Manipulation of Leukocytes Using Therapeutic RNAi Delivered by Targeted and Stabilized Nanoparticles - Nanotechnology for the Delivery of Therapeutic Nucleic Acids - page 188

b

to induce approximately 80% of the target gene expression in

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integrin-positive mononuclear leukocytes. In contrast, no silencing
effect was observed in mononuclear leukocytes from

b

integrin-
knockout mice that received the same treatment, demonstrating the
robust and high targeting specificity of gene silencing

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in vivo using

b

this approach. In addition, the same anti- I-tsNP platform was

used to validate cyclin D1 as an anti-inflammatory target. Cyclin D1
regulates both entry into and progression throughout the cell cycle,
and was determined to be upregulated in T-lymphocytes at sites of
inflammation, such as in inflamed gut inflammatory bowel disease
cells. When

7

b

I-tsNP-entrapped cyclin D1 siRNA was intravenously
injected into mice with dextran sulphate sodium-induced colitis,
cyclin D1 mRNA levels were reduced and led to a notable reduction
in intestinal inflammation and tissue destruction. Moreover, in
humanized mice, anti-LFA-1-tsNPs carrying siRNAs against the
chemokine receptor CCR5 protected mice from HIV infection.
Remarkably, the systemic administration of I-tsNP-encapsulated
siRNA did not induce interferon responses or lymphocyte activation
[24]. The minimal off-target effects and toxicities, in addition to the
low doses of siRNA necessary and the high payload capacity, make the
delivery of siRNAs via I-tsNPs an economically feasible approach.

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8.10 Conclusion

RNAi-based therapy appears to be a promising “magic bullet” for
a wide range of diseases, particularly for malignancies. The
development of cancer involves alterations in the expression of
various genes that are essential for the disease progression. The
ability of siRNAs to knockdown the expression of these essential
targets might provide a substitute for the highly toxic chemother-
apeutic cocktail regimens that are often used to treat cancer. Such
RNAi-based therapies are likely to be available in the future, as a
result of the significant efforts being made to overcome the challenge
of delivering siRNAs to their target tissues . Moreover, all

siRNAs possess similar physical and chemical properties; therefore,
one effective delivery system can be used as a platform for the
delivery of different siRNAs, and by changing the surface antibodies
or targeting molecules attached, delivery to different tissues and
cells can be achieved. These features are essential for the treatment

in vivo