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_:vb594468218 _:vb594468219 _:vb594468220 _:vb594468221 _:vb594468222 _:vb594468223 _:vb594468208 _:vb594468209 _:vb594468210 _:vb594468211 _:vb594468212 _:vb594468213 _:vb594468214 _:vb594468215 _:vb594468200 _:vb594468201 _:vb594468202 _:vb594468203 _:vb594468204 _:vb594468205 _:vb594468206 _:vb594468207 _:vb594468192 _:vb594468193 _:vb594468194 _:vb594468195 _:vb594468196 _:vb594468197 _:vb594468198 _:vb594468199
n2:pmcid
PMC0
bibo:doi
10.3389%2Ffphar.2015.00286
n8:contains
_:vb46911168 _:vb46911126 _:vb46911145 _:vb46911319 _:vb46911243 _:vb46911394
Subject Item
_:vb46911126
rdf:type
n8:Section
dc:title
introduction
n8:contains
_:vb46911144 _:vb46911140 _:vb46911141 _:vb46911142 _:vb46911143 _:vb46911136 _:vb46911137 _:vb46911138 _:vb46911139 _:vb46911132 _:vb46911133 _:vb46911134 _:vb46911135 _:vb46911128 _:vb46911129 _:vb46911130 _:vb46911131 _:vb46911127
Subject Item
_:vb46911127
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:12818515
Subject Item
_:vb46911128
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:16565472
Subject Item
_:vb46911129
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:24319430
Subject Item
_:vb46911130
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:12818515
Subject Item
_:vb46911131
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:16565472
Subject Item
_:vb46911132
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:24319430
Subject Item
_:vb46911133
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:12428898
Subject Item
_:vb46911134
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:25401172
Subject Item
_:vb46911135
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:12818515
Subject Item
_:vb46911136
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:16565472
Subject Item
_:vb46911137
rdf:type
n2:Context
rdf:value
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—these all govern their stability in vitro and in vivo (Hua
n2:mentions
n3:24319430
Subject Item
_:vb46911138
rdf:type
n2:Context
rdf:value
formulations are characterized by properties such as particle size, charge, number of lamellae, lipid composition, and surface modification with polymers and ligands—these 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).
n2:mentions
n3:24319430
Subject Item
_:vb46911139
rdf:type
n2:Context
rdf:value
by properties such as particle size, charge, number of lamellae, lipid composition, and surface modification with polymers and ligands—these 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).
n2:mentions
n3:25401172
Subject Item
_:vb46911140
rdf:type
n2:Context
rdf:value
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);
n2:mentions
n3:12428898
Subject Item
_:vb46911141
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:12818515
Subject Item
_:vb46911142
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:16565472
Subject Item
_:vb46911143
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:24319430
Subject Item
_:vb46911144
rdf:type
n2:Context
rdf:value
(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.
n2:mentions
n3:19514998
Subject Item
_:vb46911145
rdf:type
n8:Section
dc:title
types of liposomal drug delivery platforms
n8:contains
_:vb46911146 _:vb46911147 _:vb46911148 _:vb46911149 _:vb46911150 _:vb46911151 _:vb46911152 _:vb46911153 _:vb46911154 _:vb46911155 _:vb46911156 _:vb46911157 _:vb46911158 _:vb46911159 _:vb46911160 _:vb46911161 _:vb46911162 _:vb46911163 _:vb46911164 _:vb46911165 _:vb46911166 _:vb46911167
Subject Item
_:vb46911146
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:7127308
Subject Item
_:vb46911147
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:12818515
Subject Item
_:vb46911148
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:16565472
Subject Item
_:vb46911149
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:24319430
Subject Item
_:vb46911150
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:1764376
Subject Item
_:vb46911151
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:8313389
Subject Item
_:vb46911152
rdf:type
n2:Context
rdf:value
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<<).
n2:mentions
n3:24319430
Subject Item
_:vb46911153
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:1612296
Subject Item
_:vb46911154
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:8932544
Subject Item
_:vb46911155
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:11718670
Subject Item
_:vb46911156
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:8321835
Subject Item
_:vb46911157
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:7940982
Subject Item
_:vb46911158
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:14559067
Subject Item
_:vb46911159
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:10837594
Subject Item
_:vb46911160
rdf:type
n2:Context
rdf:value
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<<).
n2:mentions
n3:12428898
Subject Item
_:vb46911161
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:10837594
Subject Item
_:vb46911162
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:24109453
Subject Item
_:vb46911163
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:11437687
Subject Item
_:vb46911164
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:20402623
Subject Item
_:vb46911165
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:10837594
Subject Item
_:vb46911166
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:20402623
Subject Item
_:vb46911167
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:12428903
Subject Item
_:vb46911168
rdf:type
n8:Section
dc:title
biological challenges facing liposomal drug delivery systems
n8:contains
_:vb46911236 _:vb46911237 _:vb46911238 _:vb46911239 _:vb46911232 _:vb46911233 _:vb46911234 _:vb46911235 _:vb46911240 _:vb46911241 _:vb46911242 _:vb46911204 _:vb46911205 _:vb46911206 _:vb46911207 _:vb46911200 _:vb46911201 _:vb46911202 _:vb46911203 _:vb46911212 _:vb46911213 _:vb46911214 _:vb46911215 _:vb46911208 _:vb46911209 _:vb46911210 _:vb46911211 _:vb46911220 _:vb46911221 _:vb46911222 _:vb46911223 _:vb46911216 _:vb46911217 _:vb46911218 _:vb46911219 _:vb46911228 _:vb46911229 _:vb46911230 _:vb46911231 _:vb46911224 _:vb46911225 _:vb46911226 _:vb46911227 _:vb46911172 _:vb46911173 _:vb46911174 _:vb46911175 _:vb46911169 _:vb46911170 _:vb46911171 _:vb46911180 _:vb46911181 _:vb46911182 _:vb46911183 _:vb46911176 _:vb46911177 _:vb46911178 _:vb46911179 _:vb46911188 _:vb46911189 _:vb46911190 _:vb46911191 _:vb46911184 _:vb46911185 _:vb46911186 _:vb46911187 _:vb46911196 _:vb46911197 _:vb46911198 _:vb46911199 _:vb46911192 _:vb46911193 _:vb46911194 _:vb46911195
Subject Item
_:vb46911169
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:10837594
Subject Item
_:vb46911170
rdf:type
n2:Context
rdf:value
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<<).
n2:mentions
n3:22415612
Subject Item
_:vb46911171
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:794631
Subject Item
_:vb46911172
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:3542245
Subject Item
_:vb46911173
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:3542245
Subject Item
_:vb46911174
rdf:type
n2:Context
rdf:value
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 (50–1000 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—that is, the adsorption of
n2:mentions
n3:12814645
Subject Item
_:vb46911175
rdf:type
n2:Context
rdf:value
by the RES is typically secondary to vesicle opsonization—that 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).
n2:mentions
n3:11766990
Subject Item
_:vb46911176
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:19514998
Subject Item
_:vb46911177
rdf:type
n2:Context
rdf:value
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®) in mice showed a dose-dependent clearance saturation effect due to partial blockade of the RES in the liver.
n2:mentions
n3:19514998
Subject Item
_:vb46911178
rdf:type
n2:Context
rdf:value
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® 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).
n2:mentions
n3:12683721
Subject Item
_:vb46911179
rdf:type
n2:Context
rdf:value
In addition, administration of Doxil® 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).
n2:mentions
n3:9516959
Subject Item
_:vb46911180
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:7664348
Subject Item
_:vb46911181
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:11766990
Subject Item
_:vb46911182
rdf:type
n2:Context
rdf:value
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—with pathways independent of opsonization also possible (Laverman et al., 2001; Sawant and Torchilin, 2012).
n2:mentions
n3:11766990
Subject Item
_:vb46911183
rdf:type
n2:Context
rdf:value
The use of PEG significantly minimizes, but does not completely circumvent, liposomal uptake by the RES—with pathways independent of opsonization also possible (Laverman et al., >>2001<<; Sawant and Torchilin, 2012).
n2:mentions
n3:11410330
Subject Item
_:vb46911184
rdf:type
n2:Context
rdf:value
The use of PEG significantly minimizes, but does not completely circumvent, liposomal uptake by the RES—with pathways independent of opsonization also possible (Laverman et al., 2001; Sawant and Torchilin, >>2012<<).
n2:mentions
n3:22415612
Subject Item
_:vb46911185
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:24319430
Subject Item
_:vb46911186
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:10837632
Subject Item
_:vb46911187
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:10837632
Subject Item
_:vb46911188
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:11766990
Subject Item
_:vb46911189
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:7664348
Subject Item
_:vb46911190
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:10837737
Subject Item
_:vb46911191
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:12428898
Subject Item
_:vb46911192
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:10837737
Subject Item
_:vb46911193
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:11766990
Subject Item
_:vb46911194
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:3542245
Subject Item
_:vb46911195
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:10837594
Subject Item
_:vb46911196
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:10837594
Subject Item
_:vb46911197
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:10837737
Subject Item
_:vb46911198
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:12428898
Subject Item
_:vb46911199
rdf:type
n2:Context
rdf:value
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<<).
n2:mentions
n3:24960297
Subject Item
_:vb46911200
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:22415612
Subject Item
_:vb46911201
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:24904213
Subject Item
_:vb46911202
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:24904213
Subject Item
_:vb46911203
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:10751361
Subject Item
_:vb46911204
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:10082795
Subject Item
_:vb46911205
rdf:type
n2:Context
rdf:value
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,
n2:mentions
n3:24109453
Subject Item
_:vb46911206
rdf:type
n2:Context
rdf:value
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 μm (Antohe et al., 2004).
n2:mentions
n3:15461929
Subject Item
_:vb46911207
rdf:type
n2:Context
rdf:value
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 μm (Antohe et al., >>2004<<). Pore sizes ranging from 0.2 to 1.2 μm 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).
n2:mentions
n3:15461929
Subject Item
_:vb46911208
rdf:type
n2:Context
rdf:value
Pore sizes ranging from 0.2 to 1.2 μm 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).
n2:mentions
n3:10082795
Subject Item
_:vb46911209
rdf:type
n2:Context
rdf:value
Pore sizes ranging from 0.2 to 1.2 μm 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).
n2:mentions
n3:15461929
Subject Item
_:vb46911210
rdf:type
n2:Context
rdf:value
Pore sizes ranging from 0.2 to 1.2 μm 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).
n2:mentions
n3:24109453
Subject Item
_:vb46911211
rdf:type
n2:Context
rdf:value
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<<).
n2:mentions
n3:22415612
Subject Item
_:vb46911212
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:10688625
Subject Item
_:vb46911213
rdf:type
n2:Context
rdf:value
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 “accelerated blood clearance” (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
n2:mentions
n3:12672612
Subject Item
_:vb46911214
rdf:type
n2:Context
rdf:value
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 “accelerated blood clearance” (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
n2:mentions
n3:16515818
Subject Item
_:vb46911215
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:10688625
Subject Item
_:vb46911216
rdf:type
n2:Context
rdf:value
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 4–7 days after the initial dose in rats and 10 days in mice (Ishida et al., 2003, 2006b).
n2:mentions
n3:10688625
Subject Item
_:vb46911217
rdf:type
n2:Context
rdf:value
Subsequent investigations have verified these findings, with a maximum clearance of liposomes 4–7 days after the initial dose in rats and 10 days in mice (Ishida et al., >>2003<<, 2006b).
n2:mentions
n3:12672612
Subject Item
_:vb46911218
rdf:type
n2:Context
rdf:value
Subsequent investigations have verified these findings, with a maximum clearance of liposomes 4–7 days after the initial dose in rats and 10 days in mice (Ishida et al., 2003, 2006b).
n2:mentions
n3:16515818
Subject Item
_:vb46911219
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:18083313
Subject Item
_:vb46911220
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:16515818
Subject Item
_:vb46911221
rdf:type
n2:Context
rdf:value
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 μmol phospholipids/kg) have been shown to reduce the magnitude of the ABC phenomenon (Ishida et al., 2005). Increasing the phospholipid dose has been
n2:mentions
n3:17011060
Subject Item
_:vb46911222
rdf:type
n2:Context
rdf:value
Interestingly, administration of higher doses of the initial PEGylated liposomes (>1 μmol 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
n2:mentions
n3:15908032
Subject Item
_:vb46911223
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:16515818
Subject Item
_:vb46911224
rdf:type
n2:Context
rdf:value
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 μmol phospholipid/kg) are administered clinically, which may account
n2:mentions
n3:18083313
Subject Item
_:vb46911225
rdf:type
n2:Context
rdf:value
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 μmol 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
n2:mentions
n3:11410330
Subject Item
_:vb46911226
rdf:type
n2:Context
rdf:value
Generally higher doses (15 μmol 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).
n2:mentions
n3:10964334
Subject Item
_:vb46911227
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:16515818
Subject Item
_:vb46911228
rdf:type
n2:Context
rdf:value
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<<).
n2:mentions
n3:19514998
Subject Item
_:vb46911229
rdf:type
n2:Context
rdf:value
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 (2–45%) 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
n2:mentions
n3:11789674
Subject Item
_:vb46911230
rdf:type
n2:Context
rdf:value
In addition, CARPA has been reported with both experimental and clinically approved liposomal formulations (e.g., Doxil®, Ambisome, and DaunoXome®) (Szebeni, >>2005<<; Szebeni and Moghimi, 2009).
n2:mentions
n3:16140450
Subject Item
_:vb46911231
rdf:type
n2:Context
rdf:value
In addition, CARPA has been reported with both experimental and clinically approved liposomal formulations (e.g., Doxil®, Ambisome, and DaunoXome®) (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—the latter of which may limit
n2:mentions
n3:19514998
Subject Item
_:vb46911232
rdf:type
n2:Context
rdf:value
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<<—the latter of which may limit the clinical use of potentially reactogenic liposomes in cardiac patients (Szebeni and Barenholz, 2009).
n2:mentions
n3:16140450
Subject Item
_:vb46911233
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:8553069
Subject Item
_:vb46911234
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:16140450
Subject Item
_:vb46911235
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:19514998
Subject Item
_:vb46911236
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:10226097
Subject Item
_:vb46911237
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:17613700
Subject Item
_:vb46911238
rdf:type
n2:Context
rdf:value
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,
n2:mentions
n3:19514998
Subject Item
_:vb46911239
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:17065229
Subject Item
_:vb46911240
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:9675310
Subject Item
_:vb46911241
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:19514998
Subject Item
_:vb46911242
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:19514998
Subject Item
_:vb46911243
rdf:type
n8:Section
dc:title
experimental use of liposomes for biomedical applications
n8:contains
_:vb46911304 _:vb46911305 _:vb46911306 _:vb46911307 _:vb46911308 _:vb46911309 _:vb46911310 _:vb46911311 _:vb46911296 _:vb46911297 _:vb46911298 _:vb46911299 _:vb46911300 _:vb46911301 _:vb46911302 _:vb46911303 _:vb46911312 _:vb46911313 _:vb46911314 _:vb46911315 _:vb46911316 _:vb46911317 _:vb46911318 _:vb46911244 _:vb46911245 _:vb46911246 _:vb46911247 _:vb46911256 _:vb46911257 _:vb46911258 _:vb46911259 _:vb46911260 _:vb46911261 _:vb46911262 _:vb46911263 _:vb46911248 _:vb46911249 _:vb46911250 _:vb46911251 _:vb46911252 _:vb46911253 _:vb46911254 _:vb46911255 _:vb46911272 _:vb46911273 _:vb46911274 _:vb46911275 _:vb46911276 _:vb46911277 _:vb46911278 _:vb46911279 _:vb46911264 _:vb46911265 _:vb46911266 _:vb46911267 _:vb46911268 _:vb46911269 _:vb46911270 _:vb46911271 _:vb46911288 _:vb46911289 _:vb46911290 _:vb46911291 _:vb46911292 _:vb46911293 _:vb46911294 _:vb46911295 _:vb46911280 _:vb46911281 _:vb46911282 _:vb46911283 _:vb46911284 _:vb46911285 _:vb46911286 _:vb46911287
Subject Item
_:vb46911244
rdf:type
n2:Context
rdf:value
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—this includes changes in lipid composition, charge, and the addition of surface coatings
n2:mentions
n3:24319430
Subject Item
_:vb46911245
rdf:type
n2:Context
rdf:value
are constantly being investigated in an effort to improve efficacy, reduce RES clearance and minimize toxicity—this includes changes in lipid composition, charge, and the addition of surface coatings and ligands (Hua and Wu, >>2013<<; Monteiro et al., 2014).
n2:mentions
n3:24319430
Subject Item
_:vb46911246
rdf:type
n2:Context
rdf:value
being investigated in an effort to improve efficacy, reduce RES clearance and minimize toxicity—this 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
n2:mentions
n3:25401172
Subject Item
_:vb46911247
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:20402623
Subject Item
_:vb46911248
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:23036225
Subject Item
_:vb46911249
rdf:type
n2:Context
rdf:value
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<<).
n2:mentions
n3:25678787
Subject Item
_:vb46911250
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:7820455
Subject Item
_:vb46911251
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:7820456
Subject Item
_:vb46911252
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:10837594
Subject Item
_:vb46911253
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:15268628
Subject Item
_:vb46911254
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:23914966
Subject Item
_:vb46911255
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:23703419
Subject Item
_:vb46911256
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:24524555
Subject Item
_:vb46911257
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:25784453
Subject Item
_:vb46911258
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:15967706
Subject Item
_:vb46911259
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:20402623
Subject Item
_:vb46911260
rdf:type
n2:Context
rdf:value
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;
n2:mentions
n3:19142939
Subject Item
_:vb46911261
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:7820456
Subject Item
_:vb46911262
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:20402623
Subject Item
_:vb46911263
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:23036225
Subject Item
_:vb46911264
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:24338748
Subject Item
_:vb46911265
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:14695160
Subject Item
_:vb46911266
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:23703419
Subject Item
_:vb46911267
rdf:type
n2:Context
rdf:value
the nanoparticles, with both targeted and non-targeted liposomes achieving similarly high levels of tumor tissue accumulation (7–8% 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
n2:mentions
n3:8993319
Subject Item
_:vb46911268
rdf:type
n2:Context
rdf:value
with both targeted and non-targeted liposomes achieving similarly high levels of tumor tissue accumulation (7–8% 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
n2:mentions
n3:16818648
Subject Item
_:vb46911269
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:11948130
Subject Item
_:vb46911270
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:16818648
Subject Item
_:vb46911271
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:16818648
Subject Item
_:vb46911272
rdf:type
n2:Context
rdf:value
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<<).
n2:mentions
n3:20402623
Subject Item
_:vb46911273
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:22415612
Subject Item
_:vb46911274
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:23036225
Subject Item
_:vb46911275
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:20402623
Subject Item
_:vb46911276
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:24319430
Subject Item
_:vb46911277
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:24338748
Subject Item
_:vb46911278
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:20402623
Subject Item
_:vb46911279
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:25678787
Subject Item
_:vb46911280
rdf:type
n2:Context
rdf:value
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.,
n2:mentions
n3:25784453
Subject Item
_:vb46911281
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:22820482
Subject Item
_:vb46911282
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:19321523
Subject Item
_:vb46911283
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:24574793
Subject Item
_:vb46911284
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:10406252
Subject Item
_:vb46911285
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:12135031
Subject Item
_:vb46911286
rdf:type
n2:Context
rdf:value
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.,
n2:mentions
n3:19603812
Subject Item
_:vb46911287
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:2823261
Subject Item
_:vb46911288
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:12460895
Subject Item
_:vb46911289
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:18563780
Subject Item
_:vb46911290
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:12603862
Subject Item
_:vb46911291
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:17275230
Subject Item
_:vb46911292
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:12414638
Subject Item
_:vb46911293
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:25784453
Subject Item
_:vb46911294
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:16831482
Subject Item
_:vb46911295
rdf:type
n2:Context
rdf:value
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<<).
n2:mentions
n3:16831482
Subject Item
_:vb46911296
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:22208705
Subject Item
_:vb46911297
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:12755643
Subject Item
_:vb46911298
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:15027860
Subject Item
_:vb46911299
rdf:type
n2:Context
rdf:value
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®) appears to be the most promising to date (Needham et al., 2000).
n2:mentions
n3:16754340
Subject Item
_:vb46911300
rdf:type
n2:Context
rdf:value
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®) appears to be the most promising to date (Needham et al., 2000).
n2:mentions
n3:22208705
Subject Item
_:vb46911301
rdf:type
n2:Context
rdf:value
Of these strategies, the use of an external hyperthermic trigger to release therapeutic compounds from liposomal formulations (e.g., ThermoDox®) 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
n2:mentions
n3:10728674
Subject Item
_:vb46911302
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:11744174
Subject Item
_:vb46911303
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:22616659
Subject Item
_:vb46911304
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:25176578
Subject Item
_:vb46911305
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:25176578
Subject Item
_:vb46911306
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:22208705
Subject Item
_:vb46911307
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:23036225
Subject Item
_:vb46911308
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:21226651
Subject Item
_:vb46911309
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:23036225
Subject Item
_:vb46911310
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:25895866
Subject Item
_:vb46911311
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:25787729
Subject Item
_:vb46911312
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:25895866
Subject Item
_:vb46911313
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:25787729
Subject Item
_:vb46911314
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:25190023
Subject Item
_:vb46911315
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:25190023
Subject Item
_:vb46911316
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:20222866
Subject Item
_:vb46911317
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:21226651
Subject Item
_:vb46911318
rdf:type
n2:Context
rdf:value
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<<).
n2:mentions
n3:23036225
Subject Item
_:vb46911319
rdf:type
n8:Section
dc:title
clinically approved liposomal-based therapeutics
n8:contains
_:vb46911392 _:vb46911393 _:vb46911384 _:vb46911385 _:vb46911386 _:vb46911387 _:vb46911388 _:vb46911389 _:vb46911390 _:vb46911391 _:vb46911376 _:vb46911377 _:vb46911378 _:vb46911379 _:vb46911380 _:vb46911381 _:vb46911382 _:vb46911383 _:vb46911368 _:vb46911369 _:vb46911370 _:vb46911371 _:vb46911372 _:vb46911373 _:vb46911374 _:vb46911375 _:vb46911360 _:vb46911361 _:vb46911362 _:vb46911363 _:vb46911364 _:vb46911365 _:vb46911366 _:vb46911367 _:vb46911352 _:vb46911353 _:vb46911354 _:vb46911355 _:vb46911356 _:vb46911357 _:vb46911358 _:vb46911359 _:vb46911344 _:vb46911345 _:vb46911346 _:vb46911347 _:vb46911348 _:vb46911349 _:vb46911350 _:vb46911351 _:vb46911336 _:vb46911337 _:vb46911338 _:vb46911339 _:vb46911340 _:vb46911341 _:vb46911342 _:vb46911343 _:vb46911328 _:vb46911329 _:vb46911330 _:vb46911331 _:vb46911332 _:vb46911333 _:vb46911334 _:vb46911335 _:vb46911320 _:vb46911321 _:vb46911322 _:vb46911323 _:vb46911324 _:vb46911325 _:vb46911326 _:vb46911327
Subject Item
_:vb46911320
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n2:Context
rdf:value
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
n2:mentions
n3:18077994
Subject Item
_:vb46911321
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:21850390
Subject Item
_:vb46911322
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:18203425
Subject Item
_:vb46911323
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:18203425
Subject Item
_:vb46911324
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:10964334
Subject Item
_:vb46911325
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:18077994
Subject Item
_:vb46911326
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:25577133
Subject Item
_:vb46911327
rdf:type
n2:Context
rdf:value
Camptothecin, which is formulated in PEGylated stealth liposomes, is also in Phase I trials for ovarian cancer treatment (Zamboni et al., >>2009<<).
n2:mentions
n3:19190127
Subject Item
_:vb46911328
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:19337435
Subject Item
_:vb46911329
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:22275822
Subject Item
_:vb46911330
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:22275822
Subject Item
_:vb46911331
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:22275822
Subject Item
_:vb46911332
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:25791073
Subject Item
_:vb46911333
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:22275822
Subject Item
_:vb46911334
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:22275822
Subject Item
_:vb46911335
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:25531982
Subject Item
_:vb46911336
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:17717971
Subject Item
_:vb46911337
rdf:type
n2:Context
rdf:value
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).
n2:mentions
n3:22275822
Subject Item
_:vb46911338
rdf:type
n2:Context
rdf:value
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<<).
n2:mentions
n3:23036225
Subject Item
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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).
n2:mentions
n3:14726126
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_:vb46911340
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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).
n2:mentions
n3:26124634
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_:vb46911341
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(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.
n2:mentions
n3:12935441
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_:vb46911342
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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 (Löhr et al., 2012).
n2:mentions
n3:24667715
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_:vb46911343
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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 (Löhr 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
n2:mentions
n3:21896540
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_:vb46911344
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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
n2:mentions
n3:22275822
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_:vb46911345
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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
n2:mentions
n3:22275822
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_:vb46911346
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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).
n2:mentions
n3:15567316
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_:vb46911347
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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
n2:mentions
n3:17717971
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_:vb46911348
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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
n2:mentions
n3:22275822
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_:vb46911349
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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
n2:mentions
n3:18794097
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_:vb46911350
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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.,
n2:mentions
n3:22275822
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_:vb46911351
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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
n2:mentions
n3:19495686
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_:vb46911352
rdf:type
n2:Context
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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
n2:mentions
n3:23763920
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_:vb46911353
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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.
n2:mentions
n3:8137251
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_:vb46911354
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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
n2:mentions
n3:15567316
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_:vb46911355
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DrugDiseaseStatusType of liposomal-based delivery systemSource(s)Paclitaxel LEP-ETUAdvanced triple-negative breast cancerPhase I/IIsiRNAZhang et al., 2005; Immordino et al., >>2006<<siRNAOvarian cancerPhase IDOPC neutral liposomesMangala et al., 2009Paclitaxel EndoTAG-1Advanced triple-negative breast cancerPhase IICationicChang and Yeh, 2012; Awada et al., 2014Paclitaxel EndoTAG-1Pancreatic cancerPhase IICationicLöhr
n2:mentions
n3:17717971
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_:vb46911356
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n2:Context
rdf:value
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<<Paclitaxel EndoTAG-1Advanced triple-negative breast cancerPhase IICationicChang and Yeh, 2012; Awada et al., 2014Paclitaxel EndoTAG-1Pancreatic cancerPhase IICationicLöhr et al., 2012Mitoxantrone LEM-ETUAcute myeloid leukemia, multiple
n2:mentions
n3:19495686
Subject Item
_:vb46911357
rdf:type
n2:Context
rdf:value
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 IICationicLöhr et al., 2012Mitoxantrone LEM-ETUAcute myeloid leukemia, multiple sclerosis, and prostate cancerPhase ICationicImmordino et al., 2006; Chang and Yeh,
n2:mentions
n3:22275822
Subject Item
_:vb46911358
rdf:type
n2:Context
rdf:value
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<<Paclitaxel EndoTAG-1Pancreatic cancerPhase IICationicLöhr et al., 2012Mitoxantrone LEM-ETUAcute myeloid leukemia, multiple sclerosis, and prostate cancerPhase ICationicImmordino et al., 2006; Chang and Yeh, 2012VerteporfinMolecular
n2:mentions
n3:24667715
Subject Item
_:vb46911359
rdf:type
n2:Context
rdf:value
cancerPhase IDOPC neutral liposomesMangala et al., 2009Paclitaxel EndoTAG-1Advanced triple-negative breast cancerPhase IICationicChang and Yeh, 2012; Awada et al., 2014Paclitaxel EndoTAG-1Pancreatic cancerPhase IICationicLöhr et al., >>2012<<Mitoxantrone 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
n2:mentions
n3:21896540
Subject Item
_:vb46911360
rdf:type
n2:Context
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IICationicChang and Yeh, 2012; Awada et al., 2014Paclitaxel EndoTAG-1Pancreatic cancerPhase IICationicLöhr 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;
n2:mentions
n3:17717971
Subject Item
_:vb46911361
rdf:type
n2:Context
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2012; Awada et al., 2014Paclitaxel EndoTAG-1Pancreatic cancerPhase IICationicLöhr et al., 2012Mitoxantrone LEM-ETUAcute myeloid leukemia, multiple sclerosis, and prostate cancerPhase ICationicImmordino et al., 2006; Chang and Yeh, >>2012<<VerteporfinMolecular 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.,
n2:mentions
n3:22275822
Subject Item
_:vb46911362
rdf:type
n2:Context
rdf:value
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;
n2:mentions
n3:22275822
Subject Item
_:vb46911363
rdf:type
n2:Context
rdf:value
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.,
n2:mentions
n3:23036225
Subject Item
_:vb46911364
rdf:type
n2:Context
rdf:value
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<<AmikacinLung 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
n2:mentions
n3:23335851
Subject Item
_:vb46911365
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:22275822
Subject Item
_:vb46911366
rdf:type
n2:Context
rdf:value
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.,
n2:mentions
n3:23749840
Subject Item
_:vb46911367
rdf:type
n2:Context
rdf:value
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<<VincristineNon-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.,
n2:mentions
n3:24460437
Subject Item
_:vb46911368
rdf:type
n2:Context
rdf:value
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.,
n2:mentions
n3:23036225
Subject Item
_:vb46911369
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:12935441
Subject Item
_:vb46911370
rdf:type
n2:Context
rdf:value
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<<Irinotecan 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
n2:mentions
n3:17717971
Subject Item
_:vb46911371
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:14726126
Subject Item
_:vb46911372
rdf:type
n2:Context
rdf:value
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<<AnnamycinAcute lymphoblastic leukemiaPhase I/IIConventionalWetzler et al., 2013Amphotericin BAnti-fungal prophylaxisFDA approved in 1997ConventionalChandrasekar, 2008; Allen and Cullis, 2013DaunorubicinLeukemia and solid tumorsFDA Approved
n2:mentions
n3:26124634
Subject Item
_:vb46911373
rdf:type
n2:Context
rdf:value
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<<Amphotericin 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
n2:mentions
n3:23763920
Subject Item
_:vb46911374
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:19337435
Subject Item
_:vb46911375
rdf:type
n2:Context
rdf:value
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<<DaunorubicinLeukemia and solid tumorsFDA Approved in 1996ConventionalChang and Yeh, 2012; Allen and Cullis, 2013Cytarabine or cytosine arabinosideNeoplastic meningitis and lymphomatous meningitisFDA ApprovedConventionalChang and Yeh, 2012;
n2:mentions
n3:23036225
Subject Item
_:vb46911376
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:22275822
Subject Item
_:vb46911377
rdf:type
n2:Context
rdf:value
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<<Cytarabine 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
n2:mentions
n3:23036225
Subject Item
_:vb46911378
rdf:type
n2:Context
rdf:value
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,
n2:mentions
n3:22275822
Subject Item
_:vb46911379
rdf:type
n2:Context
rdf:value
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<<Morphine 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
n2:mentions
n3:25791073
Subject Item
_:vb46911380
rdf:type
n2:Context
rdf:value
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,
n2:mentions
n3:22275822
Subject Item
_:vb46911381
rdf:type
n2:Context
rdf:value
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<<LurtotecanOvarian 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
n2:mentions
n3:23036225
Subject Item
_:vb46911382
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:15699482
Subject Item
_:vb46911383
rdf:type
n2:Context
rdf:value
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<<VinorelbineNewly diagnosed or relapsed solid tumorsPhase IConventionalAllen and Cullis, 2013TopotecanAdvanced solid tumorsPhase 1/IIConventionalSeiden et al., 2004; Allen and Cullis, 2013NystatinFungal InfectionsPhase
n2:mentions
n3:22275822
Subject Item
_:vb46911384
rdf:type
n2:Context
rdf:value
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<<TopotecanAdvanced 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
n2:mentions
n3:23036225
Subject Item
_:vb46911385
rdf:type
n2:Context
rdf:value
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
n2:mentions
n3:15047241
Subject Item
_:vb46911386
rdf:type
n2:Context
rdf:value
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<<NystatinFungal InfectionsPhase I/IIConventionalOffner et al., 2004DoxorubicinLeukemia, breast cancer, bone cancer, lung cancer, brain cancerFDA Approved in 1995PEGylatedNing et al., 2007Doxorubicin and bortezomibRelapsed or refractory
n2:mentions
n3:23036225
Subject Item
_:vb46911387
rdf:type
n2:Context
rdf:value
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<<DoxorubicinLeukemia, 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.,
n2:mentions
n3:15561860
Subject Item
_:vb46911388
rdf:type
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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<<Doxorubicin and bortezomibRelapsed or refractory multiple myelomaFDA Approved in 2007PEGylatedNing et al., 2007Thermosensitive doxorubicinLiver tumorsPhase IIIPEGylatedYarmolenko et al., 2010Thermosensitive doxorubicinChest wall
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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<<Thermosensitive doxorubicinLiver tumorsPhase IIIPEGylatedYarmolenko et al., 2010Thermosensitive doxorubicinChest wall recurrences of breast cancerPhase IPEGylatedYarmolenko et al., 2010IrinotecanAdvanced refractory solid tumors and
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Approved in 1995PEGylatedNing et al., 2007Doxorubicin and bortezomibRelapsed or refractory multiple myelomaFDA Approved in 2007PEGylatedNing et al., 2007Thermosensitive doxorubicinLiver tumorsPhase IIIPEGylatedYarmolenko et al., >>2010<<Thermosensitive doxorubicinChest wall recurrences of breast cancerPhase IPEGylatedYarmolenko et al., 2010IrinotecanAdvanced refractory solid tumors and colorectal cancerPhase IPEGylatedChang et al., 2015Camptothecin analogOvarian
n2:mentions
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myelomaFDA Approved in 2007PEGylatedNing et al., 2007Thermosensitive doxorubicinLiver tumorsPhase IIIPEGylatedYarmolenko et al., 2010Thermosensitive doxorubicinChest wall recurrences of breast cancerPhase IPEGylatedYarmolenko et al., >>2010<<IrinotecanAdvanced refractory solid tumors and colorectal cancerPhase IPEGylatedChang et al., 2015Camptothecin analogOvarian cancerPhase IPEGylatedZamboni et al., 2009Why the bottleneck for translation into clinical practice?
n2:mentions
n3:20597627
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IIIPEGylatedYarmolenko et al., 2010Thermosensitive doxorubicinChest wall recurrences of breast cancerPhase IPEGylatedYarmolenko et al., 2010IrinotecanAdvanced refractory solid tumors and colorectal cancerPhase IPEGylatedChang et al., >>2015<<Camptothecin analogOvarian cancerPhase IPEGylatedZamboni et al., 2009Why the bottleneck for translation into clinical practice?
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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<<Why the bottleneck for translation into clinical practice?
n2:mentions
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why the bottleneck for translation into clinical practice?
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_:vb46911404 _:vb46911405 _:vb46911406 _:vb46911407 _:vb46911400 _:vb46911401 _:vb46911402 _:vb46911403 _:vb46911396 _:vb46911397 _:vb46911398 _:vb46911399 _:vb46911395 _:vb46911416 _:vb46911417 _:vb46911412 _:vb46911413 _:vb46911414 _:vb46911415 _:vb46911408 _:vb46911409 _:vb46911410 _:vb46911411
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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).
n2:mentions
n3:15031496
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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).
n2:mentions
n3:23036225
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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).
n2:mentions
n3:17957183
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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).
n2:mentions
n3:22415612
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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
n2:mentions
n3:24037829
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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.,
n2:mentions
n3:24037829
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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).
n2:mentions
n3:22724618
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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.
n2:mentions
n3:24338748
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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).
n2:mentions
n3:20222866
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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;
n2:mentions
n3:24673240
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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).
n2:mentions
n3:20222866
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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
n2:mentions
n3:24673240
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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).
n2:mentions
n3:15031496
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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).
n2:mentions
n3:23036225
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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.
n2:mentions
n3:17957183
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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.
n2:mentions
n3:22415612
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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.
n2:mentions
n3:24037829
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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.
n2:mentions
n3:24673240
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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.
n2:mentions
n3:19540359
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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<<).
n2:mentions
n3:19540359
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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).
n2:mentions
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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).
n2:mentions
n3:23036225
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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
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