Biomedical Engineering Reference
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dramatically reduced because of their relatively large size compared
to PTD-DRBD-delivered siRNA. This is supported by the numerous
studies where systemically administered nanoparticle-mediated
siRNA is targeted to the liver (Meade and Dowdy, 2009, Whitehead
et al.,
2009). Therefore, it has been important to focus on developing
an alternative strategy to deliver siRNA as a single molecule that
would benefit both its potency and pharmacokinetic properties,
when delivered into tissue culture cells or mouse models
in vivo
.
4.4
Conclusions
In this chapter, we have described an alternative delivery approach
that circumvents general nanoparticle strategies. Although many
challenges in siRNA delivery can be overcome by nanoparticle
encapsulation, the most obvious disadvantage compared to the
PTD-DRBD delivery vehicle is the size. Lipid nanoparticles are
about 100 mDa in size compared to the small PTD-DRBD that
is only 16 kDa. Furthermore, DRBDs bind siRNA specifically,
sequence independently, and mask the negative charges of the
siRNA, leaving the positively charged PTD domain free to bind the
plasma membrane and induce internalization. Once inside the
cytoplasm, the siRNA is able to induce a rapid and long-lasting
RNAi response in a non-cytotoxic fashion both
.
In summary, the ability to induce synthetic RNAi with PTD-DRBD-
delivered siRNA in mouse models holds great promise for future
RNAi therapeutic development.
in vitro
and
in vivo
Acknowledgments
C. P.-A. was funded by a Knut & Alice Wallenberg's Foundation and the
Sweden-America Foundation Fellowship. This work was supported
by the Leukemia and Lymphoma Society, the Pardee Foundation,
California Institute of Regenerative Medicine, and Howard Hughes
Medical Institute.
References
1. Alexis, F., Pridgen, E., Molnar, L. K., and Farokhzad, O. C. (2008). Factors
affecting the clearance and biodistribution of polymeric nanoparticles,
Mol
.
Pharm
.
5
, pp. 505-515.
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