Biomedical Engineering Reference
In-Depth Information
in vivo
half-lives when compared to unconjugated siRNAs [3]. This
delivery strategy has been used to deliver siRNAs to treat diabetic
nephropathy in a mouse model of type I diabetes [5]. While this
study showed good efficacy of siRNA knockdown, it still required a
large dose to be delivered to achieve this result.
In addition to cholesterol, siRNAs conjugated to aptamers
such as prostate-specific membrane antigen (PSMA, an antigen
overexpressed in prostate cancer cells and tumour vascular
endothelium) have also been successful in
studies targeting
prostate tumour cells in a mouse xenograft model [6]. These synthetic
aptamers are small, synthetically prepared, highly structured nucleic
acid molecules that bind to specific targets. Thus they can facilitate
cellular internalization of linked siRNAs by binding to a specific
cellular receptor. A key advantage of the aptamer-based system over
the cholesterol protein-based system is that the reagents can be
produced in a simple
in vivo
transcription reaction that is free of
contaminating bacterial or cell products [7].
in vitro
9.2.2 
Peptide-Based Delivery Particles
Peptide-based delivery particles have been used extensively to target
siRNAs to specific cell and tissue types. One promising group of
cationic peptides is the cell-penetrating peptides (CPPs) that enhance
the uptake of a wide range of macromolecules [8, 9]. For example,
the rabies virus glycoprotein (RVG), which binds the acetylcholine
receptor expressed by neuronal cells, was fused to nine arginines
(9R) to allow siRNA binding via ionic interaction [10]. The systemic
administration of anti-viral siRNA bound to the chimeric RVG-9R
peptide resulted in protection against fatal Japanese encephalitis
virus (JEV) infection. Various other CPPs such as HIV-1 TAT and MPG
proteins [8, 9], penetratin [11], and polyarginine [12] have been
used for the delivery of both protein and nucleic acids into cells.
Another promising peptide delivery modality has been developed
by utilising the natural cationic protein, protamine, which binds and
condenses negatively charged nucleic acids [13]. Systemic delivery
and knockdown has been achieved by wrapping a protamine-
condensed siRNA core within cationic lipid membranes that facilitate
cellular uptake [14]. Through using these lipid-protamine-siRNA
(LPD) nanoparticles, Li and colleagues showed a 70-80% reduction
in lung metastatis after two to three doses of LPD particles containing
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