Biomedical Engineering Reference
In-Depth Information
DNA
Nucleus
AS-ODN or siRNA
Cytoplasm
mRNA
MicroRNA
Regulation
Cell
Protein
Figure 24.1
(See companion CD for color igure.)
.Schematic.of.nucleic.acid-based.therapy..For.gene.therapy,.large.plasmid.
DNA.is.only.effective.when.delivered.into.the.nucleus..Meanwhile,.oligonucleotides.such.as.antisense. ODN.
and.siRNA.can.function.in.the.cytoplasm.
molecule. drugs,. siRNAs. targeting. disease-causing. genes. are. easy. to. design,. based.
on. available. bioinformatic. data.. Consequently,. siRNA. has. generated. a. great. deal. of.
enthusiasm. as. an. emerging. therapeutic. strategy. (Novina. and. Sharp. 2004,. Aboul-Fadl.
2005,.Dykxhoorn.and.Lieberman.2006,.Haussecker.2008)..It.offers.signiicant.advantages.
over.plasmid-based.gene.therapy..As.depicted.in.Figure.24.1,.siRNA.molecules.function.
in.the.cytoplasm.and.therefore.do.not.require.translocation.to.the.nucleus.for.biological.
function..The.molecular.weight.of.a.double-stranded.siRNA.molecule.is.∼13.kDa,.whereas.
the.molecular.weight.of.a.plasmid.DNA.is.often.several.hundred.times.greater..Thus,.the.
biological.barriers.for.siRNAs.delivery.are.substantially.lower.
Due. to. the. physicochemical. characteristics. of. siRNA,. i.e.,. high. molecular. weight,.
polyanionic.charge,.and.hydrophilicity,.it.is.dificult.for.siRNA.to.get.across.the.plasma.
membrane. of. a. cell.. There. is. a. broad. consensus. that. the. greatest. challenge. to. clinical.
translation. of. siRNA. therapeutics. is. the. lack. of. an. eficient. and. safe. delivery. system..
Nanocarriers. (10-400.nm). are. desirable. as. drug. carriers. because. they. are. capable. of.
carrying.a.large.amount.of.drugs,.have.prolonged.circulation.time,.and.can.selectively.
accumulate. in. tumors. via. the. enhanced. permeability. and. retention. (EPR). effect. (Jain.
1999,. Allen. and. Cullis. 2004,. Alexis. et. al.. 2008,. Soussan. et. al.. 2009).. Several. classes. of.
nanocarriers. have. been. developed. for. siRNA. delivery,. including. lipid. nanoparticles,.
polymeric.nanoparticles.(e.g.,.dendrimers.and.biodegradable.polymeric.nanoparticles),.
and.micelles.(Kim.and.Rossi.2007).
Lipid.nanoparticles.(LNPs).can.be.produced.easily.and.clinical.trials.have.already.shown.
the.potential.safety.and.effectiveness.of.this.class.of.carriers.in.humans..To.achieve.even.
