Biomedical Engineering Reference
In-Depth Information
of. the. EPR. effect. of. the. vasculature.. Once. accumulated. at. the. target. site,. biodegradable.
polymeric. nanoparticles. can. act. as. a. local. drug. deposit. and. provide. a. source. for. a. con-
tinuous.supply.of.encapsulated.therapeutic.agent..The.advantages.of.nanoparticle-based.
drug.delivery.systems.include.sustained.and.controlled.drug.release,.improved.bioavail-
ability,. reduced. systemic. side. effects,. and. high. capability. to. cross. various. physiological.
barriers.
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.Nevertheless,.the.low.selectivity.of.NPs.toward.cancer.cells.hinders.the.advan-
tages.of.the.nanoparticle.formulation.for.eficient.chemotherapy,.as.the.therapeutic.agents.
also. possess. high. toxicity. to. healthy. cells.. Therefore,. it. is. necessary. to. develop. effective.
therapies.with.a.speciic.effect.on.cancer.cells.
Effective.drug.targeting.can.be.realized.by.the.functionalization.of.nanoparticles.with.small.
molecule.ligands.such.as.folate.and.thiamine,.peptides.such.as.arginine-glycine-aspartic.acid.
(RGD),. sugar. residues. such. as. galactose,. antibodies. and. antibody. fragments. such. as. anti-
HER2,.nucleic.acid.aptamers.such.as.anti-PSMA.aptamer,.and.proteins.such.as.transferrin.
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.
Among.various.ligands,.trastuzumb,.the.monoclonal.antibody.directed.against.HER2,.is.of.
great.interest.because.it.has.synergistic.therapeutic.effects.with.chemotherapy,.in.addition.to.
its.targeting.ability.
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Synergistic.antitumor.effects.were.found.when.trastuzumab.was.administered.in.com-
bination.with.chemotherapeutic.agents.such.as.paclitaxel,.docetaxel,.and.doxorubicin.
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.
Two.different.targeting.approaches.have.been.reported.by.Nobs.et.al..for.immunotargeting.
with.trastuzumab.conjugated.to.nanoparticles.
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.One.is.a.direct.method.using.trastuzumab-
labeled.NPs,.and.the.other.is.a.pretargeting.method.using.the.avidin-biotin.technology..
Speciic. trastuzumab-labeled. NPs. binding. to. tumor. cells. produced. a. mean. 10-fold. or.
higher. signal. increase. over. the. control.. The. two-step. method. was. evaluated. in. vitro. by.
incubating.SKOV-3.cells.irst.with.biotinylated.mAbs,.followed.by.NPs..The.relative.luo-
rescence. associated. with. the. speciic. binding. of. NPs. produced. a. sixfold. increase. in. the.
low.cytometry.signal,.compared.to.nonspeciic.binding,.which.suggested.that.trastuzum-
ab-functionalized.NPs.might.be.a.useful.drug.carrier.for.tumor.targeting.
Steinhauser. et. al.. reported. a. time-dependent. cell. uptake. study,. in. which. a. signiicant.
enrichment. of. trastuzumab-modiied. nanoparticles. in. 64.23%. of. HER2. positive. SK-BR-3.
cells.was.achieved,.compared.to.3.59%.of.the.nude.NPs.with.30.min.incubation..However,.
after. 24 h. incubation. the. nonspeciic. uptake. of. PEGylated. nanoparticles. without. trastu-
zumab.increased.dramatically.(39.62%).compared.to.trastuzumab-modiied.nanoparticles.
(51.22%).
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. Research. on. doxorubicin-loaded,. trastuzumab-modiied. human. serum. albu-
min. nanoparticles. was. reported. by. Anhorn. et. al.,. which. was. the. irst. demonstration. of.
doxorubicin-loaded.nanoparticles.with.a.speciic.trastuzumab-based.targeting.of.HER2-
overexpressing. breast. cancer. cells.
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. It. was. also. reported. that. there. was. speciic. target-
ing. with. trastuzumab-functionalized. doxorubicin-loaded. nanoparticles. with. a. cellular.
binding. of. 73.80%,. whereas. doxorubicin-loaded. nanoparticles. without. trastuzumab. had.
a.marginal.cellular.binding.of.5.57%..With.such.a.targeting.system,.with.trastuzumab.as.
the.targeting.ligand.binding.the.HER2.receptor,.higher.drug.levels.in.tumor.tissue.were.
achieved..Lee.et.al..employed.cationic.P(MDS-co-CES).micelles.to.delivery.paclitaxel.and.
Herceptin.simultaneously,.which.is.convenient.for.adjusting.the.dosage.of.paclitaxel.and.
Herceptin.by.simply.altering.the.initial.loading.
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.Their.results.showed.that.the.cytotoxic-
ity.of.paclitaxel.was.increased.with.codelivery.of.Herceptin,.and.the.degree.of.increment.
in. cytotoxicity. depends. on. the. level. of. HER2. expression.. All. these. results. indicate. that.
trastuzumab-functionalized.nanoparticles.can.signiicantly.promote.targeted.delivery.of.
the.drug.to.the.corresponding.cancer.cells,.and.therefore.greatly.enhance.its.therapeutic.
effects.and.reduce.its.side.effects.
