Liposomal pH-Sensitive Nanomedicines in Preclinical Development - Bionanotechnology: Global Prospects - page 385

Renal elimination
(<10 nm/70000 daltons)

Hepatocytes (<100 nm)
Spleen bone marrow

B

Kupffer cells

H
Tumor cells

A

G

C

Surrounding
tissue

F

D

E

Vascular
endothelium

Blood
compartment

FIGURE 20.1
Schematic.representation.of.the.events.occurring.in.the.blood.circulation..A:.pH-sensitive.liposomes.in.blood.
circulation. upon. intravenous. (i.v.). (or. intramuscular. (i.m.)/intraperitoneal. (i.p.). administration. if. <100. nm.
diameter). administration.. Liposomes. remain. conined. in. continuous. endothelium. vasculature.. B:. Normal.
(nonpathological). fenestrate. endothelium. in. liver. allows. the. extravasation. of. liposomes. to. reach. hepato-
cytes.. Kupffer. cells. in. light. of. liver. vasculature. phagocyte. opsonized/aggregated. pH-sensitive. liposomes..
C: Nonpegylated. pH-sensitive. liposomes. (e.g.,. DOPE/OA). aggregate. in. blood. circulation. and. block. pulmo-
nary. capillaries.. D:. Intravascular. aggregation. of. liposomes. (e.g.,. Dioleoylphosphatidylethanolamine/oleic.
acid,. (DOPE/OA)). leads. to. phase. transition. and. inner. content. leakage.. E:. Nonpegylated. pH-sensitive. lipo-
somes. are. covered. by. opsonins. (opsonization). and. albumin.. Opsonization. is. a. previous. step. to. phagocy-
tosis. 11 . Interaction. with. plasma. proteins. leads. to. loss. of. pH. sensitivity,. with. the. exception. of. pH-sensitive.
liposomes.bearing.poly(NIPA-co-MAA-co-DODA)..F:.Blood.albumin.eliminates.OA.from.DOPE/OA.pH-sen-
sitive. liposomes,. and. intravascular. leakage. is. produced.. G:. Pegylated. pH-sensitive. liposomes. have. reduced.
liposome-liposome. interactions. and. are. refractory. to. opsonization. 15-18 . Pegylated. liposomes. avoid. uptake.
by.reticuloendothelial.system.(RES).macrophages..H:.Pegylated.pH-sensitive.liposomes.are.long.circulat-
ing.and.can.extravasate.at.pathological.sites.presenting.enhanced.permeation.retention.(EPR;.resultant.from.
increased.vascular.permeability.plus.impaired.lymphatic.drainage). 12,13 .Most.gaps.in.the.leaky.vasculature.fall.
below.400.nm. 14 .The.site-speciic.extravasation.is.known.as.passive.targeting..A.previous.occurrence.of.passive.
targeting.is.required.for.active.targeting.of.liposomes.with.surfaces.bearing.ligands.or.antibodies..The.pas-
sive.targeting.can.be.limited.due.to.the.presence.of.poly(ethylene.glycol).(Peg)..Pegylated.surfaces.can.prevent.
interaction. between. liposomes. and. the. cell. surface. 19,20 . The. reduced. interactions. inhibit. effective. uptake. of.
the.payload.by.the.tumor.cells. 21 .Alternatively,.the.impaired.uptake.should.occur.above.a.threshold.value;.for.
instance,.clathrin-dependent.and.clathrin-independent.endocytosis.are.not.appreciably.affected.by.the.pres-
ence.of.<10%.surface.coverage.of.Peg,.although.internalization.is.affected.at.higher.(>20%).concentrations.in.
the.plasma.membrane. 22