Biomedical Engineering Reference
In-Depth Information
through.the.endosomes.in.cells.occurs.about.10-30.min.before.the.endosomal.contents.are.
delivered.into.the.lysosome.
49,50
The.same.as.DOPE/PE-Peg.liposomes,.pH-sensitive.DOPE/POD.liposomes.are.stable.
in. 75%. FBS. in. the. irst. 12. h,. but. POD-containing. liposomes. rapidly. release. 85%. of. the.
inner.content.during.the.following.4.h,.indicating.a.liposome.destabilization.process.spe-
ciically.mediated.by.POD.hydrolysis..DOPE/POD.liposomes.administrated.i.v..to.female.
ICR.mice.showed.a.one-compartment.clearance.kinetics,.similar.to.pH-insensitive.DOPE/
PE-Peg.liposomes.(nonpegylated.pH-insensitive.liposomes.usually.exhibit.a.two-compart-
ment.elimination.kinetics),.with.a.half-life.of.nearly.3.h,.mainly.accumulating.in.liver.and.
intestine.
91,93
20.5 LiposomesMadeofHydrolyzableLipids
In.these.strategies.the.liposomal.destabilization.is.not.based.on.a.phase.transition.but.on.
the.acid.hydrolysis.of.special.lipids.composing.the.bilayer.
The. acid. hydrolysis. of. the. vinyl. ether. lipid. diplasmenylcholine. (1,2-di-
O
-(
Z
-1'-
hexadecenyl)-sn-glycero-3-phosphocholine,. DPPlsC)
94
. produces. glycerophosphocholine.
and.fatty.aldehydes..The.permeability.of.DPPlsC.liposomes.is.enhanced.when.>20%.of.the.
vinyl.ether.lipid.is.hydrolyzed,.with.t
50%
release
.∼.1−4.h.between.pH.4.5.and.5.5..The.stability.
of.DPPlsC/dihydrocholesterol.(9:1).liposomes.in.50%.serum.is.higher.than.that.of.DOPE-
based. liposomes.. DPPlsC/PE-Peg
3350
-f. (99.5:0.5). loaded. with. ara-C. exhibit. ∼6,000-fold.
enhancement.in.cytotoxicity.on.KB.cells.compared.to.free.ara-C
95
,.and.chloroaluminum.
phthalocyanine.tetrasulfonate.(AlPcS
4
4-
;.a.water-soluble.sensitizer.used.in.photodynamic.
therapy). enhances. both. tumor. selectivity. and. phototoxicity.
96-98
. However,. the. dificulty.
and.prohibitive.cost.of.synthesizing.DPPlsC.made.necessary.the.development.of.an.alter-
native.approach.that.would.effect.cytoplasmic.delivery.of.liposomal.contents.but.require.
only.small.quantities.of.synthetic.vinyl.ether.lipids.
On.the.other.hand,.the.acid.hydrolysis.of.the.orthoester.phosphocholine.(OEPC).converts.
OEPC.from.a.double-chain.amphiphile.to.a.single-chain.lyso-phosphocholine.(lyso-PC)..
OEPC.liposomes.submitted.to.acid.hydrolysis.transform.into.lyso-phosphocholine.micelles..
The.acid.hydrolysis.consists.of.a.lag.and.a.burst.phase..The.lag.phase.is.pH.dependent:.
the.lower.the.pH,.the.shorter.the.time..The.pH-dependent.leakage.of.OEPC.liposomes.is.
similar.to.that.of.POD.liposomes,.but.with.a.relatively.shorter.lag.time..For.the.POD.lipo-
somes,.when.the.amount.of.surface.POD.is.lowered.to.a.critical.level,.the.Lα.→.H
II
.transi-
tion. is. initiated,. and. the. liposomes. aggregate. and. collapse. rapidly.. However,. the. OEPC.
liposomes.do.not.spontaneously.collapse.under.acidic.conditions..Unlike.DOPE/POD.ves-
icles,.they.do.not.show.a.concentration-dependent.release.rate.at.low.pH,.as.evidence.for.a.
non-contact-mediated.content.release.
99
.Upon.acid.hydrolysis,.OEPC.liposomes.are.trans-
formed. into. leaky. metastable. vesicles. that. rapidly. collapse. in. the. presence. of. albumin..
When.the.amount.of.lyso-phosphocholine.reaches.a.critical.level,.pores.form.on.the.surface.
of.the.vesicle,.resulting.in.rapid.content.release..Eventually,.the.metastable.liposomes.can.
be completely.destroyed.when.the.lyso-phosphocholine.and.dodecanol.are.removed.from.
the. bilayer. by. interaction. with. plasma.. OEPC. signiicantly. enhances. the. in. vitro. trans-
fection. eficiency. compared. with. pH-insensitive. phosphocholine. when. formulated. with.
cationic.lipids.(8.24.×.10
5.
vs..3.95.×.10
4
.RLU.(relative.light.units)/mg.protein).
100
.To.date,.the.
cytotoxicity,.pharmacokinetics,.and.biodistribution.of.OEPC.liposomes.are.unknown.
