Theoretical consideration behind liposome formation by broad spectrum of methods.There is a lot in common(current status) 8 MLV 米 H88 e DI参8 IPATION OF能N月信￥ ⑤ 言 w2988 LUV pid re ao dire from pre using templ Functional Classification of Liposomes(1) Liposome Plasma clearance Plasma clearance for type Main features for large liposomes small liposomes High accessibility to interact with factors from extraliposomal medium Medium(tk~>1h)） Conventional (ie., opsonins,enzymes,low Fast (t.<30 min) liposomes molecular mass agents).high RES Saturation dependent Saturation dependent uptake.For um size range,high lung Extravasation is feasible uptake Slow (t%>8h) Sterically Low accessibility to extraliposomal Slow (t >5 h) Saturation independent stabilized factors due to grafted steric barrier. Saturation liposomes low RES uptake independent Extravasation into tumors and sites of inflammation Vesicular to non vasicular transition upon contact with agent or medium components:(a)cationic liposomes- nucleic acid interaction induce lipoplex Actisomes formation.The lipoplexes when Very fast(t min exemplified injected i.v.accumulate in the lung range)Saturation Fast(t.-min range) by: where maximum transfection occurs. dependent Saturation dependent (b)pH sensitive liposomes,which fuse and release their content as a result of exposure to acidic pH(Drummond et al.2000). Based on Barenholz,1998
6 Theoretical consideration behind liposome formation by broad spectrum of methods. There is a lot in common (current status) Functional Classification of Liposomes (1) Plasma clearance for small liposomes Plasma clearance for large liposomes Main features Liposome type Medium (t½ ~> 1h) Saturation dependent Extravasation is feasible Fast (t½ < 30 min) Saturation dependent High accessibility to interact with factors from extraliposomal medium (i.e., opsonins, enzymes, low molecular mass agents), high RES uptake. For µm size range, high lung uptake Conventional liposomes Slow (t½ > 8 h) Saturation independent Extravasation into tumors and sites of inflammation Slow (t½ >5 h) Saturation independent Low accessibility to extraliposomal factors due to grafted steric barrier, low RES uptake Sterically stabilized liposomes Fast (t½-min range) Saturation dependent Very fast (t½~ min range) Saturation dependent Vesicular to non vasicular transition upon contact with agent or medium components: (a) cationic liposomes– nucleic acid interaction induce lipoplex formation. The lipoplexes when injected i.v. accumulate in the lung where maximum transfection occurs; (b) pH sensitive liposomes, which fuse and release their content as a result of exposure to acidic pH (Drummond et al., 2000). Actisomes exemplified by: aBased on Barenholz, 1998
Fate of liposomes and encapsulated drug after intravenous administration i.v.injection of liposomes Uptake RES/MPS Liposome disintegration in Long circulating liposomes blood (SSL) Release in cell Slow release of agent in blood,and/or:accumulation Release of(in)active Release in blood at non-MPS tumor and agent from cell inflammation sites Reticuloendothelial system=RES Mononuclear phagocyte system=MPS Proposed Liposome Classification Based on Pharmacologic Behavior ·Vehicle -Majority of drug rapidly released into central compartment prior to MPS uptake of liposome -Possible safety advantages over other vehicles (i.e.,cremophor/ethanol,Tween)>less hemolysis,allergic reactions -Infusion reactions to liposomes well documented,so safety trade-off uncertain
7 Fate of liposomes and encapsulated drug after intravenous administration Reticuloendothelial system = RES Mononuclear phagocyte system = MPS i.v. injection of liposomes Uptake RES/MPS Liposome disintegration in blood Long circulating liposomes (SSL) Release in cell Release of (in)active agent from cell Release in blood Slow release of agent in blood, and/or: accumulation at non-MPS tumor and inflammation sites
Proposed Liposome Classification (Cont.) ·MPS Uptake -Superior to subcutaneous where dose is concentrated in confined area>extracellular matrix cellular localization.local iritation,rapid entry into central compartment -Distributes dose to greater number of cells (volume)> MPS cells -Forms MPS "depot">slow re-release into central compartment resembles prolonged infusion Avoids peaks and associated adverse effects while maintaining AUC -Clinical benefit documented(Myocet,AmBisome) Proposed Liposome Classification (Cont.) ·MPS Avoid -Surface modification slows MPS uptake -Drug retained in liposome in plasma -Circulates for several days -Small enough to extravasate in tissues -Preferential uptake at sites with compromised endothelium -Drug released in tissue compartment
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