Biomedical Engineering Reference
In-Depth Information
24
Lipid-Base
d Nanoparticles for siRNA Delivery
Bo Yu, L. James Lee, and Robert J. Lee
CONTENTS
24.1. Introduction....................................................................................................................... 535
24.2. Mechanism.of.RNAi......................................................................................................... 537
24.3. Barriers.to.Delivery.of.siRNA.In.Vivo........................................................................... 537
24.4. Lipid.Nanoparticles.for.siRNA.Delivery....................................................................... 538
24.5. Synthesis.of.siRNA-LNPs................................................................................................ 539
24.6. Rational.Design.of.Cationic.Lipids................................................................................. 540
24.7. Endocytosis.Pathway.for.LNPs....................................................................................... 540
24.8. Mechanism.of.Endosomal.Escape.................................................................................. 540
24.8.1. Charge-Charge.Destabilization.Model........................................................... 541
24.8.2. Ion-Pair.Formation.Model................................................................................. 541
24.8.3. Proton.Sponge.Model......................................................................................... 542
24.8.4. Structure-Function.Relationship.Study.......................................................... 542
24.8.5. Advances.in.Novel.Cationic.Lipids.................................................................. 543
24.9. In.Vivo.Application.of.siRNA.........................................................................................544
24.9.1. Passive.versus.Active.Targeting........................................................................544
24.9.2. PEGylation.of.LNPs.............................................................................................544
24.9.3. Active.Targeting.in.Delivery.of.siRNA............................................................ 545
24.10. Safety.and.Eficacy.of.siRNA-LNPs.in.the.Clinic........................................................ 545
24.10.1. siRNA.and.Vehicle-Related.Side.Effects.......................................................... 546
24.10.2. Lipid-Mediated.Side.Effect................................................................................ 546
24.11. Conclusions.and.Perspectives......................................................................................... 547
References..................................................................................................................................... 547
24.1 Introduction
Nucleic.acid-based.therapeutics.hold.great.promise.for.the.treatment.of.human.diseases.
such.as.cancer.(McCormick.2001,.Juliano.et.al..2008,.Yu.et.al..2009,.Pecot.et.al..2011)..Speciic.
strategies. include. gene. therapy,. antisense. therapy,. and. RNA. interference. (RNAi)-based.
therapy.(Rayburn.and.Zhang.2008,.Yu.et.al..2009)..Small.interfering.RNA.(siRNA),.since.its.
discovery.in.the.late.90s,.has.been.recognized.as.potentially.the.most.promising.approach.
among.these.strategies..siRNAs,.which.are.duplexes.of.19-23.nts.in.length,.can.be.custom.
designed. to. speciically. and. eficiently. silence. gene. expression. (Wagner. 1994,. Fire. et. al..
1998)..They.have.been.implemented.routinely.as.a.tool.to.study.gene.function.in.laboratory.
research. and. in. drug. development. for. target. validation.. In. contrast. to. traditional. small.
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