468393 "3"^^ . . _:b594469255 "2"^^ . _:b594468877 . _:b594468392 "3"^^ . _:b594468686 . _:b594469254 "2"^^ . _:b594468660 . _:b594468395 "3"^^ . . . _:b594469249 "2"^^ . _:b46911211 "Importantly, all types of liposomal delivery systems are subjected to the EPR effect, with PEGylated liposomes having an advantage due to having reduced RES clearance and extended circulation time (Sawant and Torchilin, >>2012<<)." . _:b594468394 "3"^^ . . _:b594469248 "2"^^ . _:b594469533 . _:b594468405 "3"^^ . _:b594469251 "2"^^ . _:b594468132 . _:b594468404 "3"^^ . _:b46911230 "In addition, CARPA has been reported with both experimental and clinically approved liposomal formulations (e.g., Doxil\u00AE, Ambisome, and DaunoXome\u00AE) (Szebeni, >>2005<<; Szebeni and Moghimi, 2009)." . . _:b594469250 "2"^^ . _:b594468185 . _:b594468407 "3"^^ . _:b594468423 . _:b46911381 "cytosine arabinosideNeoplastic meningitis and lymphomatous meningitisFDA ApprovedConventionalChang and Yeh, 2012; Jahn et al., 2015Morphine sulfatePain ManagementFDA Approved in 2004ConventionalChang and Yeh, 2012; Allen and Cullis, >>2013< "2"^^ . _:b594468406 "3"^^ . _:b594469260 "2"^^ . _:b594468401 "3"^^ . _:b594468859 . _:b594468891 . _:b594469263 "2"^^ . . _:b594468400 "3"^^ . _:b594468360 . _:b594469262 "2"^^ . _:b594468238 . _:b594468403 "3"^^ . _:b594469257 "2"^^ . . _:b594468402 "3"^^ . . _:b594469731 . . _:b594469707 . _:b594469256 "2"^^ . . _:b594468413 "3"^^ . . . _:b594469259 "2"^^ . _:b594468412 "3"^^ . _:b594469258 "2"^^ . _:b594468415 "3"^^ . _:b594468619 . _:b594469269 "2"^^ . _:b594469735 . _:b594468414 "3"^^ . _:b594469485 . . _:b594469268 "2"^^ . _:b594468409 "3"^^ . . _:b46911212 "For example, repeated injection of PEGylated liposomes has been associated with loss of their long circulating properties and subsequent clearance from the blood (Dams et al., >>2000<<; Ishida et al., 2003, 2006b)." . _:b594469719 . _:b594469271 "2"^^ . _:b594468408 "3"^^ . . _:b594469270 "2"^^ . _:b46911246 "being investigated in an effort to improve efficacy, reduce RES clearance and minimize toxicity\u2014this includes changes in lipid composition, charge, and the addition of surface coatings and ligands (Hua and Wu, 2013; Monteiro et al., >>2014<<). More recent strategies to improve on conventional or stealth liposomal systems involve active targeting, charged lipids, triggered release, and multi-functional formulations (Puri et al., 2009; Allen and Cullis, 2013; Bozzuto and" . _:b594468411 "3"^^ . . _:b594469265 "2"^^ . _:b594468410 "3"^^ . . . _:b594469264 "2"^^ . _:b594468421 "3"^^ . _:b594469267 "2"^^ . _:b594468420 "3"^^ . . _:b594469266 "2"^^ . _:b594469205 . . _:b594468423 "3"^^ . _:b594469764 . . _:b594468704 . . _:b594469277 "2"^^ . _:b594468422 "3"^^ . _:b594469276 "2"^^ . _:b594469912 . _:b594468417 "3"^^ . _:b46911308 . _:b594469279 "2"^^ . _:b594468416 "3"^^ . _:b594469278 "2"^^ . . _:b594469093 . _:b594468419 "3"^^ . . . _:b594469273 "2"^^ . _:b594468418 "3"^^ . . _:b594469272 "2"^^ . _:b594468429 "3"^^ . _:b594469042 . _:b594469275 "2"^^ . _:b594468428 "3"^^ . _:b594468995 . _:b594469274 "2"^^ . . _:b594468431 "3"^^ . _:b594469250 . _:b594469285 "2"^^ . _:b594468430 "3"^^ . . _:b594469284 "2"^^ . _:b594468425 "3"^^ . _:b594469287 "2"^^ . _:b594468424 "3"^^ . _:b594469140 . _:b594469286 "2"^^ . _:b594468892 . _:b594469307 . _:b594468427 "3"^^ . . _:b594469281 "2"^^ . _:b594469088 . _:b594468426 "3"^^ . _:b594469280 "2"^^ . _:b594468437 "3"^^ . . . _:b594469283 "2"^^ . _:b594468436 "3"^^ . _:b594469666 . _:b594469282 "2"^^ . _:b594468439 "3"^^ . . _:b594469293 "2"^^ . _:b46911185 "The degree of interaction between liposomal drug delivery systems and plasma proteins is important in determining overall nanocarrier biodistribution, efficacy, and toxicity (Hua and Wu, >>2013<<). Plasma proteins have been shown to play a pivotal role in liposomal clearance by the RES via opsonization, as well as in vesicular destabilization (Cullis et al., 1998)." . _:b594468438 "3"^^ . _:b594469292 "2"^^ . _:b594468433 "3"^^ . _:b594469295 "2"^^ . . _:b594468432 "3"^^ . . _:b594468502 . . _:b594469294 "2"^^ . . _:b594468435 "3"^^ . _:b594469190 . _:b594469289 "2"^^ . _:b594469404 . _:b594468434 "3"^^ . _:b594468163 . _:b594469870 . _:b594469288 "2"^^ . _:b594468838 . _:b594468445 "3"^^ . . _:b594469291 "2"^^ . _:b594468444 "3"^^ . _:b594469075 . _:b594469290 "2"^^ . _:b594468447 "3"^^ . _:b46911232 . _:b594469301 "2"^^ . . _:b594468446 "3"^^ . _:b594469300 "2"^^ . . _:b594468441 "3"^^ . _:b46911234 . . _:b594469303 "2"^^ . _:b594468440 "3"^^ . _:b46911317 . _:b594469302 "2"^^ . . _:b594468443 "3"^^ . _:b594469331 . _:b594468788 . _:b594469297 "2"^^ . _:b594468442 "3"^^ . . _:b594468282 . _:b594469296 "2"^^ . _:b594469944 . _:b46911202 "At these sites, deregulations in angiogenesis and/or the increased expression and activation of vascular permeability factors predominates (Nehoff et al., >>2014<<), which leads to fenestrations that can range from 300 to 4700 nm." . _:b594468453 "3"^^ . _:b46911284 "In particular, high amounts of eosinophil cationic protein and transferrin have been observed in inflamed colon sections in patients with inflammatory bowel disease (IBD) (Carlson et al., >>1999<<; Peterson et al., 2002; Tirosh et al., 2009)." . _:b594468493 . _:b594469299 "2"^^ . _:b46911398 . _:b594468452 "3"^^ . . _:b594469298 "2"^^ . . . _:b594468455 "3"^^ . _:b594469762 . _:b594469309 "2"^^ . _:b594468454 "3"^^ . _:b594469308 "2"^^ . _:b594468449 "3"^^ . . _:b46911249 "recent strategies to improve on conventional or stealth liposomal systems involve active targeting, charged lipids, triggered release, and multi-functional formulations (Puri et al., 2009; Allen and Cullis, 2013; Bozzuto and Molinari, >>2015<<)." . _:b594469311 "2"^^ . . _:b594468448 "3"^^ . . _:b594469310 "2"^^ . _:b594469242 . _:b594469936 . _:b594468451 "3"^^ . _:b594469305 "2"^^ . . _:b594468450 "3"^^ . _:b594469304 "2"^^ . _:b594468461 "3"^^ . . . _:b46911341 . _:b594469307 "2"^^ . _:b594468460 "3"^^ . _:b594468698 . . _:b594469306 "2"^^ . _:b594469865 . _:b594468463 "3"^^ . . _:b594469317 "2"^^ . _:b594468462 "3"^^ . . _:b594469316 "2"^^ . _:b594468457 "3"^^ . _:b594468441 . _:b594469319 "2"^^ . _:b594468456 "3"^^ . . _:b594469318 "2"^^ . _:b594468459 "3"^^ . _:b594469313 "2"^^ . _:b594468113 . _:b594468458 "3"^^ . . _:b594469312 "2"^^ . _:b594468958 . _:b594468469 "3"^^ . . _:b594469315 "2"^^ . _:b594468468 "3"^^ . _:b594468143 . _:b594468075 . _:b594468250 . _:b594469314 "2"^^ . . _:b594469875 . _:b594468471 "3"^^ . . _:b594469325 "2"^^ . . _:b594469772 . _:b594468470 "3"^^ . . . _:b594469324 "2"^^ . . _:b594468949 . _:b594468465 "3"^^ . _:b594469327 "2"^^ . _:b46911221 "This immune response is thought to be mediated by the spleen, as the degree of anti-PEG IgM production and the ABC phenomenon is dramatically decreased in splenectomized rats (Ishida et al., 2006a). Interestingly, administration of higher doses of the initial PEGylated liposomes (>1 \u03BCmol phospholipids/kg) have been shown to reduce the magnitude of the ABC phenomenon (Ishida et al., 2005). Increasing the phospholipid dose has been" . _:b46911410 . _:b594468464 "3"^^ . _:b594468302 . _:b594469326 "2"^^ . . _:b594468467 "3"^^ . _:b46911311 "to control drug release, delivery of a combination of therapeutics (e.g., siRNA and small molecule drugs), and biomarker and imaging capabilities (Zhang et al., 2011; Allen and Cullis, 2013; Charron et al., 2015; Cole and Holland, >>2015<<). In particular, theranostic nanoparticles have generated much interest as it is both a therapeutic and diagnostic tool all-in-one (Figure 1)." . _:b594469321 "2"^^ . _:b594468466 "3"^^ . _:b46911273 "Possible reasons for this discrepancy have previously been reviewed (Sawant and Torchilin, >>2012<<; Allen and Cullis, 2013), and include factors such as disease-dependent anatomical and physiological barriers, target accessibility and expression, and formulation stability." . _:b594469320 "2"^^ . _:b594468477 "3"^^ . _:b594469323 "2"^^ . _:b594468476 "3"^^ . . _:b594468478 . _:b594469322 "2"^^ . _:b594468479 "3"^^ . _:b594468410 . _:b594469333 "2"^^ . _:b46911231 "In addition, CARPA has been reported with both experimental and clinically approved liposomal formulations (e.g., Doxil\u00AE, Ambisome, and DaunoXome\u00AE) (Szebeni, 2005; Szebeni and Moghimi, >>2009<<). CARPA is an immediate, non-IgE-mediated hypersensitivity reaction that involves symptoms such as anaphylaxis, facial flushing, facial swelling, headache, chills, and cardiopulmonary distress (Szebeni, 2005\u2014the latter of which may limit" . _:b594468478 "3"^^ . _:b46911388 "et al., 2004; Allen and Cullis, 2013NystatinFungal InfectionsPhase I/IIConventionalOffner et al., 2004DoxorubicinLeukemia, breast cancer, bone cancer, lung cancer, brain cancerFDA Approved in 1995PEGylatedNing et al., >>2007< "2"^^ . _:b594468473 "3"^^ . _:b594469335 "2"^^ . _:b594468472 "3"^^ . _:b594469334 "2"^^ . . _:b594468475 "3"^^ . _:b594469329 "2"^^ . . _:b594468474 "3"^^ . _:b594469328 "2"^^ . _:b594468485 "3"^^ . . _:b594469331 "2"^^ . . _:b594468484 "3"^^ . _:b594468754 . _:b594468157 . _:b594469330 "2"^^ . _:b594468487 "3"^^ . . . . _:b594469341 "2"^^ . _:b594468486 "3"^^ . _:b594469340 "2"^^ . _:b594468481 "3"^^ . _:b46911369 . . _:b594469343 "2"^^ . _:b594468480 "3"^^ . . _:b594468620 . _:b594469342 "2"^^ . . _:b594468483 "3"^^ . _:b594468588 . _:b594469337 "2"^^ . . _:b594468482 "3"^^ . _:b594469336 "2"^^ . _:b594468254 . _:b594468493 "3"^^ . _:b594469339 "2"^^ . _:b594468492 "3"^^ . . . . _:b594469338 "2"^^ . _:b46911352 . _:b594468495 "3"^^ . . . _:b46911220 "Repeated injection of empty PEGylated liposomes in rats has been shown to elicit marked anti-PEG IgM production (Ishida et al., 2006b). This immune response is thought to be mediated by the spleen, as the degree of anti-PEG IgM production and the ABC phenomenon is dramatically decreased in splenectomized rats (Ishida et al., 2006a). Interestingly, administration of" . _:b594469349 "2"^^ . _:b594468494 "3"^^ . _:b594469348 "2"^^ . _:b594468489 "3"^^ . _:b594469258 . . _:b594469351 "2"^^ . _:b594468488 "3"^^ . _:b594468790 . _:b594469350 "2"^^ . _:b594468491 "3"^^ . _:b594468105 . . _:b594469345 "2"^^ . _:b594468490 "3"^^ . . _:b594469344 "2"^^ . _:b594468501 "3"^^ . _:b594469511 . _:b594469347 "2"^^ . _:b594469481 . _:b594468500 "3"^^ . . _:b594469346 "2"^^ . _:b594468272 . _:b594468503 "3"^^ . _:b594469148 . _:b594469491 . _:b594469357 "2"^^ . _:b594468502 "3"^^ . . _:b594469356 "2"^^ . _:b594468497 "3"^^ . _:b594469131 . _:b594469359 "2"^^ . _:b594468485 . _:b594468496 "3"^^ . _:b594469358 "2"^^ . _:b594469594 . _:b594468499 "3"^^ . . _:b594468392 . _:b594469353 "2"^^ . _:b594468498 "3"^^ . . _:b594469352 "2"^^ . _:b594468509 "3"^^ . . _:b594469355 "2"^^ . . _:b594468111 . . _:b594468508 "3"^^ . _:b594469354 "2"^^ . . . _:b594468511 "3"^^ . _:b594468959 . _:b46911155 . _:b594469365 "2"^^ . _:b594468510 "3"^^ . _:b594469364 "2"^^ . _:b594468505 "3"^^ . _:b46911288 "such as DNA and RNA, based on electrostatic interaction between the positively charged phospholipids [e.g., dioleoylphosphatidylethanolamine (DOPE)] and negatively charged nucleic acids (Felgner et al., 1987; Campbell et al., >>2002<<, 2009; Kunstfeld et al., 2003; Wu et al., 2007)." . _:b594468281 . _:b594469061 . _:b594469367 "2"^^ . _:b594469941 . _:b594468504 "3"^^ . _:b594469366 "2"^^ . _:b594468507 "3"^^ . _:b594469361 "2"^^ . _:b594468701 . _:b594468506 "3"^^ . _:b594469360 "2"^^ . _:b594468517 "3"^^ . _:b594469363 "2"^^ . . _:b594468516 "3"^^ . _:b594468416 . _:b594469362 "2"^^ . _:b594468519 "3"^^ . . _:b594469373 "2"^^ . . _:b46911391 "myelomaFDA Approved in 2007PEGylatedNing et al., 2007Thermosensitive doxorubicinLiver tumorsPhase IIIPEGylatedYarmolenko et al., 2010Thermosensitive doxorubicinChest wall recurrences of breast cancerPhase IPEGylatedYarmolenko et al., >>2010< "3"^^ . _:b594468635 . _:b594469372 "2"^^ . _:b594468224 . _:b594468513 "3"^^ . _:b594468812 . . _:b594469375 "2"^^ . _:b594468512 "3"^^ . _:b594469657 . _:b594469374 "2"^^ . _:b594468515 "3"^^ . . _:b46911169 "These defenses include the RES, opsonization, and immunogenicity (Willis and Forssen, >>1998<<). While these obstacles must be circumvented for optimal liposome function, other factors such as the enhanced permeability and retention (EPR) effect can be exploited to enhance drug delivery (Sawant and Torchilin, 2012)." . _:b594469369 "2"^^ . _:b594468514 "3"^^ . . . _:b594469245 . _:b594469368 "2"^^ . _:b46911195 "The inclusion of cholesterol is an important factor for increasing liposome stability and minimizing phospholipid exchange (Willis and Forssen, >>1998<<). Incorporation of cholesterol into the liposomal membrane abates lipid exchange with other circulating structures (e.g., red blood cells and lipoproteins) that can cause the depletion of high phase transition temperature lipids and their" . _:b594469479 . _:b594468525 "3"^^ . . _:b594469371 "2"^^ . _:b594468524 "3"^^ . _:b594469289 . _:b594469370 "2"^^ . _:b594468527 "3"^^ . _:b594468573 . _:b594468526 "3"^^ . . _:b594468346 . . _:b594468521 "3"^^ . _:b594468277 . _:b594468520 "3"^^ . _:b594468523 "3"^^ . _:b594468522 "3"^^ . _:b594469570 . . . _:b594469618 . _:b594468533 "3"^^ . _:b594469601 . _:b594468532 "3"^^ . . _:b594468535 "3"^^ . _:b594469197 . . _:b594468534 "3"^^ . . _:b594468529 "3"^^ . _:b594468500 . _:b594468659 . . _:b594469073 . _:b594468528 "3"^^ . _:b594469186 . _:b594468531 "3"^^ . _:b594469662 . . _:b46911177 "clinically important blockade of macrophage function in humans have not yet been demonstrated, there have been indirect signs that suggest the possibility of some immune suppression (Szebeni and Barenholz, 2009; Szebeni and Moghimi, >>2009<<). For example, administration of pegylated liposomal doxorubicin (PLD) (Doxil\u00AE) in mice showed a dose-dependent clearance saturation effect due to partial blockade of the RES in the liver." . _:b594468530 "3"^^ . _:b594469222 . _:b594468309 . . _:b594468541 "3"^^ . _:b594468372 . . _:b594468540 "3"^^ . _:b594468460 . _:b594468543 "3"^^ . . _:b46911303 . _:b594469765 . . _:b594468542 "3"^^ . _:b594469179 . . _:b594468537 "3"^^ . _:b46911348 "LEP-ETU is prepared in a 90:5:5 molar ratio of DOPC, cholesterol, and cardiolipin (Chang and Yeh, >>2012<<). Higher doses of LEP-ET can be safely administered compared to paclitaxel alone (Fetterly et al., 2008). Additionally, the use of cholesterol and cardiolipin allows for greater stability and reduced cardiotoxicity, respectively (Chang" . . _:b594468536 "3"^^ . . _:b594468539 "3"^^ . . . _:b46911186 "Plasma proteins have been shown to play a pivotal role in liposomal clearance by the RES via opsonization, as well as in vesicular destabilization (Cullis et al., >>1998<<). Opsonization of liposomes by serum proteins depends on a variety of factors including size, surface charge and stability (Cullis et al., 1998; Ishida et al., 2001a). The extent of this interaction has been shown to decrease with" . _:b594468538 "3"^^ . . _:b594469117 . _:b594468549 "3"^^ . . _:b594469292 . _:b594468548 "3"^^ . _:b594468551 "3"^^ . _:b594469259 . _:b594468550 "3"^^ . _:b594468545 "3"^^ . . _:b594468544 "3"^^ . _:b594469019 . . _:b594468547 "3"^^ . _:b594468297 . _:b594468546 "3"^^ . _:b594468244 . _:b594468557 "3"^^ . . . _:b594469070 . _:b594468556 "3"^^ . . _:b46911252 "at the experimental level for a variety of biomedical applications, and particularly following parenteral administration (e.g., intravenous and intraperitoneal injection) (Torchilin, 1994; Vingerhoeds et al., 1994; Willis and Forssen, >>1998<<; Noble et al., 2004; Deshpande et al., 2013; Hua and Cabot, 2013; Rip et al., 2014; Hua et al., 2015)." . _:b594468559 "3"^^ . . . . _:b594468558 "3"^^ . _:b46911396 "Similar obstacles are faced by other nano-delivery systems for translation into the clinic (Allen and Cullis, 2004, >>2013<<; Zhang et al., 2008; Sawant and Torchilin, 2012; Narang et al., 2013)." . _:b46911298 . _:b594468711 . _:b594468499 . _:b594468553 "3"^^ . . . _:b594468552 "3"^^ . _:b594469905 . _:b46911203 . _:b594468555 "3"^^ . . _:b46911160 "While coating liposomes with PEG results in prolonged circulation times, there can be an offsetting reduction in the ability to interact with the intended targets (Willis and Forssen, 1998; Ulrich, >>2002<<)." . _:b594468554 "3"^^ . _:b594468811 . _:b594468565 "3"^^ . _:b594468564 "3"^^ . . _:b594468567 "3"^^ . _:b46911150 "However, the delivery system was prone to rapid elimination from the bloodstream, therefore limiting its therapeutic efficacy (Gabizon et al., >>1991<<, 1994). This rapid clearance was due to opsonization of plasma components and uptake by fixed macrophages of the reticuloendothelial system (RES), mainly in the liver and spleen (Hua and Wu, 2013)." . _:b594468566 "3"^^ . _:b46911164 . _:b594468561 "3"^^ . _:b594468776 . . _:b46911411 "formulations, and will require further evaluation to understand the interaction of the nanoparticles with biological tissues and cells (Allen and Cullis, 2004, 2013; Zhang et al., 2008; Sawant and Torchilin, 2012; Narang et al., >>2013<<; Tinkle et al., 2014). Improvements in the regulatory framework for the assessment of nanoformulations will require consultation with academia and industry." . _:b594468560 "3"^^ . _:b594469659 . . _:b594469545 . _:b594468536 . _:b46911166 . _:b594468563 "3"^^ . . _:b594468562 "3"^^ . _:b594468262 . _:b594468573 "3"^^ . _:b46911401 "Suitable methods for the industrial scale production of conventional liposomes have been successfully developed, without the need for numerous manufacturing steps or the use of organic solvents (Jaafar-Maalej et al., >>2012<<; Kraft et al., 2014)." . . _:b594468572 "3"^^ . . . _:b594468575 "3"^^ . . . _:b594469727 . _:b594468574 "3"^^ . _:b46911174 . . . _:b594468569 "3"^^ . _:b594468649 . _:b594469541 . _:b594468568 "3"^^ . . _:b594468571 "3"^^ . . _:b594468570 "3"^^ . _:b46911354 "DrugDiseaseStatusType of liposomal-based delivery systemSource(s)Paclitaxel LEP-ETUAdvanced triple-negative breast cancerPhase I/IIsiRNAZhang et al., >>2005<<; Immordino et al., 2006siRNAOvarian cancerPhase IDOPC neutral liposomesMangala et al., 2009Paclitaxel EndoTAG-1Advanced triple-negative breast cancerPhase IICationicChang and Yeh, 2012; Awada et al., 2014Paclitaxel EndoTAG-1Pancreatic" . _:b594468581 "3"^^ . . . _:b594468304 . _:b594469614 . _:b594468580 "3"^^ . _:b594469675 . _:b594469374 . _:b594468349 . _:b594469185 . _:b594469287 . _:b594468583 "3"^^ . . _:b594469038 . . _:b594468582 "3"^^ . . _:b594468577 "3"^^ . _:b46911263 "A number of studies have demonstrated enhanced uptake and efficacy of ligand-targeted liposomes in diseased tissue in comparison to non-targeted liposomes in vivo (Vingerhoeds et al., 1994; Puri et al., 2009; Allen and Cullis, >>2013<<; Kraft et al., 2014)." . _:b594468576 "3"^^ . . _:b594468579 "3"^^ . . _:b594468455 . . _:b594468578 "3"^^ . _:b594469128 . _:b594468589 "3"^^ . _:b594468588 "3"^^ . . _:b594468591 "3"^^ . . _:b594468692 . _:b594468590 "3"^^ . _:b594468585 "3"^^ . _:b594469774 . . _:b594468440 . _:b594468584 "3"^^ . _:b594469840 . . _:b594468697 . _:b594468587 "3"^^ . _:b594469350 . _:b594468586 "3"^^ . _:b46911382 "and Yeh, 2012; Jahn et al., 2015Morphine sulfatePain ManagementFDA Approved in 2004ConventionalChang and Yeh, 2012; Allen and Cullis, 2013LurtotecanOvarian cancer, head, and neck cancerPhase I/IIConventionalDark et al., >>2005<<; Chang and Yeh, 2012VinorelbineNewly diagnosed or relapsed solid tumorsPhase IConventionalAllen and Cullis, 2013TopotecanAdvanced solid tumorsPhase 1/IIConventionalSeiden et al., 2004; Allen and Cullis, 2013NystatinFungal InfectionsPhase" . . _:b594468597 "2"^^ . . _:b46911188 . _:b594468863 . _:b594468596 "3"^^ . _:b594469040 . _:b594468599 "2"^^ . _:b594468598 "2"^^ . . . _:b594468593 "3"^^ . . _:b594469151 . _:b594468426 . _:b594468528 . . _:b594468592 "3"^^ . _:b46911193 . _:b594468595 "3"^^ . . . _:b594468606 . _:b594468594 "3"^^ . _:b46911158 "et al., 1993), with reported half-lives varying from 2 to 24 h in rodents (mice and rats) and as high as 45 h in humans, depending on the particle size and the characteristics of the coating polymer (Allen, 1994; Moghimi and Szebeni, >>2003<<). While coating liposomes with PEG results in prolonged circulation times, there can be an offsetting reduction in the ability to interact with the intended targets (Willis and Forssen, 1998; Ulrich, 2002)." . _:b594468605 "2"^^ . _:b594469120 . _:b594469518 . . _:b594468604 "2"^^ . . . _:b594468092 . _:b594468607 "2"^^ . . _:b594468606 "2"^^ . . _:b594468601 "2"^^ . _:b594469099 . _:b594468600 "2"^^ . _:b594469059 . _:b594468952 . _:b594468603 "2"^^ . _:b594469866 . _:b594468182 . _:b46911329 "Liposomal amphotericin B for anti-fungal prophylaxis (Chandrasekar, 2008), daunorubicin for the treatment of leukemia and solid tumors (Chang and Yeh, >>2012<<), verteporfin to treat macular degeneration (Chang and Yeh, 2012), cytarabine or cytosine arabinoside to treat neoplastic meningitis and lymphomatous meningitis (Chang and Yeh, 2012; Jahn et al., 2015), and morphine sulfate for pain" . _:b594468602 "2"^^ . . _:b594468613 "2"^^ . _:b46911175 . _:b594468612 "2"^^ . . . _:b46911302 "Upon heating, these liposomes undergo a phase change that makes them more permeable, causing the release of their cargo (Kono, >>2001<<). Recent studies have investigated the use of cationic thermosensitive liposomes (CTSL) for tumor targeting (Dicheva et al., 2013, 2014), with promising results showing doxorubicin-encapsulated CTSLs having three-fold higher accumulation" . _:b594468615 "2"^^ . _:b594469303 . _:b594468623 . . . . . _:b594468614 "2"^^ . _:b594469814 . . _:b594468097 . . _:b594468609 "2"^^ . . . _:b594468358 . _:b594468608 "2"^^ . _:b594468632 . _:b594468611 "2"^^ . . _:b594468610 "2"^^ . _:b46911182 . . _:b594468621 "2"^^ . _:b594468511 . . _:b594468620 "2"^^ . _:b594468623 "2"^^ . _:b46911181 . _:b594469344 . . . _:b594468622 "2"^^ . _:b594468617 "2"^^ . _:b594469742 . _:b594468590 . . _:b594468568 . _:b594468616 "2"^^ . . _:b46911147 "potential of conventional liposomes began in the 1980s, whereby liposomal delivery proved useful for improving the therapeutic index of encapsulated drugs, such as doxorubicin and amphotericin (Gabizon et al., 1982; Koning and Storm, >>2003<<; Metselaar and Storm, 2005; Ding et al., 2006; Hua and Wu, 2013)." . _:b594468473 . _:b594468619 "2"^^ . . _:b594468618 "2"^^ . _:b46911198 "red blood cells and lipoproteins) that can cause the depletion of high phase transition temperature lipids and their replacement with less physiologically stable components (Willis and Forssen, 1998; Laverman et al., 1999; Ulrich, >>2002<<). Integrating cholesterol into small (approximately 100 nm), electrostatically neutral liposomes has been shown to prolong circulation time in the range of several hours (Geng et al., 2014)." . _:b594468422 . _:b594468629 "2"^^ . . _:b594469171 . _:b594468628 "2"^^ . _:b46911410 "profile of liposomal formulations, and will require further evaluation to understand the interaction of the nanoparticles with biological tissues and cells (Allen and Cullis, 2004, 2013; Zhang et al., 2008; Sawant and Torchilin, >>2012<<; Narang et al., 2013; Tinkle et al., 2014). Improvements in the regulatory framework for the assessment of nanoformulations will require consultation with academia and industry." . . _:b594468631 "2"^^ . . _:b594468630 "2"^^ . _:b594468625 "2"^^ . _:b594468445 . _:b594469699 . _:b594468624 "2"^^ . _:b594468627 "2"^^ . _:b46911387 . _:b46911372 "promyelocytic leukemia and hormone-refractory prostate cancerPhase IIConventionalOzpolat et al., 2003; Immordino et al., 2006Irinotecan SN-38Metastatic colorectal cancerPhase I/IIConventionalZhang et al., 2004; Suenaga et al., >>2015< . _:b594469459 . _:b594469365 . _:b594468626 "2"^^ . _:b594468637 "2"^^ . . . _:b594468636 "2"^^ . . _:b594468256 . _:b594468639 "2"^^ . _:b594468638 "2"^^ . _:b594468774 . _:b594468633 "2"^^ . _:b594469693 . _:b594468632 "2"^^ . _:b594469805 . _:b594469652 . _:b594468635 "2"^^ . _:b46911237 . _:b594468600 . _:b594469757 . . _:b594468634 "2"^^ . _:b594468269 . _:b594468645 "2"^^ . _:b594468696 . _:b594468644 "2"^^ . _:b594468613 . . . _:b594468647 "2"^^ . _:b594468932 . . _:b594468646 "2"^^ . _:b594469734 . _:b594468641 "2"^^ . _:b594468876 . _:b594468450 . _:b594468945 . _:b594468992 . _:b594468640 "2"^^ . _:b594468747 . _:b594468643 "2"^^ . _:b594468895 . . _:b594468642 "2"^^ . _:b594468350 . _:b594468653 "2"^^ . . _:b594468196 . _:b594468653 . _:b594468652 "2"^^ . _:b594468411 . . _:b594468655 "2"^^ . _:b594468654 "2"^^ . _:b594469516 . . _:b594468649 "2"^^ . . _:b594468809 . . _:b594468648 "2"^^ . . . _:b594468651 "2"^^ . _:b594469784 . _:b594468489 . . _:b594468650 "2"^^ . _:b594468661 "2"^^ . _:b594469012 . _:b594469456 . _:b594469860 . _:b594468660 "2"^^ . _:b594468976 . . . _:b594468663 "2"^^ . _:b594468242 . . _:b594468662 "2"^^ . _:b594468230 . . _:b594468657 "2"^^ . _:b594468342 . _:b594469931 . _:b594468656 "2"^^ . . _:b594469821 . _:b594468659 "2"^^ . _:b594468658 "2"^^ . . _:b594468669 "2"^^ . . _:b594468668 "2"^^ . _:b594468671 "2"^^ . _:b594468670 "2"^^ . _:b594468424 . . _:b594468665 "2"^^ . _:b594469755 . . _:b594468664 "2"^^ . _:b594468667 "2"^^ . . _:b594468666 "2"^^ . . _:b594468677 "2"^^ . . _:b594468676 "2"^^ . _:b594468799 . _:b594468076 . . . . _:b594468679 "2"^^ . _:b594468345 . . _:b594468678 "2"^^ . . . . _:b594468673 "2"^^ . _:b594468672 "2"^^ . . _:b594468675 "2"^^ . _:b594468674 "2"^^ . _:b594469786 . _:b46911281 . _:b594469424 . _:b594469889 . _:b594469824 . _:b594468685 "2"^^ . _:b594469137 . _:b594468684 "2"^^ . . . _:b594468879 . _:b594468687 "2"^^ . _:b594468686 "2"^^ . _:b46911409 "biodistribution and toxicology profile of liposomal formulations, and will require further evaluation to understand the interaction of the nanoparticles with biological tissues and cells (Allen and Cullis, 2004, 2013; Zhang et al., >>2008<<; Sawant and Torchilin, 2012; Narang et al., 2013; Tinkle et al., 2014). Improvements in the regulatory framework for the assessment of nanoformulations will require consultation with academia and industry." . _:b594468681 "2"^^ . . . _:b594468181 . . _:b594469100 . . _:b594468680 "2"^^ . _:b594468683 "2"^^ . . . . _:b594468682 "2"^^ . . _:b594468565 . _:b594468693 "2"^^ . _:b594468680 . _:b594468642 . _:b594468692 "2"^^ . . _:b594469558 . _:b594469636 . _:b594468695 "2"^^ . . _:b594468629 . _:b594468694 "2"^^ . . _:b594468689 "2"^^ . _:b594468688 "2"^^ . _:b594469561 . _:b594469283 . _:b594468512 . _:b594468691 "2"^^ . . _:b46911403 "synthesis steps and formulation processes, which inevitably pose problems for large scale good manufacturing (cGMP) production, increases the cost of production, and makes the evaluation of such products more difficult (Teli et al., >>2010<<; Tinkle et al., 2014)." . _:b594469301 . _:b594469172 . . _:b594468690 "2"^^ . _:b594468718 . _:b594468701 "2"^^ . . _:b594469025 . _:b594468700 "2"^^ . _:b594468147 . _:b594468647 . . _:b594468703 "2"^^ . _:b594468397 . _:b594468854 . _:b594468702 "2"^^ . . _:b594468697 "2"^^ . _:b594469132 . . _:b594468696 "2"^^ . _:b594468699 "2"^^ . _:b594469441 . . _:b594469264 . _:b594468698 "2"^^ . . . _:b594469732 . _:b46911364 "myeloid leukemia, multiple sclerosis, and prostate cancerPhase ICationicImmordino et al., 2006; Chang and Yeh, 2012VerteporfinMolecular degenerationFDA Approved in 2000CationicChang and Yeh, 2012; Allen and Cullis, 2013; Gross et al., >>2013< "2"^^ . _:b594468730 . _:b594468898 . _:b594468708 "2"^^ . . _:b594468711 "2"^^ . . . . _:b46911201 "Liposomes that have evaded both the RES and opsonization are subjected to the EPR effect (Sawant and Torchilin, 2012; Nehoff et al., >>2014<<). The EPR effect refers to the increased permeability of the vasculature that supplies pathological tissues (e.g., tumors and conditions involving inflammation)." . _:b46911262 "A number of studies have demonstrated enhanced uptake and efficacy of ligand-targeted liposomes in diseased tissue in comparison to non-targeted liposomes in vivo (Vingerhoeds et al., 1994; Puri et al., >>2009<<; Allen and Cullis, 2013; Kraft et al., 2014)." . _:b594468710 "2"^^ . _:b594468779 . _:b594468702 . _:b594468705 "2"^^ . _:b46911391 . _:b594468704 "2"^^ . _:b46911390 . _:b594468662 . _:b594469842 . _:b594468707 "2"^^ . _:b594468816 . _:b594468706 "2"^^ . . . _:b594468717 "2"^^ . . _:b594468268 . _:b46911290 . _:b594468716 "2"^^ . . _:b594468543 . _:b594468719 "2"^^ . . . _:b594469302 . _:b594468718 "2"^^ . _:b594468858 . _:b594468713 "2"^^ . _:b594468712 "2"^^ . . _:b594469642 . _:b594468933 . _:b594469938 . _:b46911163 . . _:b594468715 "2"^^ . . . _:b594468714 "2"^^ . _:b594468725 "2"^^ . _:b594469402 . . . _:b594468724 "2"^^ . . _:b594468727 "2"^^ . _:b594468797 . _:b594468470 . _:b594468726 "2"^^ . _:b594468721 "2"^^ . _:b594469874 . _:b594469754 . _:b594468211 . . _:b594468720 "2"^^ . _:b594468723 "2"^^ . . _:b594468722 "2"^^ . _:b46911373 . _:b46911365 "et al., 2006; Chang and Yeh, 2012VerteporfinMolecular degenerationFDA Approved in 2000CationicChang and Yeh, 2012; Allen and Cullis, 2013; Gross et al., 2013AmikacinLung infectionPhase II/IIIConventionalChang and Yeh, >>2012<<; Clancy et al., 2013; Olivier et al., 2014VincristineNon-Hodgkin lymphomaFDA Approved in 2012ConventionalAllen and Cullis, 2013; Wang et al., 2015TretinoinAcute promyelocytic leukemia and hormone-refractory prostate cancerPhase" . . . _:b594468733 "2"^^ . _:b594469285 . _:b594468732 "2"^^ . _:b594469677 . . _:b594468574 . _:b594468735 "2"^^ . _:b594468998 . _:b594469501 . . _:b594468734 "2"^^ . _:b594468729 "2"^^ . _:b594468728 "2"^^ . _:b594468731 "2"^^ . _:b594468110 . . _:b594468730 "2"^^ . _:b594468741 "2"^^ . _:b594468981 . _:b594468740 "2"^^ . . . _:b594468743 "2"^^ . _:b594469532 . . _:b594468742 "2"^^ . _:b594468953 . _:b594468127 . . _:b594468737 "2"^^ . _:b594469150 . _:b46911155 "This not only reduces the elimination of drugs by prolonging blood circulation and providing accumulation at pathological sites, but also attenuates side effects (Torchilin et al., 1992; Northfelt et al., 1996; Ishida et al., 2001b). Steric stabilization strongly influences the pharmacokinetics of liposomes (Gabizon et al., 1993), with reported half-lives varying from 2 to 24 h in rodents (mice and rats) and as high as 45 h in humans, depending on the particle size" . . _:b594468736 "2"^^ . _:b594469319 . . . _:b594468739 "2"^^ . _:b594468585 . _:b594468241 . _:b594468738 "2"^^ . _:b594469199 . _:b594469406 . . _:b594469231 . _:b594468749 "2"^^ . _:b594469880 . _:b594469371 . _:b594469181 . _:b594468748 "2"^^ . _:b594469783 . _:b594468784 . _:b594468751 "2"^^ . . _:b594468750 "2"^^ . . . _:b594469796 . _:b594468745 "2"^^ . _:b594468744 "2"^^ . . _:b46911416 "Then we can determine whether therapeutic efficacy in preclinical animal studies translate to success in humans (Allen and Cullis, 2004, >>2013<<; Narang et al., 2013)." . _:b594469846 . _:b594468747 "2"^^ . . _:b594468746 "2"^^ . _:b594468760 . _:b46911402 "methods for the industrial scale production of conventional liposomes have been successfully developed, without the need for numerous manufacturing steps or the use of organic solvents (Jaafar-Maalej et al., 2012; Kraft et al., >>2014<<). The challenges arise when the functionality of the liposomal delivery system becomes more complex, such as the addition of surface modification with coatings and/or ligands." . _:b594468757 "2"^^ . _:b594468756 "2"^^ . . _:b594469810 . _:b46911221 . . . _:b594468759 "2"^^ . _:b594469008 . . _:b594468758 "2"^^ . _:b594469162 . _:b594468753 "2"^^ . _:b594468807 . . _:b594468752 "2"^^ . _:b594469882 . . _:b594468755 "2"^^ . _:b594468408 . . . _:b594468754 "2"^^ . _:b46911249 . . _:b594469713 . _:b594468765 "2"^^ . _:b594468587 . . _:b594468764 "2"^^ . _:b594468744 . . _:b594469016 . _:b594468767 "2"^^ . _:b594468766 "2"^^ . _:b594469251 . . _:b594468761 "2"^^ . _:b46911167 "For example, integrating target-specific binding of immunoliposomes with the steric stabilization of PEG (thereby creating long-circulating immunoliposomes) has significantly improved the pharmacokinetics of immunoliposomes (Maruyama, >>2002<<). Overall as a drug delivery platform, liposomes offer a dynamic and adaptable technology for enhancing the systemic efficacy of therapeutics in various diseases." . . . _:b594468760 "2"^^ . . _:b594468204 . _:b594468763 "2"^^ . _:b594468762 "2"^^ . _:b594468519 . . . _:b594468773 "2"^^ . . _:b594468772 "2"^^ . _:b46911299 "ultrasound, magnetic, and light) and local triggers specific to the target site (e.g., enzymes and pH), through the use of specific lipid compositions and coatings (Guo and Szoka, 2003; Andresen et al., 2004; Ponce et al., >>2006<<; Bibi et al., 2012). Of these strategies, the use of an external hyperthermic trigger to release therapeutic compounds from liposomal formulations (e.g., ThermoDox\u00AE) appears to be the most promising to date (Needham et al., 2000)." . . _:b594468775 "2"^^ . _:b594468823 . _:b46911156 "Steric stabilization strongly influences the pharmacokinetics of liposomes (Gabizon et al., >>1993<<), with reported half-lives varying from 2 to 24 h in rodents (mice and rats) and as high as 45 h in humans, depending on the particle size and the characteristics of the coating polymer (Allen, 1994; Moghimi and Szebeni, 2003)." . _:b594468774 "2"^^ . _:b594469937 . _:b594468769 "2"^^ . _:b594468286 . _:b594468615 . _:b594468768 "2"^^ . _:b594469266 . _:b594468135 . _:b46911338 "vasculature permeability/accumulation at the target tissue and an ability to encapsulate drugs of different lipophilicities while protecting them from biodegradation (Immordino et al., 2006; Chang and Yeh, 2012; Allen and Cullis, >>2013<<)." . _:b594468771 "2"^^ . . _:b594469317 . _:b594468770 "2"^^ . _:b594468781 "2"^^ . _:b594468780 "2"^^ . _:b594468461 . . _:b594468783 "2"^^ . _:b594469759 . _:b594468782 "2"^^ . _:b594469613 . _:b594468777 "2"^^ . . _:b594468776 "2"^^ . . _:b594468779 "2"^^ . _:b594469935 . . _:b594469058 . . _:b594468778 "2"^^ . _:b594468104 . . _:b594468789 "2"^^ . _:b594468622 . . . _:b594468788 "2"^^ . _:b594469497 . _:b594468791 "2"^^ . . _:b594468790 "2"^^ . _:b594469422 . _:b594468205 . _:b594468770 . _:b594468785 "2"^^ . _:b594469320 . _:b46911354 . _:b594468784 "2"^^ . _:b594468124 . _:b594468787 "2"^^ . _:b594468786 "2"^^ . _:b594469548 . _:b594468797 "2"^^ . . . _:b594469017 . _:b594468796 "2"^^ . _:b594469621 . _:b594469346 . _:b594468799 "2"^^ . . _:b594468798 "2"^^ . . _:b594468793 "2"^^ . _:b594469679 . _:b594469507 . _:b46911346 . _:b594468792 "2"^^ . _:b594468607 . _:b594469465 . _:b46911175 "by the RES is typically secondary to vesicle opsonization\u2014that is, the adsorption of plasma proteins such as immunoglobulin, fibronectin, lipoproteins, and/or complement proteins onto the phospholipid membrane (Ishida et al., 2001a; Chrai et al., 2002). However, in vitro studies have demonstrated that liposomal clearance via macrophages can also occur in the absence of plasma proteins (Chrai et al., 2002)." . _:b594468795 "2"^^ . _:b594468339 . _:b594469850 . _:b594468794 "2"^^ . _:b594469445 . _:b594468805 "2"^^ . _:b46911387 "diagnosed or relapsed solid tumorsPhase IConventionalAllen and Cullis, 2013TopotecanAdvanced solid tumorsPhase 1/IIConventionalSeiden et al., 2004; Allen and Cullis, 2013NystatinFungal InfectionsPhase I/IIConventionalOffner et al., >>2004< "2"^^ . _:b46911378 "and solid tumorsFDA Approved in 1996ConventionalChang and Yeh, 2012; Allen and Cullis, 2013Cytarabine or cytosine arabinosideNeoplastic meningitis and lymphomatous meningitisFDA ApprovedConventionalChang and Yeh, >>2012<<; Jahn et al., 2015Morphine sulfatePain ManagementFDA Approved in 2004ConventionalChang and Yeh, 2012; Allen and Cullis, 2013LurtotecanOvarian cancer, head, and neck cancerPhase I/IIConventionalDark et al., 2005; Chang and Yeh," . _:b46911279 . _:b594469577 . . _:b594468807 "2"^^ . . _:b594468806 "2"^^ . _:b594468335 . _:b594468801 "2"^^ . _:b46911245 "are constantly being investigated in an effort to improve efficacy, reduce RES clearance and minimize toxicity\u2014this includes changes in lipid composition, charge, and the addition of surface coatings and ligands (Hua and Wu, >>2013<<; Monteiro et al., 2014)." . . _:b594468800 "2"^^ . . _:b46911355 "DrugDiseaseStatusType of liposomal-based delivery systemSource(s)Paclitaxel LEP-ETUAdvanced triple-negative breast cancerPhase I/IIsiRNAZhang et al., 2005; Immordino et al., >>2006< "2"^^ . _:b594469768 . . _:b594468802 "2"^^ . _:b594468813 "2"^^ . . _:b594468812 "2"^^ . _:b594469767 . . . _:b594468815 "2"^^ . . _:b594468080 . _:b594468814 "2"^^ . . _:b594468809 "2"^^ . _:b594468808 "2"^^ . _:b594469718 . _:b594468811 "2"^^ . . _:b594468267 . _:b594469244 . _:b594468810 "2"^^ . . _:b594468821 "2"^^ . . _:b594468239 . . _:b594469562 . _:b594468820 "2"^^ . _:b594468823 "2"^^ . . . _:b594468822 "2"^^ . _:b594468906 . . _:b594468817 "2"^^ . _:b46911257 "administration (e.g., intravenous and intraperitoneal injection) (Torchilin, 1994; Vingerhoeds et al., 1994; Willis and Forssen, 1998; Noble et al., 2004; Deshpande et al., 2013; Hua and Cabot, 2013; Rip et al., 2014; Hua et al., >>2015<<). Targeting ligands are used to increase the specificity of delivery of encapsulated cargo to and retain it in diseased tissues and cells, with minimal deposition in non-target sites." . . _:b594468816 "2"^^ . . _:b594468819 "2"^^ . _:b594469009 . . _:b594469895 . _:b594468818 "2"^^ . . _:b594468829 "2"^^ . _:b594468828 "2"^^ . _:b594468831 "2"^^ . _:b46911127 "improved therapies for a range of biomedical applications by stabilizing therapeutic compounds, overcoming obstacles to cellular and tissue uptake, and improving biodistribution of compounds to target sites in vivo (Koning and Storm, >>2003<<; Metselaar and Storm, 2005; Ding et al., 2006; Hua and Wu, 2013). Liposomes are defined as phospholipid vesicles consisting of one or more concentric lipid bilayers enclosing discrete aqueous spaces." . . _:b594469555 . _:b594468830 "2"^^ . _:b594468476 . _:b594468825 "2"^^ . _:b594469089 . _:b594468824 "2"^^ . _:b594469625 . . . _:b594468827 "2"^^ . _:b594469373 . _:b594468867 . . . _:b594468826 "2"^^ . . . _:b594468837 "2"^^ . _:b594469211 . . _:b594468836 "2"^^ . . _:b594469252 . . _:b594468839 "2"^^ . . _:b594468838 "2"^^ . _:b594468887 . . _:b594468833 "2"^^ . _:b46911406 "of physicochemical variables in a nanoformulation system also makes it more complicated to assess the pharmacokinetics, pharmacodynamics and toxicology of a formulation following administration (Teli et al., 2010; Tinkle et al., >>2014<<). For example, the use of synthetic coatings and ligands may affect the biocompatibility, biodistribution and toxicology profile of liposomal formulations, and will require further evaluation to understand the interaction of the" . . _:b594468832 "2"^^ . . _:b594468835 "2"^^ . . _:b594468834 "2"^^ . . _:b594468845 "2"^^ . . _:b594468844 "2"^^ . _:b594468847 "2"^^ . . _:b594468846 "2"^^ . _:b594469515 . . "PMC0" . . _:b594468841 "2"^^ . _:b594469103 . _:b594468840 "2"^^ . . _:b594468843 "2"^^ . . _:b594469298 . _:b594468842 "2"^^ . _:b594469529 . _:b594468853 "2"^^ . . _:b594468852 "2"^^ . _:b46911353 . _:b594468855 "2"^^ . . . _:b594468854 "2"^^ . . . _:b594468849 "2"^^ . _:b594468848 "2"^^ . _:b594468851 "2"^^ . . . . _:b594468850 "2"^^ . _:b46911333 "Yeh, 2012), cytarabine or cytosine arabinoside to treat neoplastic meningitis and lymphomatous meningitis (Chang and Yeh, 2012; Jahn et al., 2015), and morphine sulfate for pain management are currently on the market (Chang and Yeh, >>2012<<). Regardless, many of these drugs are still undergoing clinical trials to test their effects of dose escalation and therapeutic efficacy (Chang and Yeh, 2012)." . _:b594469473 . _:b594468861 "2"^^ . _:b594468175 . _:b594468860 "2"^^ . _:b594469068 . _:b46911255 . . _:b594468863 "2"^^ . _:b594468340 . _:b594468862 "2"^^ . _:b594468598 . _:b594468857 "2"^^ . . . _:b594468856 "2"^^ . . _:b46911322 "This allows the PLD to accumulate in the tumor tissue, rather than in non-target healthy tissues (Rahman et al., >>2007<<). Furthermore, the use of PLD ensures that doxorubicin can pass through the myocardium without being released and contributing to cardiac muscle cell toxicity (Rahman et al., 2007). Finally, PLD avoids the high plasma peak levels of free" . _:b594468859 "2"^^ . _:b594469738 . _:b594468634 . . _:b594468858 "2"^^ . _:b594469392 . . _:b46911149 "liposomal delivery proved useful for improving the therapeutic index of encapsulated drugs, such as doxorubicin and amphotericin (Gabizon et al., 1982; Koning and Storm, 2003; Metselaar and Storm, 2005; Ding et al., 2006; Hua and Wu, >>2013<<). Conventional liposomal formulations reduced the toxicity of compounds in vivo, through modifying pharmacokinetics and biodistribution to enhance drug delivery to diseased tissue in comparison to free drug." . _:b594469537 . . _:b594469293 . . . . _:b594469733 . . . . . _:b594469183 . . . . _:b594468280 . _:b594469271 . . . _:b594469010 . _:b46911206 . _:b46911207 . . _:b46911193 "Nevertheless, the presence of high electrostatic charge can still promote the interaction of liposomes with biomolecules that can serve as opsonins (Laverman et al., 1999; Ishida et al., 2001a). Previous investigation has revealed that large, charged liposomes are cleared within minutes by the liver and less than an hour by the spleen (Senior, 1987; Chrai et al., 2002). The inclusion of cholesterol is an important factor for" . _:b594468171 . . _:b594469563 . _:b594469265 . _:b594468136 . . . . . _:b46911192 "Nevertheless, the presence of high electrostatic charge can still promote the interaction of liposomes with biomolecules that can serve as opsonins (Laverman et al., >>1999<<; Ishida et al., 2001a)." . _:b46911209 . _:b594469218 . _:b594469003 . . _:b46911357 "breast cancerPhase I/IIsiRNAZhang et al., 2005; Immordino et al., 2006siRNAOvarian cancerPhase IDOPC neutral liposomesMangala et al., 2009Paclitaxel EndoTAG-1Advanced triple-negative breast cancerPhase IICationicChang and Yeh, >>2012<<; Awada et al., 2014Paclitaxel EndoTAG-1Pancreatic cancerPhase IICationicL\u00F6hr et al., 2012Mitoxantrone LEM-ETUAcute myeloid leukemia, multiple sclerosis, and prostate cancerPhase ICationicImmordino et al., 2006; Chang and Yeh," . . _:b594468434 . . _:b594469006 . . _:b594469940 . . _:b594469745 . _:b594469948 . _:b594468645 . . _:b594468833 . _:b594468274 . _:b46911352 "Another drug in Phase I/II trials is annamycin to treat acute lymphocytic leukemia (Wetzler et al., >>2013<<). With non-cross resistance properties and an enhanced cellular uptake and retention, annamycin's efficacy and anti-tumor activity is enhanced with the use of a targeted liposomal-based delivery system (Zou et al., 1994). These and more" . _:b46911151 . . _:b46911230 . . . . _:b594469559 . . . _:b594469833 . . . . _:b594469542 . . _:b46911266 . _:b594468494 . . _:b594469712 . _:b594469513 . . _:b594468575 . . . _:b594469142 . . _:b594468438 . _:b594468085 . . . . _:b594468827 . _:b594468643 . _:b594468605 . _:b594469522 . _:b46911253 . . _:b594468361 . . _:b594469929 . . . _:b46911297 . _:b46911229 . . . . . . . _:b594468802 . .