Biomedical Engineering Reference
In-Depth Information
that.the.presence.of.Peg.increases.plasma.AUC
0-∞
.above.that.of.nonpegylated.liposomes.
118
.
However,. in. spite. of. the. addition. of. VP. to. maintain. the. polymer's. solubility. in. water,.
the.pH.sensitivity.decreases. between.45.and.90%. in.the.presence. of.3-6.mol%. Peg..The.
decreased.pH.sensitivity.could.be.a.consequence.of.the.impaired.aggregation.and.dehy-
dration.of.membrane.surfaces.caused.by.Peg..Moreover,.Peg.may.also.prevent.interchain.
aggregation.of.the.poly(NIPA)copolymer,.reducing.the.extent.of.polymer.collapse.within.
the.liposomal.membrane.
The.terminal.alkylation.of.poly(NIPA-co-MAA).employing.dioctadecylamine.(DODA).
(Figure 20.3).allows.its.anchorage.to.the.lipid.bilayer,.proportioning.an.optimal.mobil-
ity.to.its.polymeric.chain,
115
.but.neither.enhances.the.liposome.circulation.time.in.rats.
117
.
However,.the.pH.sensitivity.of.poly(NIPA-co-MAA-co-DODA).pegylated.liposomes.can.
be. preserved. in. the. presence. of. human. plasma.
123
. The. combination. of. both. the. ter-
minally. alkylated. NIPA. copolymer. and. a. pegylated. lipid. in. the. vesicle. structure. was.
found.to.provide.liposomes.with.both.strong.pH-responsive.properties.and.a.long.half-
life.
123,124
Since. the. nonbiodegradability. of. the. polymer. may. be. a. serious. limitation. to. its. wide-
spread.use.in.the.biomedical.ield,.the.molecular.cutoff.for.renal.iltration.of.poly(NIPA-co-
MAA-co-DODA).was.recently.estimated.at.32,000,
124
.a.value.comparable.to.that.of.different.
polymers.like.Peg.(Mw.=.30,000)
125
.and.poly(2-hydroxypropyl)methacrylamide.(PHPMA;.
Mw.=.40,000-45,000).
126
.It.was.observed.that.NIPA.polymers.with.LCST.below.physiologi-
cal.temperature.are.highly.captured.by.the.organs.of.RES,.and.the.presence.of.terminal.
alkyl.moieties.at.the.polymer.chain.induces.the.formation.of.micelles.
127
.In.the.context.of.
designing.a.clinically.viable.pH-responsive.liposome,.high.Mw.NIPA.copolymers.(Mw.=.
30,000-50,000).with.a.long.circulation.time.and.low.apparent.volume.of.distribution,.but.
poorly. excreted. in. the. urine. and. feces,. should. be. avoided. to. minimize. the. risk. of. accu-
mulation.following.multiple.dosing..Unlike.randomly.alkylated.poly(NIPA-co-MAA).that.
rapidly.detaches.from.pegylated.liposomes.in.circulation,.it.is.suficient.to.use.a.terminally.
alkylated.poly(NIPA-co-MAA).with.a.Mw.of.10,000.to.produce.a.drastic.change.in.lipo-
somal.pharmacokinetics.parameters,.indicating.that.the.polymer.remains.anchored.in.the.
phospholipid.bilayer.in.the.bloodstream.
124
Recently,.pH-sensitive.immunoliposomes.(eggPC/Chol/PE-Peg/PE-Peg-mAb).(3:2:0.17:0.09).
containing.0.1-0.3.w/w.poly(NIPA-
co
-MAA-co-DODA).have.been.employed.to.deliver.ara-C.
to.HL60.leukemic.cells.
128
.Ara-C.is.used.alone.or.in.association.with.anthracycline.agents.in.
the.treatment.of.acute.myeloid.leukemia.(AML)..The.incorporation.of.ara-C.into.pegylated.
pH-insensitive.liposomes.has.been.found.to.substantially.increase.its.therapeutic.effect.on.
L1210/C2. leukemia.
80
. However,. when. incorporated. into. pH-insensitive. liposomes,. ara-C.
is. delivered. within. lysosomal. organelles,. where. it. degrades. into. its. inactive. form.
41,129,130
.
The. murine. anti-CD33. p67.6. monoclonal. antibody. (mAb). as. targeting. ligand. binds. the.
CD33.receptor.with.great.avidity.and.is.currently.used.in.the.clinic.to.treat.AML..These.
poly(NIPA-co-MAA-co-DODA).immunoliposomes.exhibited.the.highest.cytotoxicity.selec-
tively.against.HL60.cells..However,.they.were.less.eficient.than.DOPE-based.liposomes.in.
augmenting.the.intracellular.bioavailability.of.ara-C,.probably.because.the.copolymers.are.
devoid.of.membrane.fusion.activity.
114
The.poly(NIPA-co-MAA-co-DODA).liposomes.can.be.pegylated.without.losing.pH.sen-
sitivity,. and. this. is. undoubtedly. an. advantage. over. DOPE-based. liposomes.
123
. However,.
studies.with.the.Langmuir.balance.technique.on.lipid.monolayers.show.that.poly(NIPA-
co-MAA-co-DODA). does. not. seem. strongly. anchored. in. the. lipid. membrane. at. neutral.
pH,.as.it.can.be.expelled.from.the.phospholipid.monolayer.at.surface.pressures.above.30.
mN/m.
115
.Even.if.these.results.are.cannot.be.extrapolated.to.in.vivo,.the.relatively.weak.
