Biomedical Engineering Reference
In-Depth Information
the.Lα.→.H
II
.transition.at.low.pH..For.instance,.pegylated.liposomes.release.5.8.and.6.8%.
in.buffer.and.plasma.at.pH.5.5,.respectively.
68
It.is.noteworthy.that.though.the.uptake.of.pegylated.liposomes.by.differentiated.THP-1.
cells.was.lower.that.that.of.nonpegylated.liposomes,.the.capacity.of.intracellular.release.
of. calcein. by. DOPE/CHEMS/Peg-PE. liposomes.(measured. as. the. calcein/rhodamine-PE.
ratio). was. the. same. as. that. of. DOPE/CHEMS. liposomes.. Inside. the. endosome,. despite.
the. absence. of. pH. sensitivity,. Peg. behaves. as. a. dehydrating. agent. and. promotes. fusion.
by.a.synergistic.effect.with.DOPE,.while.in.the.presence.of.distearoylphospatydilcholine.
(DSPC),.instead.of.DOPE,.the.effect.of.Peg.alone.is.insuficient.to.promote.destabilization.
and.cytoplasmic.release.
70
An.alternative.to.the.use.of.PE-Peg.that.causes.loss.of.pH.sensitivity.is.steric.stabilization.
by.novel.nonionic.copolymers.(DDGG)
4
(EO)
114
,.bearing.short.blocks.of.lipid-mimetic.units.
and. different. Peg. molecular. weights. (Figure 20.3).
71
. The. incorporation. of. up. to. 10. mol%.
(DDGG)
4
(EO)
114.
into.DOPE/CHEM.liposomes.does.not.decrease.the.pH.sensitivity..In.25%.
human.plasma,.the.calcein.release.of.5.mol%.(DDGG)
4
(EO)
114
-containing.liposomes
.
is.less.
than. 20%. after. 5. h. (vs.. 35%. for. DOPE/CHEM. liposomes).. The. intracellular. delivery. of.
calcein.to.EJ.cells.is.similar.to.that.achieved.by.DOPE/CHEMS.liposomes.
The.leakage.from.pH-sensitive.liposomes.depends.on.the.chemical.structure.of.the.mol-
ecules. loaded. into. their. inner. aqueous. space.. For. instance,. weak. bases. such. as. quinine,.
chloroquine,.mitoxantrone,.epirubicin,.daunorrubicin,.vincristin,.and.doxorubicin.(DRX).
are.incorporated.into.liposomes.by.active.loading..DXR.(pKa.=.8.1).is.uncharged.at.neutral.
pH.and.is.membrane.permeable..To.protonate.and.accumulate.DRX.inside.liposomes,.the.
inner.aqueous.space.must.be.at.an.acidic.pH.(below.5.5)..However,.DOPE/CHEMS/PE-Peg.
5.mol%.liposomes.are.not.stable.at.that.pH,.and.between.80.and.100%.of.the.DRX.that.is.
loaded.in.the.uncharged.form.rapidly.escapes.in.90%.human.plasma.
72
.The.inclusion.of.
cholesterol. and. hydrogenated. soy. PC. increases. the. liposomal. retention. of. DXR. (10. and.
60%.release.along.12.and.24.h,.respectively).
73
20.2.2 Pharmacokinetics and Biodistribution
The.main.feature.of.DOPE/OA.(7:3).liposomes.when.administered.i.v..is.the.aggregation.
and. accumulation. in. pulmonary. capillaries. (as. well. as. important. leakage. in. circulation.
resulting.from.the.extraction.of.OA.by.albumin).that.occur.within.the.irst.minutes
61,65,74
;.
in.15.min.liposomes.devoid.of.their.aqueous.content.accumulate.in.the.liver.and.spleen.
On.the.other.hand,.DOPE/CHEMS.(6:4).liposomes.show.little.leakage,.do.not.aggregate.
or.accumulate.in.lungs,.and.are.almost.completely.captured.by.the.liver.and.spleen.after.
30 min..The.addition.of.5.mol%.PE-Peg.increases.the.half-life.to.11.h.in.rats,.with.a.sus-
tantial. proportion. of. liposomes. (8.5%). remaining. in. circulation. at. 24. h.. Remarkably,. the.
aqueous.content.of.these.liposomes,.independently.of.pegylation,.accumulates.more.in.the.
liver.and.spleen.and.is.excreted.less.in.urine.than.the.content.of.pegylated.pH-insensitive.
liposomes..This.was.attributed.to.the.fact.that.in.pH-sensitive.liposomes.the.content.exits.
the.endolysosomal.route.and.is.less.excreted.from.the.cell.
68
The. replacement. of. PE-Peg. by. 5. mol%. (DDGG)
4
(EO)
114.
in. DOPE/CHEMS. liposomes.
increases.its.half-life.in.circulation,.in.comparison.to.that.of.nonpegylated.liposomes.(that.
are. cleared. from. circulation. within. 1. h. postinjection).. Also,. (DDGG)
4
(EO)
114.
liposomes.
exhibit. even. slower. elimination. than. pegylated. liposomes,. as. ∼15%. of. the. initial. dose. is.
still.in.circulation.48.h.after.i.v..administration.in.Wistar.rats.
71
.Compared.to.pegylated,.
(DDGG)
4
(EO)
114
.liposomes.increase.the.area.under.the.plasma.concentration.vs..time.curve.
(AUC).3.31-fold.(30.6-fold.compared.to.DOPE/CHEMS.liposomes).and.reduce.the.volume.
