Biomedical Engineering Reference
In-Depth Information
20.1 Introduction:NanomedicinesAretheKeytoIntracellularTargeting
In. order. to. increase. the. therapeutic. eficacy. of. a. drug. or. to. reduce. its. toxicity,. biodis-
tribution. and. intracellular. trafic. have. to. be. changed,. since. the. sole. modiication. of. its.
pharmacokinetics.is.insuficient..Nanomedicines.(nano-objects.loaded.with.small.drugs.
or. macromolecules). are. powerful. tools. developed. in. the. framework. of. the. application.
of. nanotechnology. to. medicine
1
. that,. functioning. as. nano-drug. delivery. systems,. are.
capable.of.modifying.the.pathway.followed.by.molecules.
2-5
.Pharmacokinetics,.biodistri-
bution,.and.intracellular.trafic.of.loaded.molecules.no.longer.depend.on.their.chemical.
structures.but.on.the.size,.shape,.and.chemical.structure.of.the.nano-object.
6
.Liposomes,.
for. instance,. are. the. best. known. example. of. nano-objects,. recently. clasiied. as. nano-
particules.(with.their.three.dimensions.in.the.nanoscale.(<200-300.nm)).
7
.Different.from.
conventional.drug.delivery.systems,.and.depending.on.the.biodegradability.of.the.nano-
object,.nanomedicines.can.cross.anatomical.and.phenomenological.barriers.
8,9
.They.can.
be.administered.by.parenteral,.transcutaneous,.or.mucosal.vias,
10
.but.changes.in.biodis-
tribution.can.only.be.achieved.upon.parenteral.administration
11-22
.(Figure 20.1)..An.exclu-
sive. feature. of. nanomedicines. is. their. uptake. by. phagocytic. or. pynocitic. mechanisms.
upon. cell. recognition.
23,24
. The. structure. of. the. nanomedicine. is. responsible. for. its. own.
recognition.by.a.given.mechanism.of.cellular.uptake.
25
.Each.uptake.mechanism.leads.to.
well-deined.intracellular.trafic.mediated.by.vesicles,.which.ends.up.in.different.cellular.
compartments
26
.(Figure 20.2).
The.control.of.biodistribution.and.kinetics.of.selective.delivery.into.cell.compartments.
is.the.key.to.generate.more.eficient.and.less.toxic.therapeutic.effects..Tissue.and.cell.tar-
geting,.as.well.as.controlled.intracellular.trafic,.depend.on.the.size.and.structure.of.the.
nano-object,.which.must.be.administered.parenterally.
27
Many. therapeutic. small. molecules. or. macromolecules,. such. as. enzymes. or. peptides,.
antisense.oligonucleotides,.or.corrective.genes,.must.be.delivered.to.the.cytosol.for.thera-
peutic.effect..However,.upon.capture.by.clathrin-mediated.endocytosis,.molecules.loaded.
into.nano-objects.must.exit.the.endolysosomal.route.before.being.degraded.in.lysosomes..
To.that.aim,.nano-objects.have.to.escape.as.a.response.to.the.growing.intravesicular.acid-
ity
28
. by. experiencing. structural. changes. leading. to. the. delivery. of. their. content. to. the.
cytoplasm.
29
.Alternatively,.nano-objects.can.respond.to.stimuli.found.in.ischemic.tissues.
or. infection. sites,. primary. or. metastasized. tumors. that. exhibit. lower. extracellular. pH.
than.normal.tissue..For.instance,.the.extracellular.pH.60.h.after.the.onset.of.inlamma-
tory.reactions.drops.from.7.4.to.6.5.
30
.The.high.level.of.proteinases,
31
.increased.glycolysis,.
and.plasma.membrane.proton.pump.activity.of.tumor.cells.lowers.the.extracellular.pH.
to.between.6.5.and.7.2.
32,33
.Hence,.nano-objects.capable.of.experiencing.site-speciic.struc-
tural.changes.triggered.by.extracellular.acidity.could.contribute.to.design.more.selective.
therapies.
Since. the. first. article. published. in. 1980,
34
. the. idea. of. tailoring. liposomes. capable.
of. experiencing. structural. changes. triggered. by. acidity. (pH. sensitivity). has. evolved.
from. simple. lipid. mixtures. to. complex. lipid. matrices. combined. with. intelligent.
polymers.. In. this. chapter. we. will. survey. the. different. strategies. developed. to.
improve. the. performance. of. pH-sensitive. liposomes. and. their. current. preclinical.
applications.
