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n3:pmcid: PMC0
bibo:doi: 10.3390%2Fpharmaceutics6010137
n2:contains: _:vb29630747 _:vb29630628 _:vb29630671 _:vb29630486 _:vb29630551 _:vb29630553 _:vb29630574

Subject Item: _:vb29630486
rdf:type: n2:Section
dc:title: introduction
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Subject Item: _:vb29630487
rdf:type: n3:Context
rdf:value: Since that seminal discovery, a sustained effort has been devoted to the development of lipid vesicles (liposomes) as a drug delivery system for numerous applications, including cancer therapy [>>1<<,2]. Structurally, liposomes are microscopic vesicles that enclose an internal aqueous space within one or more bilayer membranes composed of natural or synthetic phospholipids. They are biocompatible and biodegradable, generally low in
n3:mentions: n4:15688077

Subject Item: _:vb29630488
rdf:type: n3:Context
rdf:value: Since that seminal discovery, a sustained effort has been devoted to the development of lipid vesicles (liposomes) as a drug delivery system for numerous applications, including cancer therapy [1,>>2<<]. Structurally, liposomes are microscopic vesicles that enclose an internal aqueous space within one or more bilayer membranes composed of natural or synthetic phospholipids. They are biocompatible and biodegradable, generally low in
n3:mentions: n4:21983329

Subject Item: _:vb29630489
rdf:type: n3:Context
rdf:value: Figure 1 depicts schematically the numerous physicochemical characteristics and modifications that have been employed to optimize the liposome carrier for different applications [>>3<<,4]. The limiting phospholipid bilayer membrane surrounds an internal aqueous space that can be used to encapsulate hydrophilic chemotherapeutic drugs, whereas hydrophobic agents can be accommodated by incorporation into the membrane [3,5].
n3:mentions: n4:10581328

Subject Item: _:vb29630490
rdf:type: n3:Context
rdf:value: Figure 1 depicts schematically the numerous physicochemical characteristics and modifications that have been employed to optimize the liposome carrier for different applications [3,>>4<<]. The limiting phospholipid bilayer membrane surrounds an internal aqueous space that can be used to encapsulate hydrophilic chemotherapeutic drugs, whereas hydrophobic agents can be accommodated by incorporation into the membrane [3,5].
n3:mentions: n4:9516959

Subject Item: _:vb29630491
rdf:type: n3:Context
rdf:value: The limiting phospholipid bilayer membrane surrounds an internal aqueous space that can be used to encapsulate hydrophilic chemotherapeutic drugs, whereas hydrophobic agents can be accommodated by incorporation into the membrane [>>3<<,5]. The bilayer membrane can include components that provide physicochemical control over pharmacokinetic (PK) properties such as elimination half-life, biodistribution, permeability, and drug release rate. In addition to the membrane
n3:mentions: n4:10581328

Subject Item: _:vb29630492
rdf:type: n3:Context
rdf:value: The limiting phospholipid bilayer membrane surrounds an internal aqueous space that can be used to encapsulate hydrophilic chemotherapeutic drugs, whereas hydrophobic agents can be accommodated by incorporation into the membrane [3,>>5<<]. The bilayer membrane can include components that provide physicochemical control over pharmacokinetic (PK) properties such as elimination half-life, biodistribution, permeability, and drug release rate.
n3:mentions: n4:1778891

Subject Item: _:vb29630493
rdf:type: n3:Context
rdf:value: and (iii) engineered for triggered release of the encapsulated drug at the tumor site, which can be achieved by sensitizing the bilayer membrane to a specific stimuli such pH, light, oxidation, enzymatic degradation, heat, or radiation [>>6<<,7]. As an example, through mild hyperthermia (41 °C), liposomal doxorubicin (L-DXR) showed an improvement in the tumor vasculature permeability, a subsequent increase in liposome extravasation, and an enhanced interstitial penetration
n3:mentions: n4:18351638

Subject Item: _:vb29630494
rdf:type: n3:Context
rdf:value: (iii) engineered for triggered release of the encapsulated drug at the tumor site, which can be achieved by sensitizing the bilayer membrane to a specific stimuli such pH, light, oxidation, enzymatic degradation, heat, or radiation [6,>>7<<]. As an example, through mild hyperthermia (41 °C), liposomal doxorubicin (L-DXR) showed an improvement in the tumor vasculature permeability, a subsequent increase in liposome extravasation, and an enhanced interstitial penetration [8,9].
n3:mentions: n4:23796390

Subject Item: _:vb29630495
rdf:type: n3:Context
rdf:value: As an example, through mild hyperthermia (41 °C), liposomal doxorubicin (L-DXR) showed an improvement in the tumor vasculature permeability, a subsequent increase in liposome extravasation, and an enhanced interstitial penetration [>>8<<,9].
n3:mentions: n4:23391444

Subject Item: _:vb29630496
rdf:type: n3:Context
rdf:value: As an example, through mild hyperthermia (41 °C), liposomal doxorubicin (L-DXR) showed an improvement in the tumor vasculature permeability, a subsequent increase in liposome extravasation, and an enhanced interstitial penetration [8,>>9<<].
n3:mentions: n4:23524188

Subject Item: _:vb29630497
rdf:type: n3:Context
rdf:value: Numerous liposome-based products have been approved or marketed [>>10<<]. For oncology applications, several classes of antineoplastic agents have been incorporated into liposomes in order to increase their therapeutic index.
n3:mentions: n4:22275822

Subject Item: _:vb29630498
rdf:type: n3:Context
rdf:value: They include taxanes [>>11<<,12,13], anthracyclines [14,15], platinum analogs [16,17], camptothecins [18,19,20,21], Vinca alkaloids [22,23], and antimetabolites [24].
n3:mentions: n4:15620886

Subject Item: _:vb29630499
rdf:type: n3:Context
rdf:value: They include taxanes [11,>>12<<,13], anthracyclines [14,15], platinum analogs [16,17], camptothecins [18,19,20,21], Vinca alkaloids [22,23], and antimetabolites [24].
n3:mentions: n4:9096672

Subject Item: _:vb29630500
rdf:type: n3:Context
rdf:value: They include taxanes [11,12,>>13<<], anthracyclines [14,15], platinum analogs [16,17], camptothecins [18,19,20,21], Vinca alkaloids [22,23], and antimetabolites [24].
n3:mentions: n4:7903197

Subject Item: _:vb29630501
rdf:type: n3:Context
rdf:value: They include taxanes [11,12,13], anthracyclines [>>14<<,15], platinum analogs [16,17], camptothecins [18,19,20,21], Vinca alkaloids [22,23], and antimetabolites [24].
n3:mentions: n4:9103545

Subject Item: _:vb29630502
rdf:type: n3:Context
rdf:value: They include taxanes [11,12,13], anthracyclines [14,>>15<<], platinum analogs [16,17], camptothecins [18,19,20,21], Vinca alkaloids [22,23], and antimetabolites [24].
n3:mentions: n4:8616852

Subject Item: _:vb29630503
rdf:type: n3:Context
rdf:value: They include taxanes [11,12,13], anthracyclines [14,15], platinum analogs [>>16<<,17], camptothecins [18,19,20,21], Vinca alkaloids [22,23], and antimetabolites [24].
n3:mentions: n4:11714540

Subject Item: _:vb29630504
rdf:type: n3:Context
rdf:value: They include taxanes [11,12,13], anthracyclines [14,15], platinum analogs [16,>>17<<], camptothecins [18,19,20,21], Vinca alkaloids [22,23], and antimetabolites [24].
n3:mentions: n4:15908659

Subject Item: _:vb29630505
rdf:type: n3:Context
rdf:value: They include taxanes [11,12,13], anthracyclines [14,15], platinum analogs [16,17], camptothecins [>>18<<,19,20,21], Vinca alkaloids [22,23], and antimetabolites [24].
n3:mentions: n4:10910044

Subject Item: _:vb29630506
rdf:type: n3:Context
rdf:value: They include taxanes [11,12,13], anthracyclines [14,15], platinum analogs [16,17], camptothecins [18,>>19<<,20,21], Vinca alkaloids [22,23], and antimetabolites [24].
n3:mentions: n4:15816556

Subject Item: _:vb29630507
rdf:type: n3:Context
rdf:value: They include taxanes [11,12,13], anthracyclines [14,15], platinum analogs [16,17], camptothecins [18,19,>>20<<,21], Vinca alkaloids [22,23], and antimetabolites [24].
n3:mentions: n4:10914740

Subject Item: _:vb29630508
rdf:type: n3:Context
rdf:value: They include taxanes [11,12,13], anthracyclines [14,15], platinum analogs [16,17], camptothecins [18,19,20,>>21<<], Vinca alkaloids [22,23], and antimetabolites [24].
n3:mentions: n4:16540680

Subject Item: _:vb29630509
rdf:type: n3:Context
rdf:value: They include taxanes [11,12,13], anthracyclines [14,15], platinum analogs [16,17], camptothecins [18,19,20,21], Vinca alkaloids [>>22<<,23], and antimetabolites [24].
n3:mentions: n4:11504822

Subject Item: _:vb29630510
rdf:type: n3:Context
rdf:value: They include taxanes [11,12,13], anthracyclines [14,15], platinum analogs [16,17], camptothecins [18,19,20,21], Vinca alkaloids [22,>>23<<], and antimetabolites [24].
n3:mentions: n4:15866338

Subject Item: _:vb29630511
rdf:type: n3:Context
rdf:value: They include taxanes [11,12,13], anthracyclines [14,15], platinum analogs [16,17], camptothecins [18,19,20,21], Vinca alkaloids [22,23], and antimetabolites [>>24<<]. Numerous liposomal anticancer drugs are in late stage clinical development or are clinically approved. A selection is shown in Table 1. Food and Drug Administration (FDA) approved products include conventional- and SSL-based
n3:mentions: n4:19507033

Subject Item: _:vb29630512
rdf:type: n3:Context
rdf:value: and increasing the fraction of the injected dose delivered to the tumor site because of flaws in the tumor vascular endothelium, which underlies the extended permeability and retention (EPR) of nanoparticulates in the tumor interstitium [>>3<<,26]. Examples of beneficial pharmacodynamic effects mediated by liposomes are more elusive to identify; alterations of PD would manifest themselves following careful analysis and accounting for PK effects on drug biodistribution at the
n3:mentions: n4:10581328

Subject Item: _:vb29630513
rdf:type: n3:Context
rdf:value: increasing the fraction of the injected dose delivered to the tumor site because of flaws in the tumor vascular endothelium, which underlies the extended permeability and retention (EPR) of nanoparticulates in the tumor interstitium [3,>>26<<]. Examples of beneficial pharmacodynamic effects mediated by liposomes are more elusive to identify; alterations of PD would manifest themselves following careful analysis and accounting for PK effects on drug biodistribution at the
n3:mentions: n4:2946403

Subject Item: _:vb29630514
rdf:type: n3:Context
rdf:value: in PD, such as an increase in potency of an encapsulated drug relative to the unencapsulated drug, actually arise from biodistributional (PK) effects such as demonstrated for the gemcitabine-loaded innovative nanocarrier formulation [>>27<<
n3:mentions: n4:22077480

Subject Item: _:vb29630515
rdf:type: n3:Context
rdf:value: Approved liposomal anticancer chemotherapeuticsLiposomal anticancer drugBrand nameIndicationsReferencesPegylated liposomal DXRDoxil®AIDS-related Kaposi’s sarcoma[>>28<<,29,30] Metastatic ovarian cancer Metastatic breast cancer[31,32,33,34] Multiple myeloma[35,36,37,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s
n3:mentions: n4:9469358

Subject Item: _:vb29630516
rdf:type: n3:Context
rdf:value: Approved liposomal anticancer chemotherapeuticsLiposomal anticancer drugBrand nameIndicationsReferencesPegylated liposomal DXRDoxil®AIDS-related Kaposi’s sarcoma[28,>>29<<,30] Metastatic ovarian cancer Metastatic breast cancer[31,32,33,34] Multiple myeloma[35,36,37,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s
n3:mentions: n4:9667262

Subject Item: _:vb29630517
rdf:type: n3:Context
rdf:value: Approved liposomal anticancer chemotherapeuticsLiposomal anticancer drugBrand nameIndicationsReferencesPegylated liposomal DXRDoxil®AIDS-related Kaposi’s sarcoma[28,29,>>30<<] Metastatic ovarian cancer Metastatic breast cancer[31,32,33,34] Multiple myeloma[35,36,37,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s
n3:mentions: n4:20564162

Subject Item: _:vb29630518
rdf:type: n3:Context
rdf:value: Approved liposomal anticancer chemotherapeuticsLiposomal anticancer drugBrand nameIndicationsReferencesPegylated liposomal DXRDoxil®AIDS-related Kaposi’s sarcoma[28,29,30] Metastatic ovarian cancer Metastatic breast cancer[>>31<<,32,33,34] Multiple myeloma[35,36,37,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s sarcoma[42]Liposomal cytarabine Acute myeloid leukemia[43]
n3:mentions: n4:11454878

Subject Item: _:vb29630519
rdf:type: n3:Context
rdf:value: Approved liposomal anticancer chemotherapeuticsLiposomal anticancer drugBrand nameIndicationsReferencesPegylated liposomal DXRDoxil®AIDS-related Kaposi’s sarcoma[28,29,30] Metastatic ovarian cancer Metastatic breast cancer[31,>>32<<,33,34] Multiple myeloma[35,36,37,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s sarcoma[42]Liposomal cytarabine Acute myeloid leukemia[43] DepoCyte®Lymphomas
n3:mentions: n4:19039248

Subject Item: _:vb29630520
rdf:type: n3:Context
rdf:value: Approved liposomal anticancer chemotherapeuticsLiposomal anticancer drugBrand nameIndicationsReferencesPegylated liposomal DXRDoxil®AIDS-related Kaposi’s sarcoma[28,29,30] Metastatic ovarian cancer Metastatic breast cancer[31,32,>>33<<,34] Multiple myeloma[35,36,37,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s sarcoma[42]Liposomal cytarabine Acute myeloid leukemia[43] DepoCyte®Lymphomas
n3:mentions: n4:20044128

Subject Item: _:vb29630521
rdf:type: n3:Context
rdf:value: Approved liposomal anticancer chemotherapeuticsLiposomal anticancer drugBrand nameIndicationsReferencesPegylated liposomal DXRDoxil®AIDS-related Kaposi’s sarcoma[28,29,30] Metastatic ovarian cancer Metastatic breast cancer[31,32,33,>>34<<] Multiple myeloma[35,36,37,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s sarcoma[42]Liposomal cytarabine Acute myeloid leukemia[43] DepoCyte®Lymphomas and
n3:mentions: n4:20498395

Subject Item: _:vb29630522
rdf:type: n3:Context
rdf:value: chemotherapeuticsLiposomal anticancer drugBrand nameIndicationsReferencesPegylated liposomal DXRDoxil®AIDS-related Kaposi’s sarcoma[28,29,30] Metastatic ovarian cancer Metastatic breast cancer[31,32,33,34] Multiple myeloma[>>35<<,36,37,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s sarcoma[42]Liposomal cytarabine Acute myeloid leukemia[43] DepoCyte®Lymphomas and leukemia with meningeal
n3:mentions: n4:15459210

Subject Item: _:vb29630523
rdf:type: n3:Context
rdf:value: chemotherapeuticsLiposomal anticancer drugBrand nameIndicationsReferencesPegylated liposomal DXRDoxil®AIDS-related Kaposi’s sarcoma[28,29,30] Metastatic ovarian cancer Metastatic breast cancer[31,32,33,34] Multiple myeloma[35,>>36<<,37,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s sarcoma[42]Liposomal cytarabine Acute myeloid leukemia[43] DepoCyte®Lymphomas and leukemia with meningeal
n3:mentions: n4:15367414

Subject Item: _:vb29630524
rdf:type: n3:Context
rdf:value: chemotherapeuticsLiposomal anticancer drugBrand nameIndicationsReferencesPegylated liposomal DXRDoxil®AIDS-related Kaposi’s sarcoma[28,29,30] Metastatic ovarian cancer Metastatic breast cancer[31,32,33,34] Multiple myeloma[35,36,>>37<<,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s sarcoma[42]Liposomal cytarabine Acute myeloid leukemia[43] DepoCyte®Lymphomas and leukemia with meningeal
n3:mentions: n4:19687336

Subject Item: _:vb29630525
rdf:type: n3:Context
rdf:value: chemotherapeuticsLiposomal anticancer drugBrand nameIndicationsReferencesPegylated liposomal DXRDoxil®AIDS-related Kaposi’s sarcoma[28,29,30] Metastatic ovarian cancer Metastatic breast cancer[31,32,33,34] Multiple myeloma[35,36,37,>>38<<]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s sarcoma[42]Liposomal cytarabine Acute myeloid leukemia[43] DepoCyte®Lymphomas and leukemia with meningeal
n3:mentions: n4:20361253

Subject Item: _:vb29630526
rdf:type: n3:Context
rdf:value: liposomal DXRDoxil®AIDS-related Kaposi’s sarcoma[28,29,30] Metastatic ovarian cancer Metastatic breast cancer[31,32,33,34] Multiple myeloma[35,36,37,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[>>39<<,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s sarcoma[42]Liposomal cytarabine Acute myeloid leukemia[43] DepoCyte®Lymphomas and leukemia with meningeal spread[44]Liposomal anticancer drugs in developmentDrug nameEncapsulated
n3:mentions: n4:16404741

Subject Item: _:vb29630527
rdf:type: n3:Context
rdf:value: liposomal DXRDoxil®AIDS-related Kaposi’s sarcoma[28,29,30] Metastatic ovarian cancer Metastatic breast cancer[31,32,33,34] Multiple myeloma[35,36,37,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,>>40<<,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s sarcoma[42]Liposomal cytarabine Acute myeloid leukemia[43] DepoCyte®Lymphomas and leukemia with meningeal spread[44]Liposomal anticancer drugs in developmentDrug nameEncapsulated
n3:mentions: n4:17679727

Subject Item: _:vb29630528
rdf:type: n3:Context
rdf:value: liposomal DXRDoxil®AIDS-related Kaposi’s sarcoma[28,29,30] Metastatic ovarian cancer Metastatic breast cancer[31,32,33,34] Multiple myeloma[35,36,37,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,40,>>41<<]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s sarcoma[42]Liposomal cytarabine Acute myeloid leukemia[43] DepoCyte®Lymphomas and leukemia with meningeal spread[44]Liposomal anticancer drugs in developmentDrug nameEncapsulated
n3:mentions: n4:18300257

Subject Item: _:vb29630529
rdf:type: n3:Context
rdf:value: Metastatic ovarian cancer Metastatic breast cancer[31,32,33,34] Multiple myeloma[35,36,37,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s sarcoma[>>42<<]Liposomal cytarabine Acute myeloid leukemia[43] DepoCyte®Lymphomas and leukemia with meningeal spread[44]Liposomal anticancer drugs in developmentDrug nameEncapsulated drugStage of developmentReferencesLiposomal annamycinAnnamycinPhase
n3:mentions: n4:8708728

Subject Item: _:vb29630530
rdf:type: n3:Context
rdf:value: breast cancer[31,32,33,34] Multiple myeloma[35,36,37,38]Non-pegylated liposomal DXRMyocet®Same indications as Doxil®[39,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s sarcoma[42]Liposomal cytarabine Acute myeloid leukemia[>>43<<] DepoCyte®Lymphomas and leukemia with meningeal spread[44]Liposomal anticancer drugs in developmentDrug nameEncapsulated drugStage of developmentReferencesLiposomal annamycinAnnamycinPhase II[45,46]SPI-77CisplatinPhase
n3:mentions: n4:18950458

Subject Item: _:vb29630531
rdf:type: n3:Context
rdf:value: liposomal DXRMyocet®Same indications as Doxil®[39,40,41]Liposomal daunorubicinDaunoXome®AIDS-related Kaposi’s sarcoma[42]Liposomal cytarabine Acute myeloid leukemia[43] DepoCyte®Lymphomas and leukemia with meningeal spread[>>44<<]Liposomal anticancer drugs in developmentDrug nameEncapsulated drugStage of developmentReferencesLiposomal annamycinAnnamycinPhase II[45,46]SPI-77CisplatinPhase II[16,47,48,49]LipoplatinCisplatinPhase III[50]LiPlaCisCisplatinPhase
n3:mentions: n4:10506606

Subject Item: _:vb29630532
rdf:type: n3:Context
rdf:value: cytarabine Acute myeloid leukemia[43] DepoCyte®Lymphomas and leukemia with meningeal spread[44]Liposomal anticancer drugs in developmentDrug nameEncapsulated drugStage of developmentReferencesLiposomal annamycinAnnamycinPhase II[>>45<<,46]SPI-77CisplatinPhase II[16,47,48,49]LipoplatinCisplatinPhase III[50]LiPlaCisCisplatinPhase I[51]l-NDDP/aroplatinCisplatin analoguePhase II[17,52]ThermoDox®DoxorubicinPhase II[53]JNS002DoxorubicinPhase II[54]TLITopotecanTrialwww.
n3:mentions: n4:12111105

Subject Item: _:vb29630533
rdf:type: n3:Context
rdf:value: cytarabine Acute myeloid leukemia[43] DepoCyte®Lymphomas and leukemia with meningeal spread[44]Liposomal anticancer drugs in developmentDrug nameEncapsulated drugStage of developmentReferencesLiposomal annamycinAnnamycinPhase II[45,>>46<<]SPI-77CisplatinPhase II[16,47,48,49]LipoplatinCisplatinPhase III[50]LiPlaCisCisplatinPhase I[51]l-NDDP/aroplatinCisplatin analoguePhase II[17,52]ThermoDox®DoxorubicinPhase II[53]JNS002DoxorubicinPhase II[54]TLITopotecanTrialwww.
n3:mentions: n4:23763920

Subject Item: _:vb29630534
rdf:type: n3:Context
rdf:value: leukemia[43] DepoCyte®Lymphomas and leukemia with meningeal spread[44]Liposomal anticancer drugs in developmentDrug nameEncapsulated drugStage of developmentReferencesLiposomal annamycinAnnamycinPhase II[45,46]SPI-77CisplatinPhase II[>>16<<,47,48,49]LipoplatinCisplatinPhase III[50]LiPlaCisCisplatinPhase I[51]l-NDDP/aroplatinCisplatin analoguePhase II[17,52]ThermoDox®DoxorubicinPhase II[53]JNS002DoxorubicinPhase II[54]TLITopotecanTrialwww.
n3:mentions: n4:11714540

Subject Item: _:vb29630535
rdf:type: n3:Context
rdf:value: leukemia[43] DepoCyte®Lymphomas and leukemia with meningeal spread[44]Liposomal anticancer drugs in developmentDrug nameEncapsulated drugStage of developmentReferencesLiposomal annamycinAnnamycinPhase II[45,46]SPI-77CisplatinPhase II[16,>>47<<,48,49]LipoplatinCisplatinPhase III[50]LiPlaCisCisplatinPhase I[51]l-NDDP/aroplatinCisplatin analoguePhase II[17,52]ThermoDox®DoxorubicinPhase II[53]JNS002DoxorubicinPhase II[54]TLITopotecanTrialwww.
n3:mentions: n4:11398881

Subject Item: _:vb29630536
rdf:type: n3:Context
rdf:value: DepoCyte®Lymphomas and leukemia with meningeal spread[44]Liposomal anticancer drugs in developmentDrug nameEncapsulated drugStage of developmentReferencesLiposomal annamycinAnnamycinPhase II[45,46]SPI-77CisplatinPhase II[16,47,>>48<<,49]LipoplatinCisplatinPhase III[50]LiPlaCisCisplatinPhase I[51]l-NDDP/aroplatinCisplatin analoguePhase II[17,52]ThermoDox®DoxorubicinPhase II[53]JNS002DoxorubicinPhase II[54]TLITopotecanTrialwww.
n3:mentions: n4:20332467

Subject Item: _:vb29630537
rdf:type: n3:Context
rdf:value: DepoCyte®Lymphomas and leukemia with meningeal spread[44]Liposomal anticancer drugs in developmentDrug nameEncapsulated drugStage of developmentReferencesLiposomal annamycinAnnamycinPhase II[45,46]SPI-77CisplatinPhase II[16,47,48,>>49<<]LipoplatinCisplatinPhase III[50]LiPlaCisCisplatinPhase I[51]l-NDDP/aroplatinCisplatin analoguePhase II[17,52]ThermoDox®DoxorubicinPhase II[53]JNS002DoxorubicinPhase II[54]TLITopotecanTrialwww.
n3:mentions: n4:16969346

Subject Item: _:vb29630538
rdf:type: n3:Context
rdf:value: with meningeal spread[44]Liposomal anticancer drugs in developmentDrug nameEncapsulated drugStage of developmentReferencesLiposomal annamycinAnnamycinPhase II[45,46]SPI-77CisplatinPhase II[16,47,48,49]LipoplatinCisplatinPhase III[>>50<<]LiPlaCisCisplatinPhase I[51]l-NDDP/aroplatinCisplatin analoguePhase II[17,52]ThermoDox®DoxorubicinPhase II[53]JNS002DoxorubicinPhase II[54]TLITopotecanTrialwww.
n3:mentions: n4:21301848

Subject Item: _:vb29630539
rdf:type: n3:Context
rdf:value: anticancer drugs in developmentDrug nameEncapsulated drugStage of developmentReferencesLiposomal annamycinAnnamycinPhase II[45,46]SPI-77CisplatinPhase II[16,47,48,49]LipoplatinCisplatinPhase III[50]LiPlaCisCisplatinPhase I[>>51<<]l-NDDP/aroplatinCisplatin analoguePhase II[17,52]ThermoDox®DoxorubicinPhase II[53]JNS002DoxorubicinPhase II[54]TLITopotecanTrialwww.
n3:mentions: n4:20801016

Subject Item: _:vb29630540
rdf:type: n3:Context
rdf:value: nameEncapsulated drugStage of developmentReferencesLiposomal annamycinAnnamycinPhase II[45,46]SPI-77CisplatinPhase II[16,47,48,49]LipoplatinCisplatinPhase III[50]LiPlaCisCisplatinPhase I[51]l-NDDP/aroplatinCisplatin analoguePhase II[>>17<<,52]ThermoDox®DoxorubicinPhase II[53]JNS002DoxorubicinPhase II[54]TLITopotecanTrialwww.
n3:mentions: n4:15908659

Subject Item: _:vb29630541
rdf:type: n3:Context
rdf:value: nameEncapsulated drugStage of developmentReferencesLiposomal annamycinAnnamycinPhase II[45,46]SPI-77CisplatinPhase II[16,47,48,49]LipoplatinCisplatinPhase III[50]LiPlaCisCisplatinPhase I[51]l-NDDP/aroplatinCisplatin analoguePhase II[17,>>52<<]ThermoDox®DoxorubicinPhase II[53]JNS002DoxorubicinPhase II[54]TLITopotecanTrialwww.
n3:mentions: n4:16847673

Subject Item: _:vb29630542
rdf:type: n3:Context
rdf:value: annamycinAnnamycinPhase II[45,46]SPI-77CisplatinPhase II[16,47,48,49]LipoplatinCisplatinPhase III[50]LiPlaCisCisplatinPhase I[51]l-NDDP/aroplatinCisplatin analoguePhase II[17,52]ThermoDox®DoxorubicinPhase II[53]JNS002DoxorubicinPhase II[>>54<<]TLITopotecanTrialwww.clinicaltrials.govOSI211LurtotecanPhase III[52,55]LEMMitoxantronePreclinical[56]NL CPT-11CamptothecinTrialwww.
n3:mentions: n4:18927230

Subject Item: _:vb29630543
rdf:type: n3:Context
rdf:value: govOSI211LurtotecanPhase III[>>52<<,55]LEMMitoxantronePreclinical[56]NL CPT-11CamptothecinTrialwww.
n3:mentions: n4:16847673

Subject Item: _:vb29630544
rdf:type: n3:Context
rdf:value: govOSI211LurtotecanPhase III[52,>>55<<]LEMMitoxantronePreclinical[56]NL CPT-11CamptothecinTrialwww.
n3:mentions: n4:15571957

Subject Item: _:vb29630545
rdf:type: n3:Context
rdf:value: govOSI211LurtotecanPhase III[52,55]LEMMitoxantronePreclinical[>>56<<]NL CPT-11CamptothecinTrialwww.
n3:mentions: n4:11848489

Subject Item: _:vb29630546
rdf:type: n3:Context
rdf:value: govIHL-305IrinotecanPhase I[>>57<<]PEP02IrinotecanPhase I[58]MBP426OxaliplatinPhase I[59]LE-SN38Active metabolite of IrinotecanTrialwww.
n3:mentions: n4:22941375

Subject Item: _:vb29630547
rdf:type: n3:Context
rdf:value: govIHL-305IrinotecanPhase I[57]PEP02IrinotecanPhase I[>>58<<]MBP426OxaliplatinPhase I[59]LE-SN38Active metabolite of IrinotecanTrialwww.
n3:mentions: n4:23406728

Subject Item: _:vb29630548
rdf:type: n3:Context
rdf:value: clinicaltrials.govMarqibo®VinscristinePhase II[>>60<<]VLIVinorelbineTrialwww.clinicaltrials.
n3:mentions: n4:19536896

Subject Item: _:vb29630549
rdf:type: n3:Context
rdf:value: clinicaltrials.govCPX-1Combination: Irinotecan + FloxuridinePhase I[>>61<<]CPX-351Combination:
n3:mentions: n4:19147776

Subject Item: _:vb29630550
rdf:type: n3:Context
rdf:value: govCPX-1Combination: Irinotecan + FloxuridinePhase I[61]CPX-351Combination: Cytarabine + DaunorubicinPhase I[>>62<<
n3:mentions: n4:21282541

Subject Item: _:vb29630551
rdf:type: n2:Section
dc:title: conclusions
n2:contains: _:vb29630552

Subject Item: _:vb29630552
rdf:type: n3:Context
rdf:value: industry on liposomal drug formulations provides recommendations on the chemistry, manufacturing controls, human PK and bioavailability, and labeling documentation for liposome drug products submitted in new drug applications (NDA) [>>191<<], there has been relatively little emphasis upon the use of computational tools that could streamline the development of novel liposomal formulations or provide a better means to improve the PK and PD characteristics of existing
n3:mentions: n4:10645944

Subject Item: _:vb29630553
rdf:type: n2:Section
dc:title: requisite drug and carrier properties
n2:contains: _:vb29630554 _:vb29630555 _:vb29630556 _:vb29630557 _:vb29630558 _:vb29630559 _:vb29630560 _:vb29630561 _:vb29630562 _:vb29630563 _:vb29630564 _:vb29630565 _:vb29630566 _:vb29630567 _:vb29630568 _:vb29630569 _:vb29630570 _:vb29630571 _:vb29630572 _:vb29630573

Subject Item: _:vb29630554
rdf:type: n3:Context
rdf:value: Common examples include anthracyclines and Vinca alkaloids, which have shown activity against a broad range of cancers [>>14<<,15,22,23,63].
n3:mentions: n4:9103545

Subject Item: _:vb29630555
rdf:type: n3:Context
rdf:value: Common examples include anthracyclines and Vinca alkaloids, which have shown activity against a broad range of cancers [14,>>15<<,22,23,63].
n3:mentions: n4:8616852

Subject Item: _:vb29630556
rdf:type: n3:Context
rdf:value: Common examples include anthracyclines and Vinca alkaloids, which have shown activity against a broad range of cancers [14,15,>>22<<,23,63].
n3:mentions: n4:11504822

Subject Item: _:vb29630557
rdf:type: n3:Context
rdf:value: Common examples include anthracyclines and Vinca alkaloids, which have shown activity against a broad range of cancers [14,15,22,>>23<<,63].
n3:mentions: n4:15866338

Subject Item: _:vb29630558
rdf:type: n3:Context
rdf:value: Common examples include anthracyclines and Vinca alkaloids, which have shown activity against a broad range of cancers [14,15,22,23,>>63<<].
n3:mentions: n4:7017406

Subject Item: _:vb29630559
rdf:type: n3:Context
rdf:value: electrochemical gradients coupled with a trapping agent within the liposome interior, which can raise encapsulation efficiency for amphipathic basic amines such as DXR or vinblastine to essentially 100%, with high drug:lipid loadings [>>64<<,65,66,67,68,69,70].
n3:mentions: n4:11002

Subject Item: _:vb29630560
rdf:type: n3:Context
rdf:value: gradients coupled with a trapping agent within the liposome interior, which can raise encapsulation efficiency for amphipathic basic amines such as DXR or vinblastine to essentially 100%, with high drug:lipid loadings [64,>>65<<,66,67,68,69,70].
n3:mentions: n4:3839135

Subject Item: _:vb29630561
rdf:type: n3:Context
rdf:value: gradients coupled with a trapping agent within the liposome interior, which can raise encapsulation efficiency for amphipathic basic amines such as DXR or vinblastine to essentially 100%, with high drug:lipid loadings [64,65,>>66<<,67,68,69,70].
n3:mentions: n4:1972352

Subject Item: _:vb29630562
rdf:type: n3:Context
rdf:value: gradients coupled with a trapping agent within the liposome interior, which can raise encapsulation efficiency for amphipathic basic amines such as DXR or vinblastine to essentially 100%, with high drug:lipid loadings [64,65,66,>>67<<,68,69,70].
n3:mentions: n4:1426260

Subject Item: _:vb29630563
rdf:type: n3:Context
rdf:value: gradients coupled with a trapping agent within the liposome interior, which can raise encapsulation efficiency for amphipathic basic amines such as DXR or vinblastine to essentially 100%, with high drug:lipid loadings [64,65,66,67,>>68<<,69,70].
n3:mentions: n4:8373796

Subject Item: _:vb29630564
rdf:type: n3:Context
rdf:value: gradients coupled with a trapping agent within the liposome interior, which can raise encapsulation efficiency for amphipathic basic amines such as DXR or vinblastine to essentially 100%, with high drug:lipid loadings [64,65,66,67,68,>>69<<,70].
n3:mentions: n4:9325441

Subject Item: _:vb29630565
rdf:type: n3:Context
rdf:value: gradients coupled with a trapping agent within the liposome interior, which can raise encapsulation efficiency for amphipathic basic amines such as DXR or vinblastine to essentially 100%, with high drug:lipid loadings [64,65,66,67,68,69,>>70<<].
n3:mentions: n4:19508880

Subject Item: _:vb29630566
rdf:type: n3:Context
rdf:value: With this drug category, it is possible to modulate the drug-release rates by employing gradient-based loading techniques in order to maintain stable encapsulation in the circulation, yet allow the drug to be released at the tumor site [>>14<<,65,66,68,71,72,73,74].
n3:mentions: n4:9103545

Subject Item: _:vb29630567
rdf:type: n3:Context
rdf:value: this drug category, it is possible to modulate the drug-release rates by employing gradient-based loading techniques in order to maintain stable encapsulation in the circulation, yet allow the drug to be released at the tumor site [14,>>65<<,66,68,71,72,73,74].
n3:mentions: n4:3839135

Subject Item: _:vb29630568
rdf:type: n3:Context
rdf:value: drug category, it is possible to modulate the drug-release rates by employing gradient-based loading techniques in order to maintain stable encapsulation in the circulation, yet allow the drug to be released at the tumor site [14,65,>>66<<,68,71,72,73,74].
n3:mentions: n4:1972352

Subject Item: _:vb29630569
rdf:type: n3:Context
rdf:value: drug category, it is possible to modulate the drug-release rates by employing gradient-based loading techniques in order to maintain stable encapsulation in the circulation, yet allow the drug to be released at the tumor site [14,65,66,>>68<<,71,72,73,74].
n3:mentions: n4:8373796

Subject Item: _:vb29630570
rdf:type: n3:Context
rdf:value: category, it is possible to modulate the drug-release rates by employing gradient-based loading techniques in order to maintain stable encapsulation in the circulation, yet allow the drug to be released at the tumor site [14,65,66,68,>>71<<,72,73,74].
n3:mentions: n4:15157619

Subject Item: _:vb29630571
rdf:type: n3:Context
rdf:value: category, it is possible to modulate the drug-release rates by employing gradient-based loading techniques in order to maintain stable encapsulation in the circulation, yet allow the drug to be released at the tumor site [14,65,66,68,71,>>72<<,73,74].
n3:mentions: n4:18569449

Subject Item: _:vb29630572
rdf:type: n3:Context
rdf:value: it is possible to modulate the drug-release rates by employing gradient-based loading techniques in order to maintain stable encapsulation in the circulation, yet allow the drug to be released at the tumor site [14,65,66,68,71,72,>>73<<,74].
n3:mentions: n4:16203786

Subject Item: _:vb29630573
rdf:type: n3:Context
rdf:value: it is possible to modulate the drug-release rates by employing gradient-based loading techniques in order to maintain stable encapsulation in the circulation, yet allow the drug to be released at the tumor site [14,65,66,68,71,72,73,>>74<<].
n3:mentions: n4:10604968

Subject Item: _:vb29630574
rdf:type: n2:Section
dc:title: integration of in vivo factors influencing pharmacokinetic (pk) and performance of liposomal formulations
n2:contains: _:vb29630588 _:vb29630589 _:vb29630590 _:vb29630591 _:vb29630584 _:vb29630585 _:vb29630586 _:vb29630587 _:vb29630580 _:vb29630581 _:vb29630582 _:vb29630583 _:vb29630576 _:vb29630577 _:vb29630578 _:vb29630579 _:vb29630575 _:vb29630620 _:vb29630621 _:vb29630622 _:vb29630623 _:vb29630616 _:vb29630617 _:vb29630618 _:vb29630619 _:vb29630612 _:vb29630613 _:vb29630614 _:vb29630615 _:vb29630608 _:vb29630609 _:vb29630610 _:vb29630611 _:vb29630604 _:vb29630605 _:vb29630606 _:vb29630607 _:vb29630600 _:vb29630601 _:vb29630602 _:vb29630603 _:vb29630596 _:vb29630597 _:vb29630598 _:vb29630599 _:vb29630592 _:vb29630593 _:vb29630594 _:vb29630595 _:vb29630624 _:vb29630625 _:vb29630626 _:vb29630627

Subject Item: _:vb29630575
rdf:type: n3:Context
rdf:value: The processes by which liposomes and other nanoparticles are cleared from the bloodstream have been investigated in considerable detail [>>75<<,76]. The main mechanism for their elimination is through recognition and uptake by macrophages of the reticuloendothelial system (RES), which reside primarily within the liver and spleen [77,78,79,80].
n3:mentions: n4:12428901

Subject Item: _:vb29630576
rdf:type: n3:Context
rdf:value: The processes by which liposomes and other nanoparticles are cleared from the bloodstream have been investigated in considerable detail [75,>>76<<]. The main mechanism for their elimination is through recognition and uptake by macrophages of the reticuloendothelial system (RES), which reside primarily within the liver and spleen [77,78,79,80].
n3:mentions: n4:22035254

Subject Item: _:vb29630577
rdf:type: n3:Context
rdf:value: The main mechanism for their elimination is through recognition and uptake by macrophages of the reticuloendothelial system (RES), which reside primarily within the liver and spleen [>>77<<,78,79,80].
n3:mentions: n4:3542245

Subject Item: _:vb29630578
rdf:type: n3:Context
rdf:value: The main mechanism for their elimination is through recognition and uptake by macrophages of the reticuloendothelial system (RES), which reside primarily within the liver and spleen [77,>>78<<,79,80]. Liposome clearance may be influenced by physicochemical factors that are discussed below, including the vesicle size, lipid composition of the membrane, and release rate of liposome contents. Liposomes can also interact with
n3:mentions: n4:6692424

Subject Item: _:vb29630579
rdf:type: n3:Context
rdf:value: The main mechanism for their elimination is through recognition and uptake by macrophages of the reticuloendothelial system (RES), which reside primarily within the liver and spleen [77,78,>>79<<,80]. Liposome clearance may be influenced by physicochemical factors that are discussed below, including the vesicle size, lipid composition of the membrane, and release rate of liposome contents. Liposomes can also interact with plasma
n3:mentions: n4:785256

Subject Item: _:vb29630580
rdf:type: n3:Context
rdf:value: The main mechanism for their elimination is through recognition and uptake by macrophages of the reticuloendothelial system (RES), which reside primarily within the liver and spleen [77,78,79,>>80<<]. Liposome clearance may be influenced by physicochemical factors that are discussed below, including the vesicle size, lipid composition of the membrane, and release rate of liposome contents. Liposomes can also interact with plasma
n3:mentions: n4:958245

Subject Item: _:vb29630581
rdf:type: n3:Context
rdf:value: Liposomes can also interact with plasma constituents such as proteins, thus affecting their fate in vivo, either by affecting their stability and/or modulating their subsequent interaction with the target cells [>>75<<]. Plasma protein interactions may extract or exchange lipids from the carrier, compromising its integrity. Mediators of clearance include plasma protein opsonins, fibronectin, C-reactive protein (CRP), the C3b complement fragment,
n3:mentions: n4:12428901

Subject Item: _:vb29630582
rdf:type: n3:Context
rdf:value: Mediators of clearance include plasma protein opsonins, fibronectin, C-reactive protein (CRP), the C3b complement fragment, β2-glycoprotein I, or the Fc portion of an immunoglobulin G (IgG) [>>77<<,81,82]. Opsonization can compromise liposome stability and promote endocytosis or phagocytosis by macrophages of the RES. Renal excretion may represent a significant component of total clearance for very small nanoparticles (<4–8 nm
n3:mentions: n4:3542245

Subject Item: _:vb29630583
rdf:type: n3:Context
rdf:value: Mediators of clearance include plasma protein opsonins, fibronectin, C-reactive protein (CRP), the C3b complement fragment, β2-glycoprotein I, or the Fc portion of an immunoglobulin G (IgG) [77,>>81<<,82]. Opsonization can compromise liposome stability and promote endocytosis or phagocytosis by macrophages of the RES. Renal excretion may represent a significant component of total clearance for very small nanoparticles (<4–8 nm
n3:mentions: n4:1574654

Subject Item: _:vb29630584
rdf:type: n3:Context
rdf:value: Mediators of clearance include plasma protein opsonins, fibronectin, C-reactive protein (CRP), the C3b complement fragment, β2-glycoprotein I, or the Fc portion of an immunoglobulin G (IgG) [77,81,>>82<<]. Opsonization can compromise liposome stability and promote endocytosis or phagocytosis by macrophages of the RES. Renal excretion may represent a significant component of total clearance for very small nanoparticles (<4–8 nm diameter)
n3:mentions: n4:9107519

Subject Item: _:vb29630585
rdf:type: n3:Context
rdf:value: Renal excretion may represent a significant component of total clearance for very small nanoparticles (<4–8 nm diameter) but does not impact clearance of most liposome formulations (>30 nm) [>>83<<,84].
n3:mentions: n4:10894790

Subject Item: _:vb29630586
rdf:type: n3:Context
rdf:value: Renal excretion may represent a significant component of total clearance for very small nanoparticles (<4–8 nm diameter) but does not impact clearance of most liposome formulations (>30 nm) [83,>>84<<].
n3:mentions: n4:12620929

Subject Item: _:vb29630587
rdf:type: n3:Context
rdf:value: For these reasons, drug release from liposomes has major impact upon toxicity and antitumor efficacy [>>3<<,85]. A number of studies identify the kinetic complexities arising from the rate of tumor accumulation of liposomes and the rate of drug release, and show that it may be necessary to modulate the rate of drug release for optimal efficacy
n3:mentions: n4:10581328

Subject Item: _:vb29630588
rdf:type: n3:Context
rdf:value: For these reasons, drug release from liposomes has major impact upon toxicity and antitumor efficacy [3,>>85<<]. A number of studies identify the kinetic complexities arising from the rate of tumor accumulation of liposomes and the rate of drug release, and show that it may be necessary to modulate the rate of drug release for optimal efficacy
n3:mentions: n4:17100556

Subject Item: _:vb29630589
rdf:type: n3:Context
rdf:value: A number of studies identify the kinetic complexities arising from the rate of tumor accumulation of liposomes and the rate of drug release, and show that it may be necessary to modulate the rate of drug release for optimal efficacy [>>71<<,74,86]. Measurement of in vivo drug release rate is enormously important in the development of liposome formulations but can be highly challenging for certain types of drugs.
n3:mentions: n4:15157619

Subject Item: _:vb29630590
rdf:type: n3:Context
rdf:value: A number of studies identify the kinetic complexities arising from the rate of tumor accumulation of liposomes and the rate of drug release, and show that it may be necessary to modulate the rate of drug release for optimal efficacy [71,>>74<<,86]. Measurement of in vivo drug release rate is enormously important in the development of liposome formulations but can be highly challenging for certain types of drugs.
n3:mentions: n4:10604968

Subject Item: _:vb29630591
rdf:type: n3:Context
rdf:value: of studies identify the kinetic complexities arising from the rate of tumor accumulation of liposomes and the rate of drug release, and show that it may be necessary to modulate the rate of drug release for optimal efficacy [71,74,>>86<<]. Measurement of in vivo drug release rate is enormously important in the development of liposome formulations but can be highly challenging for certain types of drugs.
n3:mentions: n4:10429242

Subject Item: _:vb29630592
rdf:type: n3:Context
rdf:value: Released drug has been measured directly by numerous methods including microdialysis or solid-phase micro-extraction techniques [>>87<<,88], both of which are tedious and expensive.
n3:mentions: n4:15920767

Subject Item: _:vb29630593
rdf:type: n3:Context
rdf:value: Released drug has been measured directly by numerous methods including microdialysis or solid-phase micro-extraction techniques [87,>>88<<], both of which are tedious and expensive.
n3:mentions: n4:16795010

Subject Item: _:vb29630594
rdf:type: n3:Context
rdf:value: Indirect approaches for measuring in vivo drug release rates include simply measuring changes in the plasma drug-to-liposome ratio [>>21<<,89], which is valid for cases in which the clearance rate of the released drug from plasma is sufficiently faster than the release rate from liposomes.
n3:mentions: n4:16540680

Subject Item: _:vb29630595
rdf:type: n3:Context
rdf:value: Indirect approaches for measuring in vivo drug release rates include simply measuring changes in the plasma drug-to-liposome ratio [21,>>89<<], which is valid for cases in which the clearance rate of the released drug from plasma is sufficiently faster than the release rate from liposomes.
n3:mentions: n4:7547237

Subject Item: _:vb29630596
rdf:type: n3:Context
rdf:value: One recently described indirect approach permitted inference of drug release rates based upon measurements of the free fraction of drug in plasma (i.e., the fraction of released drug unbound by plasma proteins) [>>90<<], which was employed successful in a PK modeling application for a nanoemulsion paclitaxel formulation.
n3:mentions: n4:18791718

Subject Item: _:vb29630597
rdf:type: n3:Context
rdf:value: A second approach employed simple compartmental modeling of liposomal- and unencapsulated amphotericin B PK to estimate a single, species-independent first-order release rate constant for rats and humans [>>91<<].
n3:mentions: n4:21431453

Subject Item: _:vb29630598
rdf:type: n3:Context
rdf:value: The accumulation of liposomes in tumors is controlled by numerous processes, including tumor perfusion, extravasation into the tumor tissue, and transport within the interstitium [>>92<<,93]. The permeability of the tumor microvasculature governs the influx and efflux of drugs [92,94,95,96,97].
n3:mentions: n4:3555767

Subject Item: _:vb29630599
rdf:type: n3:Context
rdf:value: The accumulation of liposomes in tumors is controlled by numerous processes, including tumor perfusion, extravasation into the tumor tissue, and transport within the interstitium [92,>>93<<]. The permeability of the tumor microvasculature governs the influx and efflux of drugs [92,94,95,96,97].
n3:mentions: n4:2649688

Subject Item: _:vb29630600
rdf:type: n3:Context
rdf:value: The permeability of the tumor microvasculature governs the influx and efflux of drugs [>>92<<,94,95,96,97].
n3:mentions: n4:3555767

Subject Item: _:vb29630601
rdf:type: n3:Context
rdf:value: The permeability of the tumor microvasculature governs the influx and efflux of drugs [92,>>94<<,95,96,97].
n3:mentions: n4:2292138

Subject Item: _:vb29630602
rdf:type: n3:Context
rdf:value: The permeability of the tumor microvasculature governs the influx and efflux of drugs [92,94,95,>>96<<,97]. Most liposome deposition results from the EPR effect [26], in which the discontinuous, permeable tumor vascular endothelium, and impaired lymphatics surrounding the tumor [26,98,99,100,101], permit extravasation and accumulation.
n3:mentions: n4:1763060

Subject Item: _:vb29630603
rdf:type: n3:Context
rdf:value: The permeability of the tumor microvasculature governs the influx and efflux of drugs [92,94,95,96,>>97<<]. Most liposome deposition results from the EPR effect [26], in which the discontinuous, permeable tumor vascular endothelium, and impaired lymphatics surrounding the tumor [26,98,99,100,101], permit extravasation and accumulation. Drug
n3:mentions: n4:8012948

Subject Item: _:vb29630604
rdf:type: n3:Context
rdf:value: Most liposome deposition results from the EPR effect [>>26<<], in which the discontinuous, permeable tumor vascular endothelium, and impaired lymphatics surrounding the tumor [26,98,99,100,101], permit extravasation and accumulation.
n3:mentions: n4:2946403

Subject Item: _:vb29630605
rdf:type: n3:Context
rdf:value: Most liposome deposition results from the EPR effect [26], in which the discontinuous, permeable tumor vascular endothelium, and impaired lymphatics surrounding the tumor [>>26<<,98,99,100,101], permit extravasation and accumulation.
n3:mentions: n4:2946403

Subject Item: _:vb29630606
rdf:type: n3:Context
rdf:value: Most liposome deposition results from the EPR effect [26], in which the discontinuous, permeable tumor vascular endothelium, and impaired lymphatics surrounding the tumor [26,>>98<<,99,100,101], permit extravasation and accumulation.
n3:mentions: n4:8599082

Subject Item: _:vb29630607
rdf:type: n3:Context
rdf:value: Most liposome deposition results from the EPR effect [26], in which the discontinuous, permeable tumor vascular endothelium, and impaired lymphatics surrounding the tumor [26,98,>>99<<,100,101], permit extravasation and accumulation.
n3:mentions: n4:8062241

Subject Item: _:vb29630608
rdf:type: n3:Context
rdf:value: Most liposome deposition results from the EPR effect [26], in which the discontinuous, permeable tumor vascular endothelium, and impaired lymphatics surrounding the tumor [26,98,99,>>100<<,101], permit extravasation and accumulation.
n3:mentions: n4:1386002

Subject Item: _:vb29630609
rdf:type: n3:Context
rdf:value: Most liposome deposition results from the EPR effect [26], in which the discontinuous, permeable tumor vascular endothelium, and impaired lymphatics surrounding the tumor [26,98,99,100,>>101<<], permit extravasation and accumulation.
n3:mentions: n4:8317543

Subject Item: _:vb29630610
rdf:type: n3:Context
rdf:value: from which they extravasated because of the high tumor interstitial pressure, the dense extracellular tissue stromal matrix, a large interstitial space compared with normal tissues, and the low diffusion coefficient of nanoparticulates [>>93<<,95,96,97,99,101].
n3:mentions: n4:2649688

Subject Item: _:vb29630611
rdf:type: n3:Context
rdf:value: they extravasated because of the high tumor interstitial pressure, the dense extracellular tissue stromal matrix, a large interstitial space compared with normal tissues, and the low diffusion coefficient of nanoparticulates [93,95,>>96<<,97,99,101].
n3:mentions: n4:1763060

Subject Item: _:vb29630612
rdf:type: n3:Context
rdf:value: they extravasated because of the high tumor interstitial pressure, the dense extracellular tissue stromal matrix, a large interstitial space compared with normal tissues, and the low diffusion coefficient of nanoparticulates [93,95,96,>>97<<,99,101]. The high interstitial pressure of larger tumors has been reported to reduce liposome distribution into the tumor interstitium in comparison to smaller tumors, and, as expected for regions of tumor into which oxygen and nutrients
n3:mentions: n4:8012948

Subject Item: _:vb29630613
rdf:type: n3:Context
rdf:value: extravasated because of the high tumor interstitial pressure, the dense extracellular tissue stromal matrix, a large interstitial space compared with normal tissues, and the low diffusion coefficient of nanoparticulates [93,95,96,97,>>99<<,101]. The high interstitial pressure of larger tumors has been reported to reduce liposome distribution into the tumor interstitium in comparison to smaller tumors, and, as expected for regions of tumor into which oxygen and nutrients do
n3:mentions: n4:8062241

Subject Item: _:vb29630614
rdf:type: n3:Context
rdf:value: extravasated because of the high tumor interstitial pressure, the dense extracellular tissue stromal matrix, a large interstitial space compared with normal tissues, and the low diffusion coefficient of nanoparticulates [93,95,96,97,99,>>101<<]. The high interstitial pressure of larger tumors has been reported to reduce liposome distribution into the tumor interstitium in comparison to smaller tumors, and, as expected for regions of tumor into which oxygen and nutrients do not
n3:mentions: n4:8317543

Subject Item: _:vb29630615
rdf:type: n3:Context
rdf:value: It is generally accepted that the majority of liposomes enter cells through the endocytic pathway, which is supported by both direct and functional evidence [>>102<<,103,104,105,106].
n3:mentions: n4:8969457

Subject Item: _:vb29630616
rdf:type: n3:Context
rdf:value: It is generally accepted that the majority of liposomes enter cells through the endocytic pathway, which is supported by both direct and functional evidence [102,>>103<<,104,105,106].
n3:mentions: n4:7877976

Subject Item: _:vb29630617
rdf:type: n3:Context
rdf:value: It is generally accepted that the majority of liposomes enter cells through the endocytic pathway, which is supported by both direct and functional evidence [102,103,>>104<<,105,106]. However, the molecular mechanisms of cellular binding and internalization of liposomes are not yet fully understood. If targeting cell surface receptors that are endocytosed can enhance intracellular delivery, tumor cell killing
n3:mentions: n4:6404557

Subject Item: _:vb29630618
rdf:type: n3:Context
rdf:value: It is generally accepted that the majority of liposomes enter cells through the endocytic pathway, which is supported by both direct and functional evidence [102,103,104,>>105<<,106]. However, the molecular mechanisms of cellular binding and internalization of liposomes are not yet fully understood. If targeting cell surface receptors that are endocytosed can enhance intracellular delivery, tumor cell killing and
n3:mentions: n4:4018256

Subject Item: _:vb29630619
rdf:type: n3:Context
rdf:value: If targeting cell surface receptors that are endocytosed can enhance intracellular delivery, tumor cell killing and antitumor efficacy can be increased [>>107<<,108,109,110].
n3:mentions: n4:2788031

Subject Item: _:vb29630620
rdf:type: n3:Context
rdf:value: If targeting cell surface receptors that are endocytosed can enhance intracellular delivery, tumor cell killing and antitumor efficacy can be increased [107,>>108<<,109,110]. Intracellular release of drug from the endocytic compartment is a necessity, and various approaches to enhance release to the cytoplasm have been investigated. One involves pH-triggered strategies that exploit the acidic tumor
n3:mentions: n4:16818648

Subject Item: _:vb29630621
rdf:type: n3:Context
rdf:value: If targeting cell surface receptors that are endocytosed can enhance intracellular delivery, tumor cell killing and antitumor efficacy can be increased [107,108,>>109<<,110]. Intracellular release of drug from the endocytic compartment is a necessity, and various approaches to enhance release to the cytoplasm have been investigated. One involves pH-triggered strategies that exploit the acidic tumor
n3:mentions: n4:19686789

Subject Item: _:vb29630622
rdf:type: n3:Context
rdf:value: If targeting cell surface receptors that are endocytosed can enhance intracellular delivery, tumor cell killing and antitumor efficacy can be increased [107,108,109,>>110<<]. Intracellular release of drug from the endocytic compartment is a necessity, and various approaches to enhance release to the cytoplasm have been investigated. One involves pH-triggered strategies that exploit the acidic tumor
n3:mentions: n4:23723124

Subject Item: _:vb29630623
rdf:type: n3:Context
rdf:value: One involves pH-triggered strategies that exploit the acidic tumor microenvironment or acidic endosomal compartments to destabilize liposomes [>>111<<,112,113]. Another example employs the selection of agents that require a liposome carrier for optimal delivery to the endocytic compartment; such “liposome dependent drugs” are polar, weakly acidic drugs that become more membrane
n3:mentions: n4:4019583

Subject Item: _:vb29630624
rdf:type: n3:Context
rdf:value: One involves pH-triggered strategies that exploit the acidic tumor microenvironment or acidic endosomal compartments to destabilize liposomes [111,>>112<<,113]. Another example employs the selection of agents that require a liposome carrier for optimal delivery to the endocytic compartment; such “liposome dependent drugs” are polar, weakly acidic drugs that become more membrane permeable at
n3:mentions: n4:2578112

Subject Item: _:vb29630625
rdf:type: n3:Context
rdf:value: One involves pH-triggered strategies that exploit the acidic tumor microenvironment or acidic endosomal compartments to destabilize liposomes [111,112,>>113<<]. Another example employs the selection of agents that require a liposome carrier for optimal delivery to the endocytic compartment; such “liposome dependent drugs” are polar, weakly acidic drugs that become more membrane permeable at
n3:mentions: n4:2172955

Subject Item: _:vb29630626
rdf:type: n3:Context
rdf:value: selection of agents that require a liposome carrier for optimal delivery to the endocytic compartment; such “liposome dependent drugs” are polar, weakly acidic drugs that become more membrane permeable at endosomal and lysosomal pH [>>105<<,106,114].
n3:mentions: n4:4018256

Subject Item: _:vb29630627
rdf:type: n3:Context
rdf:value: of agents that require a liposome carrier for optimal delivery to the endocytic compartment; such “liposome dependent drugs” are polar, weakly acidic drugs that become more membrane permeable at endosomal and lysosomal pH [105,106,>>114<<].
n3:mentions: n4:6572395

Subject Item: _:vb29630628
rdf:type: n2:Section
dc:title: physicochemical properties of liposomal formulations and their effects upon pharmacokinetics
n2:contains: _:vb29630660 _:vb29630661 _:vb29630662 _:vb29630663 _:vb29630656 _:vb29630657 _:vb29630658 _:vb29630659 _:vb29630668 _:vb29630669 _:vb29630670 _:vb29630664 _:vb29630665 _:vb29630666 _:vb29630667 _:vb29630644 _:vb29630645 _:vb29630646 _:vb29630647 _:vb29630640 _:vb29630641 _:vb29630642 _:vb29630643 _:vb29630652 _:vb29630653 _:vb29630654 _:vb29630655 _:vb29630648 _:vb29630649 _:vb29630650 _:vb29630651 _:vb29630629 _:vb29630630 _:vb29630631 _:vb29630636 _:vb29630637 _:vb29630638 _:vb29630639 _:vb29630632 _:vb29630633 _:vb29630634 _:vb29630635

Subject Item: _:vb29630629
rdf:type: n3:Context
rdf:value: In general, the clearance of liposomes and other nano- or micro-particulates from the blood increases with increasing particle size [>>85<<,115,116], and clearance is mediated principally by the RES.
n3:mentions: n4:17100556

Subject Item: _:vb29630630
rdf:type: n3:Context
rdf:value: In general, the clearance of liposomes and other nano- or micro-particulates from the blood increases with increasing particle size [85,115,>>116<<], and clearance is mediated principally by the RES.
n3:mentions: n4:10837781

Subject Item: _:vb29630631
rdf:type: n3:Context
rdf:value: tend to have longer circulation half-lives than larger liposomes of the same membrane composition, and distribute more rapidly in solid tumors due to their enhanced ability to extravasate across the more porous tumor endothelia [>>85<<,116]. It has been suggested that despite their slower clearance from the circulation, smaller liposomes (60–80 nm) tend to accumulate in tumors less efficiently than slightly larger liposomes [115,116].
n3:mentions: n4:17100556

Subject Item: _:vb29630632
rdf:type: n3:Context
rdf:value: tend to have longer circulation half-lives than larger liposomes of the same membrane composition, and distribute more rapidly in solid tumors due to their enhanced ability to extravasate across the more porous tumor endothelia [85,>>116<<]. It has been suggested that despite their slower clearance from the circulation, smaller liposomes (60–80 nm) tend to accumulate in tumors less efficiently than slightly larger liposomes [115,116].
n3:mentions: n4:10837781

Subject Item: _:vb29630633
rdf:type: n3:Context
rdf:value: It has been suggested that despite their slower clearance from the circulation, smaller liposomes (60–80 nm) tend to accumulate in tumors less efficiently than slightly larger liposomes [115,>>116<<]. Thus the longer circulating lifetime of the smallest liposomes may be counter-balanced by an increase in reversible permeability (enhanced influx and efflux rate constants), and therefore the role of diameter in optimizing liposome
n3:mentions: n4:10837781

Subject Item: _:vb29630634
rdf:type: n3:Context
rdf:value: Liposomes of approximately 100 nm diameter have been reported to distribute into solid tumors with an efficiency that is partly dependent on the anatomical location of the tumor [>>117<<].
n3:mentions: n4:9539785

Subject Item: _:vb29630635
rdf:type: n3:Context
rdf:value: of relatively large diameters (80–250 nm), such as SSL that bear a polyethylene glycol corona on their surface, is less sensitive to the effects of particle size than is clearance of non-pegylated liposomes of equivalent size [>>118<<,119]. Naturally occurring glycolipids and glycophospholipids can exert similar effects [120,121].
n3:mentions: n4:2719971

Subject Item: _:vb29630636
rdf:type: n3:Context
rdf:value: of relatively large diameters (80–250 nm), such as SSL that bear a polyethylene glycol corona on their surface, is less sensitive to the effects of particle size than is clearance of non-pegylated liposomes of equivalent size [118,>>119<<]. Naturally occurring glycolipids and glycophospholipids can exert similar effects [120,121].
n3:mentions: n4:1586658

Subject Item: _:vb29630637
rdf:type: n3:Context
rdf:value: Naturally occurring glycolipids and glycophospholipids can exert similar effects [>>120<<,121]. Maximum accumulation of sterically-stabilized liposomes in xenograft animal models typically occurs between 24 and 48 h post administration [96,108,120].
n3:mentions: n4:3413128

Subject Item: _:vb29630638
rdf:type: n3:Context
rdf:value: Naturally occurring glycolipids and glycophospholipids can exert similar effects [120,>>121<<]. Maximum accumulation of sterically-stabilized liposomes in xenograft animal models typically occurs between 24 and 48 h post administration [96,108,120].
n3:mentions: n4:3666140

Subject Item: _:vb29630639
rdf:type: n3:Context
rdf:value: Maximum accumulation of sterically-stabilized liposomes in xenograft animal models typically occurs between 24 and 48 h post administration [>>96<<,108,120].
n3:mentions: n4:1763060

Subject Item: _:vb29630640
rdf:type: n3:Context
rdf:value: Maximum accumulation of sterically-stabilized liposomes in xenograft animal models typically occurs between 24 and 48 h post administration [96,>>108<<,120].
n3:mentions: n4:16818648

Subject Item: _:vb29630641
rdf:type: n3:Context
rdf:value: Maximum accumulation of sterically-stabilized liposomes in xenograft animal models typically occurs between 24 and 48 h post administration [96,108,>>120<<].
n3:mentions: n4:3413128

Subject Item: _:vb29630642
rdf:type: n3:Context
rdf:value: Stearylamine has been used historically as a constituent of cationic liposomes, but is more cytotoxic than dialkyl or diacyl lipids, and more likely to undergo extraction from the membrane or inter-membrane exchange [>>122<<,123,124].
n3:mentions: n4:2730899

Subject Item: _:vb29630643
rdf:type: n3:Context
rdf:value: Stearylamine has been used historically as a constituent of cationic liposomes, but is more cytotoxic than dialkyl or diacyl lipids, and more likely to undergo extraction from the membrane or inter-membrane exchange [122,>>123<<,124].
n3:mentions: n4:3622630

Subject Item: _:vb29630644
rdf:type: n3:Context
rdf:value: Stearylamine has been used historically as a constituent of cationic liposomes, but is more cytotoxic than dialkyl or diacyl lipids, and more likely to undergo extraction from the membrane or inter-membrane exchange [122,123,>>124<<].
n3:mentions: n4:1751523

Subject Item: _:vb29630645
rdf:type: n3:Context
rdf:value: Negatively charged liposomes tend to be removed from circulation by the macrophages of the RES, and increasing charge increases total systemic clearance [>>77<<,125]. A notable exception is the anionic glycerophospholipid phosphatidylinositol (PI), which can mediate a longer circulating lifetime because of the “steric stabilization” effect of its inositol headgroup [96,119,120].
n3:mentions: n4:3542245

Subject Item: _:vb29630646
rdf:type: n3:Context
rdf:value: Negatively charged liposomes tend to be removed from circulation by the macrophages of the RES, and increasing charge increases total systemic clearance [77,>>125<<]. A notable exception is the anionic glycerophospholipid phosphatidylinositol (PI), which can mediate a longer circulating lifetime because of the “steric stabilization” effect of its inositol headgroup [96,119,120].
n3:mentions: n4:1309663

Subject Item: _:vb29630647
rdf:type: n3:Context
rdf:value: A notable exception is the anionic glycerophospholipid phosphatidylinositol (PI), which can mediate a longer circulating lifetime because of the “steric stabilization” effect of its inositol headgroup [>>96<<,119,120]. Positively charged liposomes are cleared rapidly by the RES, but also bind rapidly to vascular endothelium, sites of inflammation, and plasma proteins [126,127,128].
n3:mentions: n4:1763060

Subject Item: _:vb29630648
rdf:type: n3:Context
rdf:value: A notable exception is the anionic glycerophospholipid phosphatidylinositol (PI), which can mediate a longer circulating lifetime because of the “steric stabilization” effect of its inositol headgroup [96,>>119<<,120]. Positively charged liposomes are cleared rapidly by the RES, but also bind rapidly to vascular endothelium, sites of inflammation, and plasma proteins [126,127,128].
n3:mentions: n4:1586658

Subject Item: _:vb29630649
rdf:type: n3:Context
rdf:value: A notable exception is the anionic glycerophospholipid phosphatidylinositol (PI), which can mediate a longer circulating lifetime because of the “steric stabilization” effect of its inositol headgroup [96,119,>>120<<]. Positively charged liposomes are cleared rapidly by the RES, but also bind rapidly to vascular endothelium, sites of inflammation, and plasma proteins [126,127,128].
n3:mentions: n4:3413128

Subject Item: _:vb29630650
rdf:type: n3:Context
rdf:value: Positively charged liposomes are cleared rapidly by the RES, but also bind rapidly to vascular endothelium, sites of inflammation, and plasma proteins [>>126<<,127,128].
n3:mentions: n4:8664312

Subject Item: _:vb29630651
rdf:type: n3:Context
rdf:value: Positively charged liposomes are cleared rapidly by the RES, but also bind rapidly to vascular endothelium, sites of inflammation, and plasma proteins [126,>>127<<,128].
n3:mentions: n4:9525983

Subject Item: _:vb29630652
rdf:type: n3:Context
rdf:value: Positively charged liposomes are cleared rapidly by the RES, but also bind rapidly to vascular endothelium, sites of inflammation, and plasma proteins [126,127,>>128<<].
n3:mentions: n4:12460895

Subject Item: _:vb29630653
rdf:type: n3:Context
rdf:value: inclusion of cholesterol (Chol): decreased binding of plasma opsonins reduces RES clearance through receptor-mediated pathways, and a reduced ability of proteins to insert into cholesterol-rich, high Tm membranes reduces drug leakage [>>77<<,129,130]. Sphingomyelin (SM) also can exert a stabilizing effect on the phospholipid bilayer, and the combination of SM/Chol has been reported to extend the circulation lifetime of liposome-encapsulated drugs compared to the same drugs in
n3:mentions: n4:3542245

Subject Item: _:vb29630654
rdf:type: n3:Context
rdf:value: of cholesterol (Chol): decreased binding of plasma opsonins reduces RES clearance through receptor-mediated pathways, and a reduced ability of proteins to insert into cholesterol-rich, high Tm membranes reduces drug leakage [77,>>129<<,130]. Sphingomyelin (SM) also can exert a stabilizing effect on the phospholipid bilayer, and the combination of SM/Chol has been reported to extend the circulation lifetime of liposome-encapsulated drugs compared to the same drugs in
n3:mentions: n4:7109841

Subject Item: _:vb29630655
rdf:type: n3:Context
rdf:value: of cholesterol (Chol): decreased binding of plasma opsonins reduces RES clearance through receptor-mediated pathways, and a reduced ability of proteins to insert into cholesterol-rich, high Tm membranes reduces drug leakage [77,129,>>130<<]. Sphingomyelin (SM) also can exert a stabilizing effect on the phospholipid bilayer, and the combination of SM/Chol has been reported to extend the circulation lifetime of liposome-encapsulated drugs compared to the same drugs in
n3:mentions: n4:496958

Subject Item: _:vb29630656
rdf:type: n3:Context
rdf:value: effect on the phospholipid bilayer, and the combination of SM/Chol has been reported to extend the circulation lifetime of liposome-encapsulated drugs compared to the same drugs in distearoyl-phosphatidylcholine (DSPC)/Chol liposomes [>>131<<]. Surface modifications that sterically stabilize liposomes and extend circulating lifetime have been described above.
n3:mentions: n4:2065067

Subject Item: _:vb29630657
rdf:type: n3:Context
rdf:value: lipophilic drugs; a second is where delivery to macrophages or to the RES is an application, for example, where the objective is delivery of immunomodulators to macrophages in order to enhance their capability to kill neoplastic cells [>>132<<].
n3:mentions: n4:7768646

Subject Item: _:vb29630658
rdf:type: n3:Context
rdf:value: The development of long-circulating liposomes represents a significant advance in liposomal drug carriers [>>133<<]. The advantage of SSL is their ability to extravasate into solid tumors due to the EPR effect.
n3:mentions: n4:1510996

Subject Item: _:vb29630659
rdf:type: n3:Context
rdf:value: deposition attributable to the EPR effect may be greater than the contribution of ligand-based arrest within the tumor, and that the major advantage of the targeting ligand is to promote liposome endocytosis and intracellular delivery [>>108<<,134,135,136,137,138,139,140].
n3:mentions: n4:16818648

Subject Item: _:vb29630660
rdf:type: n3:Context
rdf:value: attributable to the EPR effect may be greater than the contribution of ligand-based arrest within the tumor, and that the major advantage of the targeting ligand is to promote liposome endocytosis and intracellular delivery [108,>>134<<,135,136,137,138,139,140].
n3:mentions: n4:10667243

Subject Item: _:vb29630661
rdf:type: n3:Context
rdf:value: attributable to the EPR effect may be greater than the contribution of ligand-based arrest within the tumor, and that the major advantage of the targeting ligand is to promote liposome endocytosis and intracellular delivery [108,134,>>135<<,136,137,138,139,140].
n3:mentions: n4:12499256

Subject Item: _:vb29630662
rdf:type: n3:Context
rdf:value: to the EPR effect may be greater than the contribution of ligand-based arrest within the tumor, and that the major advantage of the targeting ligand is to promote liposome endocytosis and intracellular delivery [108,134,135,>>136<<,137,138,139,140].
n3:mentions: n4:11156394

Subject Item: _:vb29630663
rdf:type: n3:Context
rdf:value: to the EPR effect may be greater than the contribution of ligand-based arrest within the tumor, and that the major advantage of the targeting ligand is to promote liposome endocytosis and intracellular delivery [108,134,135,136,>>137<<,138,139,140].
n3:mentions: n4:12183061

Subject Item: _:vb29630664
rdf:type: n3:Context
rdf:value: to the EPR effect may be greater than the contribution of ligand-based arrest within the tumor, and that the major advantage of the targeting ligand is to promote liposome endocytosis and intracellular delivery [108,134,135,136,137,>>138<<,139,140]. The necessity for the drug to escape the endocytic pathway suggests an advantage of the enhanced permeability of “liposome-dependent” drugs [105,106,114], many of which are weakly acidic and would be more permeant at acidic pH
n3:mentions: n4:9699662

Subject Item: _:vb29630665
rdf:type: n3:Context
rdf:value: to the EPR effect may be greater than the contribution of ligand-based arrest within the tumor, and that the major advantage of the targeting ligand is to promote liposome endocytosis and intracellular delivery [108,134,135,136,137,138,>>139<<,140]. The necessity for the drug to escape the endocytic pathway suggests an advantage of the enhanced permeability of “liposome-dependent” drugs [105,106,114], many of which are weakly acidic and would be more permeant at acidic pH of
n3:mentions: n4:11948130

Subject Item: _:vb29630666
rdf:type: n3:Context
rdf:value: EPR effect may be greater than the contribution of ligand-based arrest within the tumor, and that the major advantage of the targeting ligand is to promote liposome endocytosis and intracellular delivery [108,134,135,136,137,138,139,>>140<<]. The necessity for the drug to escape the endocytic pathway suggests an advantage of the enhanced permeability of “liposome-dependent” drugs [105,106,114], many of which are weakly acidic and would be more permeant at acidic pH of
n3:mentions: n4:16357174

Subject Item: _:vb29630667
rdf:type: n3:Context
rdf:value: The necessity for the drug to escape the endocytic pathway suggests an advantage of the enhanced permeability of “liposome-dependent” drugs [>>105<<,106,114], many of which are weakly acidic and would be more permeant at acidic pH of endosomes/lysosomes.
n3:mentions: n4:4018256

Subject Item: _:vb29630668
rdf:type: n3:Context
rdf:value: The necessity for the drug to escape the endocytic pathway suggests an advantage of the enhanced permeability of “liposome-dependent” drugs [105,106,>>114<<], many of which are weakly acidic and would be more permeant at acidic pH of endosomes/lysosomes.
n3:mentions: n4:6572395

Subject Item: _:vb29630669
rdf:type: n3:Context
rdf:value: Ligand-targeted liposomes, being highly multivalent, show much higher affinities for target cells than do the individual ligands [>>141<<]. A recent example demonstrated that the anticancer activity of human epidermal growth factor receptor 2 (HER2)-targeted immunoliposomes is relatively independent of the intrinsic affinity of the receptor for its cognate ligand: despite
n3:mentions: n4:6421325

Subject Item: _:vb29630670
rdf:type: n3:Context
rdf:value: affinity of the receptor for its cognate ligand: despite relatively low binding affinity of the targeting ligand (kD = 160 nM), the targeted liposome construct showed improved efficacy as a result of its efficient internalization [>>137<<].
n3:mentions: n4:12183061

Subject Item: _:vb29630671
rdf:type: n2:Section
dc:title: pk/ pharmacodynamic (pd) analysis of liposomal formulations
n2:contains: _:vb29630715 _:vb29630716 _:vb29630717 _:vb29630718 _:vb29630719 _:vb29630704 _:vb29630705 _:vb29630706 _:vb29630707 _:vb29630708 _:vb29630709 _:vb29630710 _:vb29630711 _:vb29630696 _:vb29630697 _:vb29630698 _:vb29630699 _:vb29630700 _:vb29630701 _:vb29630702 _:vb29630703 _:vb29630688 _:vb29630689 _:vb29630690 _:vb29630691 _:vb29630692 _:vb29630693 _:vb29630694 _:vb29630695 _:vb29630744 _:vb29630745 _:vb29630746 _:vb29630736 _:vb29630737 _:vb29630738 _:vb29630739 _:vb29630740 _:vb29630741 _:vb29630742 _:vb29630743 _:vb29630728 _:vb29630729 _:vb29630730 _:vb29630731 _:vb29630732 _:vb29630733 _:vb29630734 _:vb29630735 _:vb29630720 _:vb29630721 _:vb29630722 _:vb29630723 _:vb29630724 _:vb29630725 _:vb29630726 _:vb29630727 _:vb29630680 _:vb29630681 _:vb29630682 _:vb29630683 _:vb29630684 _:vb29630685 _:vb29630686 _:vb29630687 _:vb29630672 _:vb29630673 _:vb29630674 _:vb29630675 _:vb29630676 _:vb29630677 _:vb29630678 _:vb29630679 _:vb29630712 _:vb29630713 _:vb29630714

Subject Item: _:vb29630672
rdf:type: n3:Context
rdf:value: Unmodified first-generation liposomes typically exhibit nonlinear, saturable PK after intravenous administration, with relatively short elimination half-lives at low, non-saturating doses [>>142<<]. Although sterically-stabilized liposomes may show linear PK over a wide range of doses [142], their PK and biodistributional pattern is also complicated at low doses and upon repeated administration schedules [143,144,145,146,147,148].
n3:mentions: n4:7622296

Subject Item: _:vb29630673
rdf:type: n3:Context
rdf:value: Although sterically-stabilized liposomes may show linear PK over a wide range of doses [>>142<<], their PK and biodistributional pattern is also complicated at low doses and upon repeated administration schedules [143,144,145,146,147,148].
n3:mentions: n4:7622296

Subject Item: _:vb29630674
rdf:type: n3:Context
rdf:value: Although sterically-stabilized liposomes may show linear PK over a wide range of doses [142], their PK and biodistributional pattern is also complicated at low doses and upon repeated administration schedules [>>143<<,144,145,146,147,148].
n3:mentions: n4:14559067

Subject Item: _:vb29630675
rdf:type: n3:Context
rdf:value: Although sterically-stabilized liposomes may show linear PK over a wide range of doses [142], their PK and biodistributional pattern is also complicated at low doses and upon repeated administration schedules [143,>>144<<,145,146,147,148].
n3:mentions: n4:11980650

Subject Item: _:vb29630676
rdf:type: n3:Context
rdf:value: Although sterically-stabilized liposomes may show linear PK over a wide range of doses [142], their PK and biodistributional pattern is also complicated at low doses and upon repeated administration schedules [143,144,>>145<<,146,147,148].
n3:mentions: n4:10869403

Subject Item: _:vb29630677
rdf:type: n3:Context
rdf:value: Although sterically-stabilized liposomes may show linear PK over a wide range of doses [142], their PK and biodistributional pattern is also complicated at low doses and upon repeated administration schedules [143,144,145,>>146<<,147,148]. It is hypothesized that at lower doses, the differences in plasma half-lives between conventional liposomes and SSL should result in a greater pool of SSL available for tumor deposition. For higher doses, the saturable
n3:mentions: n4:16515818

Subject Item: _:vb29630678
rdf:type: n3:Context
rdf:value: Although sterically-stabilized liposomes may show linear PK over a wide range of doses [142], their PK and biodistributional pattern is also complicated at low doses and upon repeated administration schedules [143,144,145,146,>>147<<,148]. It is hypothesized that at lower doses, the differences in plasma half-lives between conventional liposomes and SSL should result in a greater pool of SSL available for tumor deposition. For higher doses, the saturable elimination
n3:mentions: n4:17045355

Subject Item: _:vb29630679
rdf:type: n3:Context
rdf:value: Although sterically-stabilized liposomes may show linear PK over a wide range of doses [142], their PK and biodistributional pattern is also complicated at low doses and upon repeated administration schedules [143,144,145,146,147,>>148<<]. It is hypothesized that at lower doses, the differences in plasma half-lives between conventional liposomes and SSL should result in a greater pool of SSL available for tumor deposition.
n3:mentions: n4:12586501

Subject Item: _:vb29630680
rdf:type: n3:Context
rdf:value: The PK of SSL formulations of DXR are clearly distinct from that of unencapsulated DXR [>>149<<]. The SSL formulation has an extended circulating lifetime and a pattern of tumor- and tissue distribution that reduces drug deposition in heart, a major organ of DXR toxicity; it also increases deposition in skin [115], which appears to
n3:mentions: n4:2778836

Subject Item: _:vb29630681
rdf:type: n3:Context
rdf:value: and a pattern of tumor- and tissue distribution that reduces drug deposition in heart, a major organ of DXR toxicity; it also increases deposition in skin [115], which appears to correlate with a novel adverse effect of SSL-DXR [>>150<<,151].
n3:mentions: n4:10964334

Subject Item: _:vb29630682
rdf:type: n3:Context
rdf:value: and a pattern of tumor- and tissue distribution that reduces drug deposition in heart, a major organ of DXR toxicity; it also increases deposition in skin [115], which appears to correlate with a novel adverse effect of SSL-DXR [150,>>151<<].
n3:mentions: n4:17229768

Subject Item: _:vb29630683
rdf:type: n3:Context
rdf:value: Arnold et al developed a simple PK model for brain tumor deposition of SSL-DXR in rats [>>152<<], which consisted of a one-compartment model having linear elimination from the plasma that was linked to a peripheral compartment representing the site of action (i.e., the brain tumor).
n3:mentions: n4:16361575

Subject Item: _:vb29630684
rdf:type: n3:Context
rdf:value: for development of the model was to understand why specifically-timed dosing schemes with SSL-DXR mediated a progressive increase in brain tumor vascular permeability, and resulted in elevated deposition of subsequent SSL-DXR doses [>>144<<]. The objective was to identify quantitatively the pharmacokinetic factors that might underlie the elevated deposition of subsequent doses in this “tumor priming” administration schedule.
n3:mentions: n4:11980650

Subject Item: _:vb29630685
rdf:type: n3:Context
rdf:value: A subsequently developed PK model for SSL-DXR (Figure 2) [>>153<<] included estimates of drug release rate along with tumor drug delivery.
n3:mentions: n4:23115220

Subject Item: _:vb29630686
rdf:type: n3:Context
rdf:value: in the context of understanding PK/PD relationships for SSL-DXR in a “tumor priming” combination strategy, in which a prior dose of paclitaxel increased tumor permeability, as well as deposition and intra-tumor diffusion of SSL-DXR [>>154<<]. Data for tumor deposition that discriminated liposome-encapsulated vs. released DXR were not available.
n3:mentions: n4:11181938

Subject Item: _:vb29630687
rdf:type: n3:Context
rdf:value: the half-life of DXR release from liposomes to be approximately 15 h (first order release constant krel = 0.046), which is consistent with other studies of in vitro and in vivo drug release rates for similar liposome formulations [>>71<<,155].
n3:mentions: n4:15157619

Subject Item: _:vb29630688
rdf:type: n3:Context
rdf:value: the half-life of DXR release from liposomes to be approximately 15 h (first order release constant krel = 0.046), which is consistent with other studies of in vitro and in vivo drug release rates for similar liposome formulations [71,>>155<<].
n3:mentions: n4:15948037

Subject Item: _:vb29630689
rdf:type: n3:Context
rdf:value: by traditional compartmental models, but plasma PK is linked to tumor drug concentrations using physiologically-based pharmacokinetic (PBPK) models that include mechanism-based terms such as tumor blood flow and tissue volume [>>156<<,157]. Model sensitivity analysis clearly identified the release rate of DXR as an important parameter for the optimization of liposomal delivery.
n3:mentions: n4:10837779

Subject Item: _:vb29630690
rdf:type: n3:Context
rdf:value: by traditional compartmental models, but plasma PK is linked to tumor drug concentrations using physiologically-based pharmacokinetic (PBPK) models that include mechanism-based terms such as tumor blood flow and tissue volume [156,>>157<<]. Model sensitivity analysis clearly identified the release rate of DXR as an important parameter for the optimization of liposomal delivery.
n3:mentions: n4:10469906

Subject Item: _:vb29630691
rdf:type: n3:Context
rdf:value: to mice, showing the change in plasma concentrations of unbound DXR as krel parameter is varied over a 1000-fold range around the value for SSL-DXR (0.046 h−1) obtained from the analysis of [>>153<<]; and (C) Model simulations for a 175 mg/m2 dose of LEP-ETU administered intravenously (i.
n3:mentions: n4:23115220

Subject Item: _:vb29630692
rdf:type: n3:Context
rdf:value: to humans by infusion over a 3 h period, showing the change in plasma concentrations of released paclitaxel (PAC) as krel is varied around the value for LEP-ETU (1.26 h−1) obtained from the analysis of [>>159<<].
n3:mentions: n4:22588463

Subject Item: _:vb29630693
rdf:type: n3:Context
rdf:value: (PAC), in which the drug is intercalated in the membrane bilayer; and (ii) SSL-DXR, a highly stable formulation in which doxorubicin is encapsulated in the aqueous interior by a “remote loading” pH/electrochemical gradient procedure [>>67<<,160,161]. Unbound drug was selected for estimation because the fraction of released drug that is not bound to plasma proteins is the pharmacologically active form.
n3:mentions: n4:1426260

Subject Item: _:vb29630694
rdf:type: n3:Context
rdf:value: in which the drug is intercalated in the membrane bilayer; and (ii) SSL-DXR, a highly stable formulation in which doxorubicin is encapsulated in the aqueous interior by a “remote loading” pH/electrochemical gradient procedure [67,>>160<<,161]. Unbound drug was selected for estimation because the fraction of released drug that is not bound to plasma proteins is the pharmacologically active form.
n3:mentions: n4:3964703

Subject Item: _:vb29630695
rdf:type: n3:Context
rdf:value: in which the drug is intercalated in the membrane bilayer; and (ii) SSL-DXR, a highly stable formulation in which doxorubicin is encapsulated in the aqueous interior by a “remote loading” pH/electrochemical gradient procedure [67,160,>>161<<]. Unbound drug was selected for estimation because the fraction of released drug that is not bound to plasma proteins is the pharmacologically active form.
n3:mentions: n4:8323951

Subject Item: _:vb29630696
rdf:type: n3:Context
rdf:value: Figure 2A shows a general schematic of the two models that were utilized [>>153<<,159]. The model assumptions are that liposomal drugs (L-drug) are injected into the vascular compartment while incorporated within a liposomal carrier “compartment” (AL-drug), from which free drug (Adrug) is released through a first-order
n3:mentions: n4:23115220

Subject Item: _:vb29630697
rdf:type: n3:Context
rdf:value: Figure 2A shows a general schematic of the two models that were utilized [153,>>159<<]. The model assumptions are that liposomal drugs (L-drug) are injected into the vascular compartment while incorporated within a liposomal carrier “compartment” (AL-drug), from which free drug (Adrug) is released through a first-order
n3:mentions: n4:22588463

Subject Item: _:vb29630698
rdf:type: n3:Context
rdf:value: estimated drug release term krel for SSL-DXR was varied 1000-fold around a baseline value for krel of 0.046 h−1 (release half-life of 15 h), which was determined from a previous analysis of SSL-DXR PK data in various model systems [>>153<<]. The simulations showed that increases in krel up to 100-fold above the baseline value had relatively little effect upon unbound DXR concentration or the duration of the distribution phase.
n3:mentions: n4:23115220

Subject Item: _:vb29630699
rdf:type: n3:Context
rdf:value: A previous analysis of published clinical data for four paclitaxel formulations estimated krel values in the range of 0.7 to 5.2 h−1; a baseline krel of 1.26 h−1 (0.55 h half-life) was estimated for PAC in LEP-ETU [>>159<<]. Simulations with the model (Figure 2C) show that increases in krel up to 10-fold above the baseline have little effect on the PK profile of unbound PAC. In contrast, decreasing krel to values 100-fold below the baseline (from 1.26 h−1
n3:mentions: n4:22588463

Subject Item: _:vb29630700
rdf:type: n3:Context
rdf:value: A hypothesis based upon these simulations is that the mean estimates of krel for SSL-DXR [>>153<<] and LEP-ETU [159] are close not only to their optima, but also to threshold values beyond which further changes in krel alone are unlikely to result in an improved therapeutic outcome without concomitant changes in other formulation
n3:mentions: n4:23115220

Subject Item: _:vb29630701
rdf:type: n3:Context
rdf:value: A hypothesis based upon these simulations is that the mean estimates of krel for SSL-DXR [153] and LEP-ETU [>>159<<] are close not only to their optima, but also to threshold values beyond which further changes in krel alone are unlikely to result in an improved therapeutic outcome without concomitant changes in other formulation characteristics.
n3:mentions: n4:22588463

Subject Item: _:vb29630702
rdf:type: n3:Context
rdf:value: surrounding tumor parenchyma (typically acidic compared to plasma pH), enzymes released from apoptotic or inflammatory cells (such as lipases), and oxidizing radicals that may be released during an immune response against the tumor [>>21<<]. In vitro studies suggest that cellular transporters can extrude cytoplasmically-released compounds from the cell or that endocytosed drug may be regurgitated during endocytic vesicle recycling [162,163].
n3:mentions: n4:16540680

Subject Item: _:vb29630703
rdf:type: n3:Context
rdf:value: In vitro studies suggest that cellular transporters can extrude cytoplasmically-released compounds from the cell or that endocytosed drug may be regurgitated during endocytic vesicle recycling [>>162<<,163]. In vivo, macrophages residing within the tumor can degrade liposomes and liberate the encapsulated drug [4]. One study investigated the effect of interstitial fluid on the release of DXR from SSL-DXR in vitro by harvesting malignant
n3:mentions: n4:9327449

Subject Item: _:vb29630704
rdf:type: n3:Context
rdf:value: In vitro studies suggest that cellular transporters can extrude cytoplasmically-released compounds from the cell or that endocytosed drug may be regurgitated during endocytic vesicle recycling [162,>>163<<]. In vivo, macrophages residing within the tumor can degrade liposomes and liberate the encapsulated drug [4]. One study investigated the effect of interstitial fluid on the release of DXR from SSL-DXR in vitro by harvesting malignant
n3:mentions: n4:3409248

Subject Item: _:vb29630705
rdf:type: n3:Context
rdf:value: In vivo, macrophages residing within the tumor can degrade liposomes and liberate the encapsulated drug [>>4<<]. One study investigated the effect of interstitial fluid on the release of DXR from SSL-DXR in vitro by harvesting malignant pleural effusions [149]. The rate of drug leakage appeared to be faster in malignant effusions than in plasma
n3:mentions: n4:9516959

Subject Item: _:vb29630706
rdf:type: n3:Context
rdf:value: One study investigated the effect of interstitial fluid on the release of DXR from SSL-DXR in vitro by harvesting malignant pleural effusions [>>149<<]. The rate of drug leakage appeared to be faster in malignant effusions than in plasma (t1/2 = 1 vs. 100 h). That work also described a method for selective destabilization of liposomes within the tumor environment as a promising approach
n3:mentions: n4:2778836

Subject Item: _:vb29630707
rdf:type: n3:Context
rdf:value: In a comprehensive study evaluating several liposomal DXR formulations, increasing liposome stability was associated with increased total drug and released free drug in the tumor, and increased therapeutic efficacy [>>71<<,73,85,164].
n3:mentions: n4:15157619

Subject Item: _:vb29630708
rdf:type: n3:Context
rdf:value: In a comprehensive study evaluating several liposomal DXR formulations, increasing liposome stability was associated with increased total drug and released free drug in the tumor, and increased therapeutic efficacy [71,>>73<<,85,164]. Similarly, the antitumor pharmacodynamic effects of two liposomal formulations of irinotecan, having slow- and moderate release rates (t1/2 of release = 58.6 h vs. 14 h), were evaluated in mice bearing human colon carcinoma
n3:mentions: n4:16203786

Subject Item: _:vb29630709
rdf:type: n3:Context
rdf:value: In a comprehensive study evaluating several liposomal DXR formulations, increasing liposome stability was associated with increased total drug and released free drug in the tumor, and increased therapeutic efficacy [71,73,>>85<<,164]. Similarly, the antitumor pharmacodynamic effects of two liposomal formulations of irinotecan, having slow- and moderate release rates (t1/2 of release = 58.6 h vs. 14 h), were evaluated in mice bearing human colon carcinoma
n3:mentions: n4:17100556

Subject Item: _:vb29630710
rdf:type: n3:Context
rdf:value: In a comprehensive study evaluating several liposomal DXR formulations, increasing liposome stability was associated with increased total drug and released free drug in the tumor, and increased therapeutic efficacy [71,73,85,>>164<<]. Similarly, the antitumor pharmacodynamic effects of two liposomal formulations of irinotecan, having slow- and moderate release rates (t1/2 of release = 58.6 h vs. 14 h), were evaluated in mice bearing human colon carcinoma xenografts.
n3:mentions: n4:20184929

Subject Item: _:vb29630711
rdf:type: n3:Context
rdf:value: Published data also suggest a higher-stability vincristine formulation in sphingomyelin/cholesterol liposomes was more efficacious than a less stable formulation of DSPC/cholesterol liposomes [>>89<<].
n3:mentions: n4:7547237

Subject Item: _:vb29630712
rdf:type: n3:Context
rdf:value: rates could demonstrate antitumor activity if they are targeted to antigens that are easily accessible from the vasculature, such as may be the case for leukemias and lymphomas, or to micrometastases in which extravasation is rapid [>>165<<,166,167]. However, DXR-containing immunoliposome formulations bearing anti-CD19 and having varying drug release rates (t1/2 of 1.9 h to 315 h) were compared in a B-cell lymphoma model.
n3:mentions: n4:16028012

Subject Item: _:vb29630713
rdf:type: n3:Context
rdf:value: could demonstrate antitumor activity if they are targeted to antigens that are easily accessible from the vasculature, such as may be the case for leukemias and lymphomas, or to micrometastases in which extravasation is rapid [165,>>166<<,167]. However, DXR-containing immunoliposome formulations bearing anti-CD19 and having varying drug release rates (t1/2 of 1.9 h to 315 h) were compared in a B-cell lymphoma model.
n3:mentions: n4:7882453

Subject Item: _:vb29630714
rdf:type: n3:Context
rdf:value: could demonstrate antitumor activity if they are targeted to antigens that are easily accessible from the vasculature, such as may be the case for leukemias and lymphomas, or to micrometastases in which extravasation is rapid [165,166,>>167<<]. However, DXR-containing immunoliposome formulations bearing anti-CD19 and having varying drug release rates (t1/2 of 1.9 h to 315 h) were compared in a B-cell lymphoma model.
n3:mentions: n4:11030591

Subject Item: _:vb29630715
rdf:type: n3:Context
rdf:value: The antitumor activity correlated inversely with the drug release rates [>>168<<]: immunoliposomes with the most rapid DXR release rate demonstrated little efficacy, whereas the most stable formulations showed the greatest activity.
n3:mentions: n4:15867261

Subject Item: _:vb29630716
rdf:type: n3:Context
rdf:value: First, liposomal drugs generally show longer plasma circulation half-lives in human than in rodents (e.g., SSL-DXR has a circulation t1/2 of 56–59 h in humans [>>150<<,169] vs. 21–23 h in rodents [169]), suggesting that greater stability may be required in humans in order to maximize tumor deposition. Second, the tumor growth rate generally is slower in humans than in most animal xenograft models. Thus
n3:mentions: n4:10964334

Subject Item: _:vb29630717
rdf:type: n3:Context
rdf:value: First, liposomal drugs generally show longer plasma circulation half-lives in human than in rodents (e.g., SSL-DXR has a circulation t1/2 of 56–59 h in humans [150,>>169<<] vs. 21–23 h in rodents [169]), suggesting that greater stability may be required in humans in order to maximize tumor deposition. Second, the tumor growth rate generally is slower in humans than in most animal xenograft models. Thus a
n3:mentions: n4:8880211

Subject Item: _:vb29630718
rdf:type: n3:Context
rdf:value: 21–23 h in rodents [>>169<<]), suggesting that greater stability may be required in humans in order to maximize tumor deposition.
n3:mentions: n4:8880211

Subject Item: _:vb29630719
rdf:type: n3:Context
rdf:value: Rapid tumor growth may favor more rapidly-releasing formulations, as has been concluded in analysis such as [>>156<<], which is discussed in greater detail below.
n3:mentions: n4:10837779

Subject Item: _:vb29630720
rdf:type: n3:Context
rdf:value: long-circulating, slow-release SSL-DXR in mouse tumor models compared to equivalent doses of free DXR; free DXR rapidly establishes high peak levels in tumor but clears quickly from the tumor when blood concentrations of drug decline [>>170<<]. Interestingly, a recent multi-scale analysis suggest that in humans, free DXR may be more efficacious than SSL-DXR under certain specific conditions relating to tumor perfusion and vascular permeability [110].
n3:mentions: n4:10589782

Subject Item: _:vb29630721
rdf:type: n3:Context
rdf:value: Interestingly, a recent multi-scale analysis suggest that in humans, free DXR may be more efficacious than SSL-DXR under certain specific conditions relating to tumor perfusion and vascular permeability [>>110<<]. Overall, there are few studies that permit direct and quantitative comparison of the effect of in vivo drug-release rates for liposomal formulations upon the observed efficacy in preclinical species vs. humans. Further studies,
n3:mentions: n4:23723124

Subject Item: _:vb29630722
rdf:type: n3:Context
rdf:value: The influence of tumor drug deposition and the effect of liposomal lipid composition on therapeutic efficacy was evaluated for DXR using human tumor xenografts in immunodeficient mice [>>171<<]. A pegylated SSL-DXR formulation was shown to be more effective than free DXR and other non-pegylated liposomal formulations of DXR, and SSL-DXR efficacy was observed at doses lower than the maximal tolerated dose of free DXR, indicating
n3:mentions: n4:9361957

Subject Item: _:vb29630723
rdf:type: n3:Context
rdf:value: SSL-DXR at 1–2 mg/kg was equipotent in activity to free DXR at 6 mg/kg, indicating a 3–6-fold increase in drug efficacy [>>172<<]. Similarly, the 50% lethal dose of SSL-DXR was nearly twice that of free DXR after a single intravenous injection in mice [68], and in rabbits, the cardiac toxicity of SSL-DXR was considerably less than that of free DXR in a multiple
n3:mentions: n4:12739982

Subject Item: _:vb29630724
rdf:type: n3:Context
rdf:value: Similarly, the 50% lethal dose of SSL-DXR was nearly twice that of free DXR after a single intravenous injection in mice [>>68<<], and in rabbits, the cardiac toxicity of SSL-DXR was considerably less than that of free DXR in a multiple dose study [173].
n3:mentions: n4:8373796

Subject Item: _:vb29630725
rdf:type: n3:Context
rdf:value: the 50% lethal dose of SSL-DXR was nearly twice that of free DXR after a single intravenous injection in mice [68], and in rabbits, the cardiac toxicity of SSL-DXR was considerably less than that of free DXR in a multiple dose study [>>173<<].
n3:mentions: n4:10215696

Subject Item: _:vb29630726
rdf:type: n3:Context
rdf:value: Liposome-mediated drug delivery has limitations, given that drug transport and deposition are controlled by tumor structure and drug-specific properties [>>174<<,175]. Whereas drug transport via the blood stream and across the tumor vascular barrier is dominated by convection, a transport mechanism that is relatively insensitive to molecular mass, the subsequent distribution into the tumor
n3:mentions: n4:20838415

Subject Item: _:vb29630727
rdf:type: n3:Context
rdf:value: Liposome-mediated drug delivery has limitations, given that drug transport and deposition are controlled by tumor structure and drug-specific properties [174,>>175<<]. Whereas drug transport via the blood stream and across the tumor vascular barrier is dominated by convection, a transport mechanism that is relatively insensitive to molecular mass, the subsequent distribution into the tumor
n3:mentions: n4:16862189

Subject Item: _:vb29630728
rdf:type: n3:Context
rdf:value: insensitive to molecular mass, the subsequent distribution into the tumor interstitium after extravasation is dominated by diffusion, which is slower than convection and heavily influenced by molecular mass or radius of hydration [>>174<<]. With relatively few exceptions, there exists a general lack of quantitative, model-based analysis of the dynamic interplay of liposome deposition and delivery events within the tumor.
n3:mentions: n4:20838415

Subject Item: _:vb29630729
rdf:type: n3:Context
rdf:value: Several compartmental and physiologically-based models have been used to quantify transport processes across rodent and human scales [>>176<<], and mechanism-based models have been developed that integrate drug interactions with cell-specific surface receptors and ligands [177].
n3:mentions: n4:7553638

Subject Item: _:vb29630730
rdf:type: n3:Context
rdf:value: models have been used to quantify transport processes across rodent and human scales [176], and mechanism-based models have been developed that integrate drug interactions with cell-specific surface receptors and ligands [>>177<<].
n3:mentions: n4:18388873

Subject Item: _:vb29630731
rdf:type: n3:Context
rdf:value: continuous infusions of varying duration [>>178<<]. Relationships were developed between plasma and tumor concentrations of drug, and rates of drug equilibration into tumor cells were estimated.
n3:mentions: n4:11005567

Subject Item: _:vb29630732
rdf:type: n3:Context
rdf:value: The model captured the time course of free DXR concentration in the extracellular space, and was linked to a pharmacodynamic model for tumor cell kill kinetics [>>156<<]. The simulations suggested that for rats, reducing the rates of RES clearance and drug release enhanced tumor drug delivery and efficacy of liposomes. However, whereas efficacy continued to increase as RES clearance was decreased, there
n3:mentions: n4:10837779

Subject Item: _:vb29630733
rdf:type: n3:Context
rdf:value: Interestingly, paclitaxel-mediated neutropenia, one biomarker of toxicity, is related to the time-over-threshold-concentration of unbound drug [>>179<<]. It appears from the modeling that the unique combination of CLL-drug (liposome PK) and krel for LEP-ETU results in high initial unbound drug concentrations that fall more rapidly below the toxicity threshold than they do with Taxol®,
n3:mentions: n4:7799018

Subject Item: _:vb29630734
rdf:type: n3:Context
rdf:value: rapidly below the toxicity threshold than they do with Taxol®, the conventional clinical formulation of PAC, and this complex interplay of CLL-drug and krel could be responsible for the lower toxicity of LEP-ETU compared to Taxol® [>>159<<]. This is an important hypothesis to test experimentally.
n3:mentions: n4:22588463

Subject Item: _:vb29630735
rdf:type: n3:Context
rdf:value: with paclitaxel, which creates a wave of apoptosis within solid tumors, resulting in altered tumor vascular perfusion/permeability, reduced tumor interstitial pressure and cellular density, and increased intra-tumor diffusion [>>180<<,181]. The subsequently-delivered agent was SSL-DXR [181]. It was observed experimentally that a 48 h inter-dose interval increased SSL-DXR tumor deposition, efficacy, and time to tumor regrowth.
n3:mentions: n4:10446995

Subject Item: _:vb29630736
rdf:type: n3:Context
rdf:value: with paclitaxel, which creates a wave of apoptosis within solid tumors, resulting in altered tumor vascular perfusion/permeability, reduced tumor interstitial pressure and cellular density, and increased intra-tumor diffusion [180,>>181<<]. The subsequently-delivered agent was SSL-DXR [181]. It was observed experimentally that a 48 h inter-dose interval increased SSL-DXR tumor deposition, efficacy, and time to tumor regrowth.
n3:mentions: n4:17420296

Subject Item: _:vb29630737
rdf:type: n3:Context
rdf:value: The subsequently-delivered agent was SSL-DXR [>>181<<]. It was observed experimentally that a 48 h inter-dose interval increased SSL-DXR tumor deposition, efficacy, and time to tumor regrowth.
n3:mentions: n4:17420296

Subject Item: _:vb29630738
rdf:type: n3:Context
rdf:value: In order to develop a hypothesis describing the linkage between PK and PD in tumor priming strategies, a quantitative system pharmacological model was developed using available data from the literature [>>155<<,181,182,183,184,185].
n3:mentions: n4:15948037

Subject Item: _:vb29630739
rdf:type: n3:Context
rdf:value: In order to develop a hypothesis describing the linkage between PK and PD in tumor priming strategies, a quantitative system pharmacological model was developed using available data from the literature [155,>>181<<,182,183,184,185].
n3:mentions: n4:17420296

Subject Item: _:vb29630740
rdf:type: n3:Context
rdf:value: In order to develop a hypothesis describing the linkage between PK and PD in tumor priming strategies, a quantitative system pharmacological model was developed using available data from the literature [155,181,>>182<<,183,184,185].
n3:mentions: n4:19523755

Subject Item: _:vb29630741
rdf:type: n3:Context
rdf:value: In order to develop a hypothesis describing the linkage between PK and PD in tumor priming strategies, a quantitative system pharmacological model was developed using available data from the literature [155,181,182,>>183<<,184,185]. The final model [153] captured the observed data [181] for the PK of paclitaxel and SSL-DXR as single agents, as well as effects on tumor drug exposure, cellular responses such as apoptosis, and tumor volume progression when the
n3:mentions: n4:16489089

Subject Item: _:vb29630742
rdf:type: n3:Context
rdf:value: In order to develop a hypothesis describing the linkage between PK and PD in tumor priming strategies, a quantitative system pharmacological model was developed using available data from the literature [155,181,182,183,>>184<<,185]. The final model [153] captured the observed data [181] for the PK of paclitaxel and SSL-DXR as single agents, as well as effects on tumor drug exposure, cellular responses such as apoptosis, and tumor volume progression when the
n3:mentions: n4:7828272

Subject Item: _:vb29630743
rdf:type: n3:Context
rdf:value: In order to develop a hypothesis describing the linkage between PK and PD in tumor priming strategies, a quantitative system pharmacological model was developed using available data from the literature [155,181,182,183,184,>>185<<]. The final model [153] captured the observed data [181] for the PK of paclitaxel and SSL-DXR as single agents, as well as effects on tumor drug exposure, cellular responses such as apoptosis, and tumor volume progression when the drugs
n3:mentions: n4:8616858

Subject Item: _:vb29630744
rdf:type: n3:Context
rdf:value: The final model [>>153<<] captured the observed data [181] for the PK of paclitaxel and SSL-DXR as single agents, as well as effects on tumor drug exposure, cellular responses such as apoptosis, and tumor volume progression when the drugs were administered alone,
n3:mentions: n4:23115220

Subject Item: _:vb29630745
rdf:type: n3:Context
rdf:value: The final model [153] captured the observed data [>>181<<] for the PK of paclitaxel and SSL-DXR as single agents, as well as effects on tumor drug exposure, cellular responses such as apoptosis, and tumor volume progression when the drugs were administered alone, combined in a priming-inducing
n3:mentions: n4:17420296

Subject Item: _:vb29630746
rdf:type: n3:Context
rdf:value: Results are extracted from the analysis of [>>153<<].
n3:mentions: n4:23115220

Subject Item: _:vb29630747
rdf:type: n2:Section
dc:title: translation of pk system parameters from animal models to humans
n2:contains: _:vb29630748 _:vb29630749 _:vb29630750 _:vb29630751 _:vb29630760 _:vb29630752 _:vb29630753 _:vb29630754 _:vb29630755 _:vb29630756 _:vb29630757 _:vb29630758 _:vb29630759

Subject Item: _:vb29630748
rdf:type: n3:Context
rdf:value: A single, species-independent first-order release rate constant (t1/2 of release = 198 h) was estimated for rats and humans [>>91<<]. Drug release kinetics were then incorporated into vascular- and tissue sub-compartments of PBPK models to describe amphotericin B biodistribution in mice and rats, systems for which such data were available, and then to predict the
n3:mentions: n4:21431453

Subject Item: _:vb29630749
rdf:type: n3:Context
rdf:value: the fitting of a coefficient for DXR transport into human tumors (transvascular flux into the tumor for DXR; tvf_in_dox) based upon an underlying assumption that gadolinium has similar diffusive transport characteristics as free DXR [>>186<<,187,188]. The coefficient parameter for DXR transport out of the tumor (tvf_out_dox) was also fitted from human data for SSL-DXR and unencapsulated DXR [29].
n3:mentions: n4:18927299

Subject Item: _:vb29630750
rdf:type: n3:Context
rdf:value: fitting of a coefficient for DXR transport into human tumors (transvascular flux into the tumor for DXR; tvf_in_dox) based upon an underlying assumption that gadolinium has similar diffusive transport characteristics as free DXR [186,>>187<<,188]. The coefficient parameter for DXR transport out of the tumor (tvf_out_dox) was also fitted from human data for SSL-DXR and unencapsulated DXR [29].
n3:mentions: n4:18060716

Subject Item: _:vb29630751
rdf:type: n3:Context
rdf:value: of a coefficient for DXR transport into human tumors (transvascular flux into the tumor for DXR; tvf_in_dox) based upon an underlying assumption that gadolinium has similar diffusive transport characteristics as free DXR [186,187,>>188<<]. The coefficient parameter for DXR transport out of the tumor (tvf_out_dox) was also fitted from human data for SSL-DXR and unencapsulated DXR [29].
n3:mentions: n4:17222711

Subject Item: _:vb29630752
rdf:type: n3:Context
rdf:value: The coefficient parameter for DXR transport out of the tumor (tvf_out_dox) was also fitted from human data for SSL-DXR and unencapsulated DXR [>>29<<]. For DXR, the tumor influx parameter tvf_in_dox was approxiamtely 12-fold greater in humans than mice, and the efflux (tvf_out_dox) was approxiamtely 7-fold greater in humans. For SSL-DXR, the inward transvascular flux coefficient for
n3:mentions: n4:9667262

Subject Item: _:vb29630753
rdf:type: n3:Context
rdf:value: For SSL-DXR, the inward transvascular flux coefficient for liposomes (tvf_in_lipo) was estimated from available clinical data [>>47<<,189], and the outward transvascular flux (from the tumor interstitial space to the capillary space, tvf_out_lipo) was based upon data from mouse models [115].
n3:mentions: n4:11398881

Subject Item: _:vb29630754
rdf:type: n3:Context
rdf:value: For SSL-DXR, the inward transvascular flux coefficient for liposomes (tvf_in_lipo) was estimated from available clinical data [47,>>189<<], and the outward transvascular flux (from the tumor interstitial space to the capillary space, tvf_out_lipo) was based upon data from mouse models [115].
n3:mentions: n4:10331240

Subject Item: _:vb29630755
rdf:type: n3:Context
rdf:value: to central compartment1.25 × 10−3 (0.2)[158]kel_DXR (1/min)Rate constant of DXR elimination from central compartment8.2 × 10−2 (0.2)[158]tvf_in_DXR (cm/min)Rate constant of DXR elimination from central compartment3.63 × 10−3 (12.3)[>>186<<,187,188]tvf_out_DXR (cm/min)Rate constant of liposome elimination from central compartment8.45 × 10−3 (7.2)[158]Human Liposome kel_lipo (1/min)Rate constant of liposome elimination from central compartment1.67 × 10−4 (0.1)[47]tvf_in_lipo
n3:mentions: n4:18927299

Subject Item: _:vb29630756
rdf:type: n3:Context
rdf:value: to central compartment1.25 × 10−3 (0.2)[158]kel_DXR (1/min)Rate constant of DXR elimination from central compartment8.2 × 10−2 (0.2)[158]tvf_in_DXR (cm/min)Rate constant of DXR elimination from central compartment3.63 × 10−3 (12.3)[186,>>187<<,188]tvf_out_DXR (cm/min)Rate constant of liposome elimination from central compartment8.45 × 10−3 (7.2)[158]Human Liposome kel_lipo (1/min)Rate constant of liposome elimination from central compartment1.67 × 10−4 (0.1)[47]tvf_in_lipo
n3:mentions: n4:18060716

Subject Item: _:vb29630757
rdf:type: n3:Context
rdf:value: compartment1.25 × 10−3 (0.2)[158]kel_DXR (1/min)Rate constant of DXR elimination from central compartment8.2 × 10−2 (0.2)[158]tvf_in_DXR (cm/min)Rate constant of DXR elimination from central compartment3.63 × 10−3 (12.3)[186,187,>>188<<]tvf_out_DXR (cm/min)Rate constant of liposome elimination from central compartment8.45 × 10−3 (7.2)[158]Human Liposome kel_lipo (1/min)Rate constant of liposome elimination from central compartment1.67 × 10−4 (0.1)[47]tvf_in_lipo
n3:mentions: n4:17222711

Subject Item: _:vb29630758
rdf:type: n3:Context
rdf:value: (12.3)[186,187,188]tvf_out_DXR (cm/min)Rate constant of liposome elimination from central compartment8.45 × 10−3 (7.2)[158]Human Liposome kel_lipo (1/min)Rate constant of liposome elimination from central compartment1.67 × 10−4 (0.1)[>>47<<]tvf_in_lipo (cm/min)Transvascular flux per surface area for liposome from capillary to interstitial space2.64 × 10−6 (1.0)[158]tvf_out_lipo (cm/min)Transvascular flux per surface area for liposome from interstitial to capillary space7.14
n3:mentions: n4:11398881

Subject Item: _:vb29630759
rdf:type: n3:Context
rdf:value: to interstitial space2.64 × 10−6 (1.0)[158]tvf_out_lipo (cm/min)Transvascular flux per surface area for liposome from interstitial to capillary space7.14 × 10−6 (1.0)[158]Tumor Qtumor (L/min/kg)Blood flow into tumor2.82 × 10−2 (0.1)[>>176<<
n3:mentions: n4:7553638

Subject Item: _:vb29630760
rdf:type: n3:Context
rdf:value: interstitial space2.64 × 10−6 (1.0)[158]tvf_out_lipo (cm/min)Transvascular flux per surface area for liposome from interstitial to capillary space7.14 × 10−6 (1.0)[158]Tumor Qtumor (L/min/kg)Blood flow into tumor2.82 × 10−2 (0.1)[176,>>190<<
n3:mentions: n4:8137258

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