Biomedical Engineering Reference
In-Depth Information
association. of. poly(NIPA-co-MAA-co-DODA). to. bilayers. raises. doubts. about. its. perma-
nence. on. long-circulating. liposomes.. This. fact,. together. with. the. excellent. intracellular.
pH-sensitive.response.of.the.DOPE/CHEMS.liposomes,.indicates.the.need.for.compara-
tive.in.vivo.studies.
20.6.2 Liposomes Bearing Polyphosphazenes: Speed of Release
Polyphosphazenes.(PPZs).are.biodegradable.inorganic.polymers.with.backbones.consist-
ing.of.alternating.nitrogen.and.phosphorus.atoms.linked.by.alternating.single.and.double.
bonds.(Figure 20.3).
131
Amphiphilic. temperature-. and. pH-sensitive. poly(organophosphazenes). with. varying.
ratios. of. ethylene. oxide,. alkyl. chains,. and. free. acid. units. synthesized. by. living. cationic.
polymerization. exhibit. an. LCST. that. is. dependent. on. their. composition.
132
. The. same. as.
poly(NIPA).copolymers,.the.hydrophilic.comonomers.(carboxilic.acids).increase.the.LCST.
from.32°C.to.44°C.and.make.it.pH.sensitive..Stimuli-responsive.liposomes.that.release.their.
content.upon.a.change.in.temperature.or.pH.can.be.obtained.when.alkylated.copolymers.
(for. instance,. (ethoxyethoxyethoxy)
1.72
(amino. butyric. acid)
0.18
. (C
18
(EO)
10
. = polyoxyethylen.
stearyl.ether.(Brij).76)
0.1
.polymer;.Mw.=.38,000;.9.2.mol%.acid).are.anchored.in.0.05-0.1%.
w/w.into.eggPC/Chol.(3:2).liposomes..Lowering.the.pH.to.5-6.causes.polymer.dehydra-
tion,.and.within.1.min.a.virtually.complete.release.of.entrapped.HPTS.(hydrophilic.dye.
pyranine).is.triggered..Such.a.rate.is.thought.to.be.related.to.the.high.cooperativity.of.the.
phase.transition,.which.favors.polymer.collapse..The.short.time.span.over.which.release.
occurs.is.an.important.feature.of.the.system.since,.upon.endocytosis,.the.transit.time.from.
uptake. to. degradation. in. lysosomes. is. generally. about. 30. min.
133
. However,. the. formula-
tions.still.require.optimization.to.minimize.leakage.at.pH.7.4.
20.6.3 Liposomes Bearing Polyglycidols
Polyglycidol. (PG). polymers. are. biocompatible
134
. lexible. hydrophilic. aliphatic. polyether.
polyols.that.can.be.prepared.in.branched.or.linear.forms,.and.share.structural.similari-
ties. with. Peg. (Figure 20.3).. PG. polymers. become. pH. sensitive. by. incorporating. varying.
amounts.of.carboxylic.acids.as.side.chains.to.their.backbones..The.hydrophobic-hydrophilic.
balance.of.the.carboxylated.PG.polymer.changes.as.the.pH.shifts.from.neutral.(where.the.
hydrophilic.COO
-.
form.predominates).to.low.(where.the.more.hydrophobic.COOH.form.
predominates)..Accordingly,.the.carboxylated.PG.polymer.conformation.changes.from.an.
extended.form.at.neutral.pH.to.a.collapsed.form.at.low.pH.
As. the. hydrophobicity. of. the. carboxylic. residue. increases,. polymer. collapse. and. pre-
cipitation.occur.at.higher.pH:.SucPG.(succinic.anhydride-modiied.PG).collapses.at.pH.4,.
GluPG.(glutaric.anhydride-modiied.PG).at.pH.4.7,.MGluPG.(3-methylglutaric.anhydride-
modiied.PG).at.pH.5,.and.CHexPG.(1,2-.cyclohexanedicarboxylic.anhydride-modiied.PG).
at. pH. 5.4,. which. is. consistent. with. the. number. of. carbon. atoms. of. these. polymers'. side.
chains.
135
Free.polymers.collapse.and.precipitate.at.a.pH.that.is.lower.than.the.pH.that.triggers.
liposomal. destabilization. upon. mixing. with. polymers.. For. instance,. after. being. mixed.
with. liposomes,. only. CHexPG. polymer. induces. a. marked. release. of. the. aqueous. con-
tent. at. pH. 6.5.. However,. polymers. inserted. in. the. bilayer. through. hydrophobic. anchors.
increase. the. liposomal. pH. sensitivity.. Liposomes. with. anchored. SucPG-C
10
,. GluPG-C
10
,.
and.MGluPG-C
10
.exhibit.a.similar.pH.response,.retaining.HPTS.at.pH.7.4,.with.an.almost.
complete.release.at.pH.5.5.
