Biomedical Engineering Reference
In-Depth Information
hydrocarbon.chain.length.(C
14
.>.C
20
).and.the.degree.of.saturation.(unsaturated.>.saturated)..
For.example,.inclusion.of.10.mol%.PEG-CerC
14
.in.SNALP.results.in.approximately.10-fold.
higher. gene. expression. compared. with. the. PEG-CerC
20
-containing. formulation. (Cullis.
2002)..Alternatively,.an.acid.cleavable.linker.between.PEG.and.lipid.can.be.used.to.address.
this.problem.(Romberg.et.al..2008).
24.9.3 Active Targeting in Delivery of sirNA
Receptor-mediated. delivery. can. provide. added. speciicity. (Qian. et. al.. 2002,. Yu. et. al..
2009).. Targeting. ligands. may. consist. of. folate,. transferrin,. antibodies,. peptides,. or.
polysaccharides.(Yu.et.al..2010)..For.example,.cyclin.D1.targeted.siRNAs.were.systemically.
delivered. selectively. to. activated. leukocytes. by. LNPs. conjugated. to. antibodies. to. β7.
integrin.(Peer.et.al..2008)..These.nanoparticles.were.used.to.selectively.deliver.cyclin.D1.
siRNA.to.β7-positive.leukocytes.both.in.vitro.and.in.vivo..With.siRNA-mediated.silencing.
of. cyclin. D1. expression,. leukocyte. proliferation. was. suppressed. in. a. mouse. model.
of. colitis,. which. validated. CyD1. as. a. potential. anti-inlammatory. target.. Transferrin-
associated.LNPs.have.been.used.extensively.for.siRNA.delivery.as.well..Using.a.single-
chain.anti-Tf.antibody.fragment.as.the.targeting.ligand,.Chang.et.al..(Xu.et.al..2001,.2002,.
Yu.et.al..2004,.Hu-Lieskovan.et.al..2005,.Pirollo.et.al..2006,.2007).developed.a.nano-sized.
immunoliposome-based.delivery.complex.(scL).to.deliver.nucleic.acids,.including.plasmid.
DNA,.antisense.ODN,.and.siRNA,.to.both.primary.and.metastatic.diseases..To.enhance.the.
eficiency.of.this.complex,.a.pH-sensitive.histidine-lysine.peptide.(scL-HoKC).was.added..
In. the. delivery. of. anti-HER-2. siRNA. by. scL-HoKC,. human. tumor. cells. were. sensitized.
toward. chemo-therapeutics. and. the. target. gene. was. effectively. silenced,. signiicantly.
inhibiting.tumor.growth.in.a.pancreatic.cancer.model.(Pirollo.et.al..2006,.2007).
24.10 Safety and Efficacy of siRNA-LNPs in the Clinic
In.terms.of.eficacy,.there.are.many.successful.examples.of.the.in.vivo.delivery.of.siRNA.
using. LNPs. in. mice. and. nonhuman. primates.. In. addition,. there. have. been. a. few. early.
stage.clinical.trials.on.siRNA.therapeutics..Davis.et.al..developed.a.polymer-based.delivery.
system,.which.consists.of.a.cyclodextrin-containing.cationic.polymer.(CDP),.a.polyethylene.
glycol.(PEG).steric.stabilization.agent,.and.human.transferrin.(Tf).(Hu-Lieskovan.et.al..2005,.
Heidel.et.al..2007a,b,.Davis.2009)..They.employed.their.Tf-CDP.nanoparticles.for.delivery.
of.siRNA.targeting.RRM2,.which.is.a.M2.subunit.of.ribonucleotide.reductase.(Heidel.et.al..
2007a,b)..Compared.to.the.nontargeted.nanoparticles,.the.Tf-CDP.nanoparticles.containing.
RRM2. siRNA. showed. signiicant. antitumor. effect. for. the. treatment. of. solid. tumors..
Subsequently,.this.delivery.system.formed.the.basis.of.the.irst.clinical.trial.on.systemic.
targeted.delivery.of.siRNA..The.siRNA-mediated.mRNA.cleavage.was.observed.from.a.
patient.who.received.the.highest.dose.of.nanoparticles..These.data.conirmed.that.siRNA.
administered.systemically.to.a.human.could.produce.speciic.gene.inhibition.by.a.RNAi.
mechanism.of.action.(Davis.2009).
Several.companies.currently.have.Phase.I.programs.to.study.the.safety.and.tolerability.
of.systemic.delivery.of.siRNA..Alnylam.is.studying.the.delivery.of.two.siRNAs,.KSP.and.
VEGF.(ALN-VSP-.02),.using.the.SNALP.formulation.for.therapy.of.hepatocellular.carcinoma.
(HCC)..In.addition,.Tekmira.has.used.the.SNALP.delivery.technology.in.a.Phase.I.study.to.
