Biomedical Engineering Reference
In-Depth Information
charged.cellular.components.such.as.opsonins,.serum.proteins,.and.enzymes..This.leads.
to.interference.with.the.activity.of.ion.channels,.which.causes.the.cellular.toxicity.(Lonez.
et.al..2008)..Recent.studies.by.Kedmi.et.al..(2010).using.siRNA-LNPs.revealed.that.cationic.
LNPs. caused. hepatotoxicity. as. well. as. signiicant. weight. loss. in. mice. when. compared.
to. neutral. and. negatively. charged. LNPs.. Tekmira. Pharmaceuticals. recently. terminated.
a. clinical. trial. of. a. SNALP. formulation. of. siRNA. for. hypercholesterolemia. because. the.
cytokine.response.interfered.with.dose.escalation..Although.the.underlying.reasons.have.
not. been. clearly. identiied,. the. immunostimulatory. activity. of. cationic. lipid. should. be.
considered.carefully.
24.11 Conclusions and Perspectives
According. to. the. aforementioned. discussion,. siRNA-based. therapeutics. have. yet. to. be.
developed. as. an. effective. therapeutic. modality.. A. safe,. eficient. and. cell-type. speciic.
delivery. system. is. prerequisite. for. successful. clinic. applications. of. siRNAs.. Due. to. the.
overall.similarity.in.the.nucleic.acid.backbone,.the.ield.of.siRNA.formulation.development.
has. also. experienced. similar. development. and. delivery. hurdles. that. have. impacted. the.
commercial.product.development.of.other.nucleic.acid.therapeutics.such.as.plasmid.DNA.
and. AS-ODN.. LNPs. are. one. of. the. most. promising. delivery. systems. for. siRNAs.. When.
designing. cationic. LNPs,. both. the. molecular. and. meta-molecular. scale. factors. must. be.
taken. into. consideration.. The. fate. of. siRNA-LNPs. in. vivo. is. affected. by. various. factors.
such.as.particle.size,.morphology,.and.surface.chemistry..Sophisticated.structures.of.the.
particles. and. preparation. methods. also. inluence. the. in. vivo. effect. considerably.. Better.
understanding.of.the.morphology.and.mechanism.of.endosomal.escape.is.important.for.
rational.development.of.siRNA-LNPs..Other.strategies,.such.as.attaching.a.targeting.ligand.
to. the. LNPs,. could. further. enhance. the. delivery. eficiency.. The. safety. issues. associated.
with.siRNA.and.LNP.carriers.need.to.be.fully.addressed..We.believe.that.development.of.a.
rational.strategy.for.designing.siRNA-LNPs.that.is.based.on.interdisciplinary.collaboration.
is.needed.to.advance.siRNA.therapeutics.toward.eventual.clinical.success.
References
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Agrawal,. S.. and. Kandimalla,. E.. R.. (2004). Role. of. toll-like. receptors. in. antisense. and. siRNA..
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Akinc,.A.,. Zumbuehl,.A.,. Goldberg,. M.,. Leshchiner,. E.. S.,. Busini,. V.,. Hossain,. N.,. Bacallado,. S..A..
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Alexis,.F.,.Pridgen,.E.,.Molnar,.L..K.,.and.Farokhzad,.O..C..(2008).Factors.affecting.the.clearance.and.
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