Biomedical Engineering Reference
In-Depth Information
that.tell.cancer.cells.to.grow.and.divide.uncontrollably,.the.approaches.can.help.to.stop.the.
growth. and. division. of. cancer. cells.. This. new. type. of. approach. has. been. termed. targeted.
therapy,.the.goal.of.which.is.to.provide.molecular.level-based.agents.that.are.more.speciic.for.
cancer.cells.
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.Targeted.therapies.are.also.often.useful.in.combination.with.cytotoxic.chemo-
therapy.or.radiotherapy.to.produce.additive.or.synergistic.anticancer.activity.because.their.
toxicity.proiles.often.do.not.overlap.with.traditional.cytotoxic.chemotherapy..Thus,.targeted.
therapies. represent. a. new. and. promising. approach. to. cancer. therapy. leading. to. beneicial.
clinical.effects..There.are.multiple.types.of.targeted.therapies.available,.including.monoclonal.
antibodies,.tyrosine.kinase.inhibitors,.and.antisense.inhibitors.of.growth.factor.receptors.
8.2.3.1 Passive Targeting
Targeted. delivery. can. be. achieved. in. two. manners:. passive. and. active.. Passive. targeting.
makes.use.of.the.tumor.microenvironment,.which.is.characterized.by.a.leaky.tumor.vascu-
lature.and.a.dysfunctional.lymphatic.drainage.system..Most.polymeric.nanoparticles.dis-
play.the.EPR.effect,.which.is.a.consequence.of.the.increased.vasculature.permeability.and.
decreased.lymphatic.function.of.tumors..It.occurs.when.nanoparticles.extravasate.out.of.the.
tumor.microvasculature,.leading.to.an.accumulation.of.drugs.in.the.tumor.interstitium.
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.
Thus,.passive.targeting.is.achieved.by.incorporating.the.therapeutic.agent.into.a.macromol-
ecule.or.nanoparticle.that.passively.reaches.the.target.organ.through.the.EPR.effect.
Passive. targeting. also. involves. the. use. of. other. innate. characteristics. of. the. nanopar-
ticles.that.can.induce.targeting.to.the.tumor,.such.as.surface.charge..For.example,.cationic.
liposomes. have. been. found. to. exhibit. a. tendency. to. bind. through. electrostatic. interac-
tions.to.negatively.charged.phospholipid.head.groups.preferentially.expressed.on.tumor.
endothelial.cells.
28,29
.Catheters.can.be.alternatively.used.to.infuse.nanoparticles.to.the.tar-
get.organ.or.tissues..For.example,.localized.delivery.of.drug-loaded.nanoparticles.to.sites.
of.vascular.restenosis.may.be.helpful.for.providing.sustained.drug.release.at.speciic.sites.
on.the.arterial.wall.
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For.passive.targeting.to.be.successful,.the.nanoparticles.with.chemotherapeutic.agents.
encapsulated.have.to.circulate.in.the.blood.for.an.extended.time.so.that.there.will.be.mul-
tiple.possibilities.for.the.nanoparticles.to.pass.by.the.target.sites..Nanoparticles.normally.
have.short-circulation.half-lives.due.to.natural.defense.mechanisms.of.the.body.to.elimi-
nate.them.after.opsonization.by.the.mononuclear.phagocytic.system.(MPS).
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.Therefore,.
the.particle.surfaces.need.to.be.modiied.to.be.invisible.to.opsonization..A.number.of.stud-
ies.applied.various.surface.modiication.approaches.to.classical.nanocarriers.to.increase.
their.circulation.half-lives. for.effective.passive.targeting.or.sustained.drug.effect..These.
approaches. include. incorporation. of. linear. dextrans,. sialic. acid-containing. gangliosides,.
and.lipid.derivatives.of.hydrophilic.polymers.such.as.polyethylene.glycol.(PEG),.to.pro-
vide.steric.stabilization.around.the.liposomes.for.protection.from.the.MPS.uptake.
32,33
.For.
example,.PEG,.a.hydrophilic.polymer,.is.commonly.used.to.lengthen.the.circulation.time..
This.is.because.PEG.has.desirable.attributes,.such.as.a.low.degree.of.immunogenicity.and.
antigenicity,.chemical.inertness.of.the.polymer.backbone,.and.availability.of.the.terminal.
primary.hydroxyl.groups.for.derivatization.
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Passive.targeting.results.in.high.drug.concentrations.in.tumors.and.reduced.drug.tox-
icities. to. the. normal. tissues.. However,. the. biggest. limitation. of. passive. targeting. lies. in.
its. inability. to. deliver. a. suficiently. high. level. of. drug. concentration. to. the. tumor. site.
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.
Because.this.technology.lacks.tumor.speciicity.and.has.less.ability.to.control.the.release.
of.the.entrapped.agents,.the.focus.has.gradually.shifted.from.passive.to.active.targeting.
nanoparticles.
