Biomedical Engineering Reference
In-Depth Information
of.distribution.and.plasma.clearance.1.4-.and.4.5-fold,.respectively..Compared.to.DOPE/
CHEMS.liposomes,.the.liver.and.spleen.accumulation.is.reduced.by.a.factor.of.1.3.and.2.2.
for.the.pegylated.and.(DDGG)
4
(EO)
114
.liposomes,.respectively.
20.3 TunablepH-SensitiveLiposomes:Plasma-StableLiposomes
A. drawback. associated. with. DOPE/titrable. anionic. lipid. liposomes. is. that. the. pH. at.
which.the.Lα.→.H
II
.transition.occurs.is.determined.by.the.pKa.of.the.ionizable.compo-
nent. and. is,. therefore,. not. easily. tuned;. only. discrete. tuning. can. be. obtained. by. using.
different. ionizable. components.
44
. On. the. contrary,. liposomes. made. of. a. molar. excess. of.
ionizable.anionic.lipid,.CHEMS,.and.a.permanently.charged.cationic.lipid.
N
,
N
-dioleoyl-
N
,
N
-dimethylammonium. chloride. (DODAC). exhibit. Lα. →. H
II
. transition. at. a. pH. value.
that.can.be.tuned.continuously.
75
.At.neutral.pH,.CHEMS.is.negatively.charged.and.asso-
ciates. with. great. amounts. of. contra-ions. and. hydration. water.. These. interactions. make.
CHEMS's. shape. cilindric. and. stabilize. the. lamellar. phase.. As. the. pH. is. decreased,. the.
negative.charges.are.neutralized.and.CHEMS's.shape.turns.from.cylindric.to.an.inverted.
cone,. therefore. resulting. in. the. Lα. →. H
II
. transition.. The. addition. of. varying. amounts.
of.DODAC.competes.with.the.contra-ions,.and.the.acidity.required.to.induce.the.phase.
transition.is.a.monotonically.increasing.function.of.the.DODAC.concentration..The.phase.
transition.occurs.when.the.molar.fraction.of.the.negatively.charged.CHEMS.equals.the.
molar.fraction.of.DODAC,.at.a.pH.that.can.be.calculated.employing.a.modiied.Henderson-
Hasselbach.equation.
76
.These.liposomes.can.also.be.stabilized.by.a.strong.bilayer-forming.
lipid,.such.as.phosphatidylcholine.
77
The. possibility. of. tuning. the. pH. of. the. phase. transition. could. be. used. to. trigger. site-
speciic. extracellular. release. from. liposomes,. but. currently. remains. unexplored.. Only. a.
slight. increase. of. plasma. stability. has. been. reported,. in. comparison. to. plasma. stability.
of.nonpegylated.DOPE/CHEMS.liposomes..Nonetheless,.liposomes.made.of.anionic/cat-
ionic. lipids. (eggPC/CHEMS/DDAB. (dimethyldioctadecylammonium. bromide),. 25:49:25).
require.the.addition.of.1.mol%.Tween.80.to.decrease.the.calcein.release.from.38%.to.4%.in.
buffer.containing.10%.FBS..Tween.80.is.thought.to.increase.liposomal.stability.and.avoid.
aggregation,.providing.steric.stabilization.by.its.polyoxyethylene.headgroup..The.pH.sen-
sitivity. of. these. liposomes. in. buffer. is. similar. to. that. of. DOPE/CHEMS. liposomes. (50%.
release.at.pH.5.5),.and.remains.at.the.same.value.in.90%.plasma,.while.the.pH.sensitivity.
of.DOPE/CHEMS.liposomes.decreases.to.25%.
78
Similarly,. pH-sensitive. liposomes. made. of. phosphatidylcholine. from. egg. yolk. (eggPC)/
CHEMS/OAlc.(oleyl.alcohol)/Tween.80.(50:50:80:2).exhibit.excellent.stability.at.pH.7.4.and.
undergo.rapid.destabilization.upon.acidiication,.as.shown.by.calcein.release.and.particle.
size.increase.
79
.Higher.Tween.80.content.improves.stability.but.reduces.liposomal.pH.sen-
sitivity..The.degree.of.pH.sensitivity.could.be.conveniently.tuned.by.altering.the.amount.
of. OAlc. in. the. formulation,. since. higher. OAlc. content. exhibits. greater. content. release. in.
response.to.low.pH..The.unsaturated.fatty.alcohol.OAlc.is.capable.of.forming.a.hydrogen.
bond.through.its.hydroxyl.to.an.oxygen.atom.on.the.phosphate.group.on.the.phosphaty-
dilcholine.(PC).molecule,.resulting.in.the.formation.of.a.complex.with.geometry.similar.to.
that.of.DOPE.(Figure 20.3)..This.could.result.in.a.lowering.of.the.energy.barrier.for.the.Lα.→.
H
II
.transition..The.observed.pH-dependent.leakage.among.these.liposomes.entrapping.cal-
cein.might.primarily.be.due.to.membrane.destabilization,.without.inducing.bilayer.fusion.
