Biomedical Engineering Reference
In-Depth Information
nucleocapsid.protein.(M6).were.i.m..administered.to.C57BL/6.and.boosted.after.a.week..
It.was.found.that.pH-sensitive.liposomes.more.eficiently.generate.peptide-speciic.CTL.
responses.than.the.free.peptide..One.week.after.the.immunization,.the.mice.were.chal-
lenged.with.1.×.10 5 .M6-transfected.B16.melanoma.cells..Seventy.percent.of.the.immunized.
mice.rejected.the.tumor.development,.whereas.the.mice.immunized.with.irrelevant.pep-
tide. in. pH-sensitive. liposomes. suffered. the. growing. tumors. and. died. at. day. 45.. These.
results. indicate. that. the. CTL. response. could. block. tumor. formation. in. an. antigen-
speciic.manner..On.the.other.hand,.mice.were.irst.inoculated.with.M6-transfected.mela-
noma.cells.subcutaneously,.and.3.days.later.immunized.with.pH-sensitive.liposomes.and.
boosted.after.a.week..All.the.mice.immunized.with.irrelevant.peptide.in.liposomes.died.
on.day.32.after.tumor.cell.inoculation,.and.40%.of.the.mice.immunized.with.M6.in.lipo-
somes.remained.alive.for.40.days.after.tumor.inoculation..It.was.also.observed.that.the.
pH-sensitive.liposomes.induced.Th1-type.cytokine-mediated.CTL.responses. 165
20.8.4.2  Induction of Cellular Immunity
Recently,.SucPG.and.MGluPG.liposomes.(eggPC/DOPE,.1:1,.30%.w/w.SucPG.or.MGluPG).
containing.ovalbumin.(OVA).were.employed.as.carriers.for.induction.of.cellular.immunity. 166 .
Confocal.laser.scanning.microscopy.shows.that.PG.liposomes.are.taken.up.eficiently.by.
DC2.4.cells.(a.murine.dendritic.cell.line),.thereafter.delivering.their.contents.into.the.cyto-
sol,. probably. through. fusion. with. endosomal. membranes.. Murine. bone. marrow-derived.
dendritic.cells.treated.with.OVA.PG.liposomes.stimulate.CD8-OVA1.3.cells.more.strongly.
than. OT4H.1D5. cells,. indicating. that. the. liposomes. induce. major. histocompatibility. com-
plex.(MHC).class.I-restricted.presentation.
Nasal. immunization. with. PG. liposomes. (100. mg. OVA,. female. C57BL/6. mice. on. days.
0. and. 14). results. in. stronger. cellular. immune. responses. than. the. OVA. pH-insensitive.
liposomes. (eggPC/DOPE).. Splenocytes. of. the. immunized. mice. exhibit. high. toxicity.
toward. OVA-presenting. E.G7-OVA. cells,. but. almost. no. toxicity. toward. their. parent. EL4.
cells,. indicating. that. both. liposomes. are. able. to. induce. OVA-speciic. CTLs.. Remarkably,.
the.polymer-modiied.liposomes.activate.cellular.immunity.in.the.absence.of.additional.
immunostimulating.molecules.such.as.monophosphoryl.lipid A.(MPL),.in.a.fashion.com-
parable.to.that.of.complete.Freund.adjuvant.(which.is.a.toxic.adjuvant.only.used.in.veteri-
nary)..Hence,.their.potential.use.in.the.production.of.eficient.vaccines.for.immunotherapy.
requires.further.studies.to.guarantee.safety.for.human.use.
20.8.5 Gene Therapy
Nonviral.gene.therapy.still.suffers.from.limited.eficacy.in.order.to.be.involved.in.more.
clinical.trials..The.major.problems.are.degradation.in.biological.luids.in.vitro.and.in.vivo.
by.nucleases,.the.weak.intracellular.penetration,.and.poor.cytoplasmic.delivery.of.genes.or.
antisense.oligonucleotides.(AOs)..pH-sensitive.liposomes.could.be.used.to.increase.nucleic.
acids'.stability.or.to.improve.their.cell.penetration.
The. eficacy. of. AOs. loaded. in. DOPE/CHEMS/Chol. (7:4:2,. 100-200. nm). to. suppress.
lipopolysaccharide.(LPS)-induced.production.of.tumor.necrosis.factor.(TNF)-α.in.Kupffer.
cells.of.Sprague-Dawley.rats.has.been.determined. 167 .The.in.vivo.effects.of.the.liposomal.
AO.are.time.dependent,.exhibiting.a.maximal.inhibition.of.30%.of.TNF-α.production.at.
48.h.post-i.v..injection..Two.daily.doses.result.in.a.cumulative.increase.in.tissue.levels.of.
the.AO,.which.is.also.associated.with.a.signiicant.inhibition.of.LPS-induced.TNF-α.pro-
duction,.in.both.the.liver.(50%).and.plasma.(68%)..On.the.other.hand,.no.inhibitory.effect.
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