Biomedical Engineering Reference
In-Depth Information
resulted.in.20.and.0%.survival,.respectively..The.pH-sensitive.liposomes.were.signiicantly.
more.effective.than.pH-insensitive.liposomes.and.free.Nys.in.eliminating.the.fungi.from.
the.liver.and.brain.at.day.9.postinfection,.as.well.as.in.eliminating.the.residual.fungi.in.
surviving.animals.(insigniicant.number.of.colony-forming.units.in.liver.vs..50-350.and.
25-160.in.pH-insensitive.liposomes.and.free.Nys,.respectively)..Since.the.phagocytic.activ-
ity. is. maintained. upon. infection,. probably. the. released. acid-solubilized. Nys. diffuses. to.
the.fungi.across.the.leaky.membrane.of.phagolysosomes.
20.8.3 Skin Papilloma
In.2007,.the.same.group.in.India.studied.the.potential.of.diallyl.sulide.(DAS),.a.water-insol-
uble.active.component.of.garlic,.topically.applied.as.DAS.pH-sensitive.liposomes.against.
skin.cancer.in.a.murine.model.of.dimethyl.benzanthracene.(DMBA)-induced.skin.papil-
loma..Swiss.albino.mice.were.exposed.to.DMBA.dissolved.in.acetone.and.applied.topically.
three.times.a.week.for.12.weeks.
161
.The.tumor.suppressor.gene.p53.can.induce.cell.cycle.
arrest,. DNA. repair. processes,. and. apoptosis;. in. 80%. of. human. malignnant. tumors. this.
gene.is.mutated.(p53mut)..Exposure.to.DMBA.induces.downregulation.of.p53wt.protein.
and.upregulation.of.p53mut.protein..One.hour.after.DMBA.exposure,.pH-sensitive.lipo-
somes.containing.DAS.(250.µg).were.applied.on.the.shaven.dorsal.skin..DAS.pH-sensitive.
(DOPE/CHEMS,.6:4).liposomes.and.DAS.pH-insensitive.(eggPC/Chol,.49:21).liposomes.are.
more.eficacious.in.delaying.the.induction.of.tumors.(for.more.than.1.week).and.in.reduc-
ing. the. total. number. of. tumors. (3.92,. 5.84,. 10.6,. and. 20. for. pH-sensitive,. pH-insensitive,.
free. DAS,. and. nontreated. animals,. respectively).. The. mean. tumor. volume. was. signii-
cantly. lower. for. pH-sensitive. than. pH-insensitive. liposomes,. free. DAS,. and. nontreated.
animals.(62,.169,.309,.and.1,041.mm
3
,.respectively)..The.survival.(animals.completely.free.
of.tumor.incidences.upon.treatment).of.treated.animals.was.34.and.23%.for.pH-sensitive.
and.pH-insensitive.liposomes,.respectively..Inhibition.of.tumor.growthe.(calculated.from.
the.average.size.of.the.tumor.induced).was.signiicantly.higher.for.pH-sensitive.liposomes.
(94%). than. for. pH-insensitive. (84%). and. free. DAS. (70%).. Treatment. with. the. liposomal.
formulations.ensured.an.upregulation.of.p53wt.(147,.94,.and.23%.for.pH-sensitive.and.pH-
insensitive.liposomes.and.free.DAS,.respectively),.while.levels.of.p53mut.expression.were.
reduced.(normal.levels.and.64%.and.40%.reduction.for.pH-sensitive,.pH-insensitive,.and.
free.DAS,.respectively).
162
.The.tumors'.induction.by.DMBA/acetone.generates.ulcerations.
and.wounding..The.observed.chemoprotectant.activity.of.DAS.is.exerted.by.modulation.
of.apoptotic.factors.at.the.cytoplasmic.level..Probably,.the.absence.of.the.stratum.corneum.
enables.the.liposomal.formulations.to.access.the.tumor.cells.in.the.deep.epidermal.layer.
for.cytoplasmic.delivery.of.DAS.
20.8.4 Immune Therapy/Vaccination
20.8.4.1 Induction of Cytotoxic T Lymphocyte (CTL) Responses
Tumor.therapy.can.be.mediated.by.CTLs.that.recognize.tumor-associated.antigens.gener-
ally.derived.from.mutants.of.self-proteins.or.of.viral.origin..It.is.generally.accepted.that.
CTL.responses.are.induced.when.antigen.is.delivered.into.the.cytosol.(Figure 20.2)..It.has.
been.reported.that.humoral.and.cellular.immunity.were.induced.simultaneously.in.Balb/c.
mice. by. the. HIV.
gag
protein. or. the. 15-mer. peptide. from. the. HIV. V3. loop. encapsulated.
in.pH-sensitive.liposomes.
163,164
.pH-sensitive.liposomes.(POPE/CHEMS/MPL.(monophos-
phoryl.lipid A),.7:3:0.01;.1,100.nm).containing.a.CTL.epitope.peptide.from.Hantaan.virus.
