Biomedical Engineering Reference
In-Depth Information
8.2.3.2 Active Targeting
In.comparison.with.passive.targeting,.exploiting.the.characteristic.features.of.tumor.biol-
ogy. that. allow. nanocarriers. to. accumulate. in. the. tumor. by. the. EPR. effect,. active. target-
ing.is.achieved.by.delivering.drug-encapsulated.nanoparticles.to.uniquely.identiied.sites.
while. having. minimal. side. effects.
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. There. are. still. several. limitations. in. passive. target-
ing. approaches,. although. they. form. the. basis. of. clinical. therapy.. Certain. tumors. do. not.
exhibit.the.EPR.effect,.and.the.permeability.of.vessels.may.not.be.the.same.through.a.single.
tumor.
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.It.is.dificult.to.control.the.passive.targeting.process.due.to.the.ineficient.diffusion.
of. some. drugs. as. well. as. the. random. nature. of. the. approach.. Thus,. multiple-drug. resis-
tance.(MDR).might.occur,.which.is.a.situation.where.chemotherapy.treatments.fail.patients.
owing.to.the. resistance.of.cancer.cells.to.one.or. multiple.different.drugs..MDR. happens.
when. transporter. proteins. that. expel. drugs. from. cells. are. overexpressed. on. the. surface.
of.cancer.cells..This.drug.resistance,.at.its.worst.when.the.toxic.side.effects.are.still.in.full.
force,.will.kill.healthy.cells.in.the.body.but.has.no.harmful.effects.on.the.cancer.cells.
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Active. targeting. attempts. to. take. advantage. of. overexpressed. tumor-associated. anti-
gens.or.receptors.to.selectively.target.the.drug.to.the.tumor..In.general,.active.targeting.is.
achieved.through.the.administration.of.nanoparticles.with.cell-speciic.ligands.conjugated.
on.their.surface..These.ligands.can.recognize.and.then.bind.to.speciic.receptors.that.are.
uniquely.expressed.on.cancer.cells..In.the.case.of.local.drug.delivery,.the.cytotoxic.drug.
encapsulated.in.the.nanoparticles.can.be.delivered.directly.to.cancer.cells.while.minimiz-
ing.harmful.toxicity.to.healthy.cells.adjacent.to.the.target.tissue.
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8.3 Antibody-ConjugatedNanoparticlesforTargeting
8.3.1 Functionalization of Nanoparticles for Targeting
As. described. above,. tyrosine. kinase. inhibitors,. monoclonal. antibodies,. and. antisense.
inhibitors.of.growth.factor.receptors.can.function.as.a.cell-speciic.homing.device.
8.3.1.1 Tyrosine Kinase Inhibitors
Protein.tyrosine.kinases.(PTKs).are.enzymes.that.catalyze.the.phosphorylation.of.tyrosine.
residues.and.are.especially.important.targets,.as.they.play.an.important.role.in.the.modu-
lation. of. growth. factor. signaling. and. oncogenic. transformation. of. cells.
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. There. are. two.
main.classes.of.PTKs:.receptor.PTKs.and.nonreceptor.PTKs..Receptor.tyrosine.kinases.are.
multidomain.proteins..Several.approaches.to.target.PTKs.have.been.developed,.and.classi-
ication.of.such.inhibitors.is.based.on.the.mode.of.action..It.has.been.found.that.activation.
of.protein.phosphorylation-related.pathways.in.tumors.can.occur.through.overexpression.
of.this.protein,.compared.to.normal.cells.
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.Therefore,.the.targeted.therapeutics.ascribed.
to.therapeutic.agents.are.as.close.to.being.monospeciic.as.possible.to.avoid.the.harmful.
side.effects.that.sometimes.arise.with.traditional.cancer.therapies..For.this.reason,.small.
molecule. inhibitors. of. protein. kinases. have. emerged. as. essential. for. studying. targeted.
therapy,.and.these.drugs.are.also.called.signal.transduction.inhibitors.
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Among.the.tyrosine.kinases,.the.epidermal.growth.factor.receptor.(EGFR).family.is.the.
most.widely.investigated..EGFR.is.the.cell.surface.receptor.for.members.of.the.EGFR.fam-
ily.of.extracellular.protein.ligands..EGFR.is.a.member.of.the.ErbB.family.of.receptors,.a.
