Biomedical Engineering Reference
In-Depth Information
Love.et.al..2010)..Based.on.a.high-throughput.screening.approach,.they.developed.a.very.
potent.molecule,.lipidoid.C12-200,.for.liver.targeted.delivery.of.siRNA.in.vivo.(Love.et.al..
2010)..Using.this.novel.lipidoid,.in.vivo.ED
50
.of.0.03.mg/kg.was.achieved.in.nonhuman.pri-
mates..In.addition,.it.was.found.that.in.vitro.and.in.vivo.delivery.eficiencies.could.not.be.
directly.correlated..According.to.these.studies,.at.least.two.design.features.were.generally.
deemed.favorable:.one.or.more.tertiary.amines.containing.head.groups.and.polyunsatu-
rated.lipid.chains.consisting.of.16-18.carbon.tails.
24.9 In Vivo Application of siRNA
The. feasibility. of. selective. and. eficient. delivery. of. siRNA. therapeutics. using. LNPs. has.
been.demonstrated.in.numerous.studies..There.are.two.major.mechanisms.behind.tissue.
selective.delivery.in.vivo:.passive.targeting.and.active.targeting.
24.9.1 Passive versus Active Targeting
In. contrast. to. normal. tissues,. many. solid. tumors. possess. certain. structural. features.
including. hyperpermeable. vasculature. and. impaired. lymphatic. drainage. (Matsumura.
and.Maeda.1986,.Hobbs.et.al..1998)..Passive.targeting.refers.to.the.selective.extravasation.
and.retention.of.long-circulating.nanoparticles.at.tumor.sites.due.to.the.EPR.effect..In.con-
trast,.active.targeting.is.based.on.speciic.interactions.with.receptors.on.target.cells,.which.
often.mediate.endocytosis..In.general,.LNPs.with.a.particle.size.between.10.and.200.nm.are.
favorable.for.tumor.delivery..Zeta.potential.is.another.important.parameter..Both.highly.
positive.and.highly.negative.charged.LNPs.are.susceptible.to.rapid.clearance.by.the.RES..
Thus,.it.is.important.to.design.LNPs.with.either.neutral.or.slight.anionic.charge..Passive.
targeting.only.facilitates.the.eficient.localization.of.LNPs.in.the.tumor.interstitium..It.can-
not.further.promote.their.intratumoral.distribution.and.uptake.by.cancerous.cells..For.this.
reason,.receptor-based.active.targeting.strategies.are.being.investigated.for.nanoparticles.
24.9.2 Pegylation of LNPs
A.common.method.for.reducing.the.recognition.of.nanoparticles.by.the.RES.is.to.coat.their.
surfaces. with. polyethylene. glycol. (PEG). (Caliceti. and. Veronese. 2003,. Alexis. et. al.. 2008)..
Due.to.the.steric.effect.of.the.hydrophilic.PEG,.the.binding.of.LNPs.to.opsonins,.which.
promote. RES. clearance,. is. signiicantly. reduced,. resulting. in. prolonged. circulation. time.
and.increased.accumulation.at.the.tumor.sites.via.EPR.effect..However,.once.the.siRNA-
LNPs.localize.in.the.pathological.site,.LNPs.are.expected.to.disassemble.and.release.their.
genomic. payload. in. an. eficient. manner.. The. PEG. coating. can. reduce. the. interactions.
between.the.LNPs.and.the.cells.and.hinder.siRNA.release.from.the.endosome..According.
to.the.ion.pair.formation.mechanism.for.endosomal.release,.H
II
.phase.formation.requires.
close.contact.between.the.head.groups.of.the.lipids.of.the.LNP.and.those.of.the.endosomal.
membrane.. PEGylation. of. LNPs. may. signiicantly. reduce. the. interactions. between. the.
cationic.lipids.and.the.endosomal.lipids.due.to.steric.hindrance.(Tseng.et.al..2009)..Hence,.
de-PEGylation.of.the.LNPs.is.very.important.for.high.transfection.activity..This.presents.a.
dilemma,.which.can.be.addressed.by.a.reversible.PEGylation.strategy..It.has.been.found.that.
PEG-lipid.conjugates.with.longer.PEG.chain(s).and/or.shorter.hydrocarbon.chains.tend.to.
diffuse.away.from.the.lipid.bilayer.at.a.faster.rate..The.diffusion.rate.is.dependent.on.the.
