Biomedical Engineering Reference
In-Depth Information
and.spleen,.and.its.accumulation.in.the.kidney.was.reduced..Finally,.an.i.v.-administered.
monodose.of.GEN.pH-sensitive.or.GEN.pH-insensitive.liposomes.reduces.10
3
-.to.10
4
-fold.
the.number.of.resident.bacteria.from.liver.and.spleen.macrophages.
170
20.8.7 Complement Activation
Recently,.it.was.determined.that.pH-insensitive.liposomes.(DOPC/Chol).activate.a.com-
plement.system.with.lower.amounts.of.phospholipid.than.pH-sensitive.(DOPE/CHEMS).
liposomes..The.presence.of.phosphorylcholine.groups.(that.bind.to.C-reactive.protein).in.
the.DOPC.molecules,.the.higher.luidity.of.DOPC/Chol.liposomal.membranes.(luid.mem-
branes.are.more.susceptible.to.binding.with.C3.fragments.(C3b)),.and.the.use.of.CHEMS.
instead. of. Chol. (the. hydroxyl. group. of. Chol. constitutes. an. activated. C3b). could. be. the.
reasons.. Whereas. pegylated. pH-insensitive. liposomes. activated. complement,. pegylated.
pH-sensitive.liposomes.proved.to.be.poor.activators.
171
20.9 Conclusions
After.three.decades.of.basic.research,.in.the.last.5.years.the.irst.preclinical.studies.employ-
ing.pH-sensitive.liposomes.have.been.published..This.is.probably.a.consequence.of.their.
major.drawback—lability.in.the.bloodstream—caused.by.the.extraction.of.lipids.from.the.
pH-sensitive.bilayers.or.the.loss.of.the.attached.pH-sensitive.polymers.
The.concept.of.tunable.pH-sensitive.liposomes.was.born.in.the.search.for.ine-tuning.
the.pH.response.that.is.poorly.achieved.with.DOPE/CHEMS.liposomes..However,.up.to.
the.moment,.only.improved.in.vitro.plasma.stability.has.been.achieved,.and.there.is.no.
evidence.for.a.better.capacity.of.tuning.in.vivo.
Pegylation.of.DOPE/CHEMS.liposomes.results.in.lack.of.pH.sensitivity.in.plasma;.hence,.
their.capacity.to.execute.simultaneously.multiple.functions.(long.circulation.and.pH.sen-
sitivity). is. arguable.. Recently. synthesized. nonionic. polymers. were. capable. of. replacing.
the.steric.stabilization.provided.by.Peg.in.DOPE/CHEMS.liposomes..However,.nothing.is.
known.about.their.biocompatibility..On.the.other.hand,.the.lower.cell.uptake.of.pegylated.
pH-sensitive.liposomes.occurring.above.a.threshold.of.Peg.content.should.be.compensated.
by.a.higher.cytoplasmic.delivery..In.this.controversial.scenario,.a.recent.series.of.preclini-
cal.studies.has.undoubtedly.shown.the.feasibility.of.tumor.therapeutics.and.diagnosis.by.
employing.pegylated.pH-sensitive.DOPE/CHEMS.liposomes.
As. an. alternative. to. the. mechanism. of. pH. sensitivity. mediated. by. the. transition. to. a.
nonlamellar.phase.triggered.by.CHEMS.protonation,.the.transition.of.DOPE.liposomes.is.
triggered.by.the.hydrolysis.of.pH-sensitive.linkages,.leading.to.the.detachment.of.the.Peg.
layer.that.avoids.liposomal.aggregation..The.hydrolysis.of.the.vinyl.ether.linkages.BVEP.
and.CVEP.is.not.accompanied.by.membrane.fusion..The.performance.of.pH.sensitivity.of.
liposomes.bearing.Peg.attached.by.these.labile.linkages.remains.to.be.compared.to.that.of.
DOPE/CHEMS.liposomes.in.vivo..This.would.decide.if.their.higher.plasma.stability.over-
comes. the. lower. eficiency. of. cytoplasmic. delivery. with. DOPE/CHEMS. liposomes.. The.
higher.rate.of.acid.hydrolysis.of.the.orthoester.linkage.showed.by.POD.was.determined.in.
the.absence.of.cells,.and.only.pharmacokinetics.and.biodistribution.were.determined.in.
mice..A.common.disadvantage.of.labile.linkages.is.the.need.for.an.ad.hoc.synthesis.
