Biomedical Engineering Reference
In-Depth Information
FIGURE 4.2
Contact.facilitated.drug.delivery.is.the.concept.wherein.drug.is.sequestered.as.part.of.the.outer.membrane.of.a.
nanoparticle,.unable.to.escape.until.binding.to.the.targeted.cell.occurs..Owing.to.the.close.proximity.and.rela-
tively.long.duration.afforded.by.binding,.the.phospholipid.monolayer.of.the.nanoparticle.and.the.phospholipid.
bilayer.of.the.cell.can.interact,.exchanging.phospholipids.and.dissolved.molecules,.such.as.drugs..Once.the.drugs.
exchange.into.the.outer.layer.of.the.cell.bilayer,.they.disperse.and.can.be.“lipped”.into.the.inner.surface.through.
normal.ATP-dependent.pathways..(Reprinted.with.permission.from.Lanza,.G.M.
,
et.al.,.
Curr Pharm Biotechnol
,
5,.
495-507,.2004.)
MRI-visible.α
ν
β
3
-targeted.particles.have.been.demonstrated.effective.in.both.atheroscle-
rosis
74
. and. cancer
43,48
. models.. Moulton. et. al.. have. shown. that. the. water-soluble. form.
of.fumagillin.(TNP-470),.when.administered.systemically,.has.an.antiangiogenic.effect.
that. reduces. the. overall. plaque. growth. in. atherosclerosis.
76
. A. model. of. early. athero-
sclerosis,.hypercholesterol.rabbits.were.given.angiogenesis-targeted.nanoparticles.either.
containing.(treatment.group).or.not.containing.(control.group).fumagillin.
74
.MRI.signal.
enhancement. averaged. over. the. entire. abdominal. aorta. was. identical. for. both. groups,.
indicating.both.presence.of.disease.and.delivery.of.theragnostic.nanoparticles..After.1.
week,. the. antiangiogenic. effect. was. assessed. using. diagnostic. α
ν
β
3
-targeted. nanopar-
ticles. (and. corroborated. with. histology),. conirming. that. the. disease. was. dramatically.
reduced.in.those.receiving.targeted.fumagillin.nanoparticles,.whereas.the.control.group.
remained. the. same. as. before. (Figure 4.4).. A. different. control. group,. which. received.
fumagillin-containing.nanoparticles.that.were.not.targeted,.also.showed.no.therapeutic.
response..While.this.study.validated.the.concept.that.targeting.is.required.for.therapeu-
tic. response,. it. further. elucidated. two. other. important. points.. One. point. was. that. the.
MRI.signal.level.at.the.time.of.initial.dosing.not.only.conirmed.the.delivery.of.drug,.but.
also. predicted. the. response. to. therapy.. Second,. the. therapeutic. effect. achieved. in. this.
study.was.similar.to.that.by.Moulton.et.al.,.but.the.total.drug.amount.used.was.more.
than. 10,000. times. less.. So. not. only. are. potentially. harmful. side. effects. reduced. by. the.
sequestration.of.the.drug.in.the.nanoparticles,.but.the.concentrating.effect.of.targeting.
can.administer.high.concentrations.of.drug.at.the.intended.site.even.though.very.small.
total.amounts.of.drug.are.used.
These.same.concepts.were.repeated.in.the.Vx-2
48
.and.MDA-MB-435
43
.cancer.models,.the.
Vx-2.being.the.larger,.more.aggressive.tumor.model..In.the.Vx-2.model,.a.single.dose.of.
30 µg/kg.of.fumagillin.(1,000.times.less.than.typical.systemic.dosing).was.administered.
intravenously. via. α
ν
β
3
-targeted. MRI. nanoparticles.. After. 16. days,. MRI. was. performed.
using.the.diagnostic-only.particles.to.quantify.tumor.size.and.assess.neovascularity..For.
those. receiving. targeted. therapy,. tumor. volume. was. reduced. signiicantly. compared. to.
controls. receiving. no. drug. (Figure 4.5).. Histology. also. conirmed. the. response. to. ther-
apy,.which.was.not.observed.in.the.control.tumors..Similarly,.Schmieder.et.al.
43
.delivered.
