Biomedical Engineering Reference
In-Depth Information
20.6 LiposomesBearingpH-SensitivePolymers
20.6.1 Liposomes Bearing NIPA Polymers
Water-soluble. nonbiodegradable. amphiphiles. N-isopropyl. acrylamide. polymers.
(poly(NIPA)).experience.a.irst-order.volume.phase.transition.in.response.to.a.change.of.
temperature.
101,102
.Poly(NIPA).presents.a.typical.lower.critical.solution.temperature.(LCST).
or.cloud.point,.a.temperature.under.which.the.polymer.is.hydrated.and.extended.as.a.
random. coil,. where. polymer-aqueous. solvent. interactions. are. predominant.. Above. the.
LCST,.polymer-polymer.hydrophobic.interactions.predominate,.the.hydrogen.bonds.are.
disrupted,.and.water.is.expelled.from.the.polymer.coils,.which.start.to.collapse.to.a.globu-
lar.form.due.to.increased.interactions.between.hydrophobic.moieties..This.process.results.
in.aggregation,.formation.of.compact.globules,.and.precipitation.
103
.In.aqueous.solution.
the.LCST.of.poly(NIPA).is.approximately.32°C.and.is.independent.of.its.molecular.weight.
and. concentration.
104,105
LCST. can. be. shifted. by. modifying. the. polymer. hydrophilic-
hydrophobic. balance.. Copolymerization. with. hydrophobic. comonomers. decreases. the.
LCST,.whereas.hydrophilic.comonomers.have.the.opposite.effect.
106-108
.Copolymerization.
with. methacrylic. acid. (MAA). (Figure 20.3). increases. the. LCST. of. the. copolymer. above.
that.of.poly(NIPA).as.the.number.of.acidic.units.is.increased,.at.all.pHs..This.is.because.
both.the.acid.and.ionic.states.of.the.MAA.units.are.more.hydrophilic.than.NIPA.units..
The.degree.of.ionization.of.MAA.(and.therefore.the.hydrophilic-hydrophobic.balance.of.
the.copolymer).changes.with.the.pH:.the.COOH.form.that.predominates.at.acid.pH.is.less.
hydrophilic. than. the. COO-. form,. which. predominates. at. neutral. pH.. Hence,. the. LCST.
of.the.copolymer.is.also.changed.with.the.pH.
109-111
.As.the.pH.decreases,.the.degree.of.
protonation.(hydrophobicity).of.the.copolymer.increases;.the.transition.peak.is.narrowed.
and. the. cooperativity. of. the. transition. increases.. As. an. example,. poly(NIPA-co-MAA)'s.
(≥20.4.mol%).LCST.decreases.from.53.7°C.at.pH.7.4.to.39.2°C.at.pH.4.0.
Above. the. LCST. and. mixed. with. liposomes,. poly(NIPA-co-MAA). destabilizes. the.
bilayer.
112
.The.collapse.of.the.polymer.in.acid.media.introduces.a.curvature.in.the.bilayer.
plane,. which. induces. membrane. defects
113-116
. and. triggers. the. release. of. the. entrapped.
molecules.
113,117
.The.poly(NIPA-co-MAA).effect.on.lipid.bilayers.would.not.be.at.the.molec-
ular. level,. but. would. instead. perturb. the. liposome. at. the. supramolecular. level.
118
. When.
liposomes.bearing.poly(NIPA-co-MAA).are.captured.by.cells.by.clathrin-dependent.endo-
cytosis,.the.collapse.is.triggered.by.the.low.pH.inside.the.endosomes,.and.the.entrapped.
molecules.inside.acidic.organelles.are.released.
113,119
Poly(NIPA-co-MAA). can. be. anchored. to. the. liposomal. bilayer. by. terminal. or. random.
alkylation. with. hydrophobic. anchors,
120
. with. a. binding. eficiency. that. is. proportional.
to. the. number. of. hydrophobic. anchors.
121
. However,. randomly. alkylated. poly(NIPA-co-
MAA).(5.mol%;.Mw.=.29,000).containing.2-4.mol%.octadecylacrylate.(ODA)
120
.is.desorbed.
from.the.lipid.bilayer.upon.interaction.with.plasma,.leading.to.a.partial.loss.(15-25%).of.
pH. responsiveness.
117-119
. In. addition,. randomly. alkylated. poly(NIPA-co-MAA). slightly.
increases.the.circulation.time.of.liposomes..The.absence.of.steric.stabilization.is.due.to.its.
partial.dehydration.at.neutral.pH,.the.random.coil.conformation.being.incomplete.
68,119,122
.
However,. the. addition. of. Peg. to. liposomes. bearing. randomly. alkylated. poly(NIPA-co-
MAA).makes.the.liposomes.long.circulating.but.diminishes.their.pH.sensitivity.
114,118,123
The.i.v..administration.to.male.Sprague-Dawley.rats.of.liposomes.made.of.eggPC/Chol.
(3:2).with.3.and.6.mol%.Peg-PE.(180-230.nm).containing.0.3.w/w.poly(NIPA-co-MAA-co-
N-vinyl-2-pyrrolidone.(VP)-co-ODA).copolymer.(90:4:2:4.molar.ratio;.Mw.=.22,600).shows.
