Journal
BIOMATERIALS
Volume 32, Issue 5, Pages 1404-1411Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2010.10.019
Keywords
Immortomouse; H-2K(b)-ts-A58; Mammary fat pad; PEGylated cationic polymers; PEGss; PPIB
Funding
- NIH (Nebraska Center for Nanomedicine) [RR021937]
- NIH [5 R21 EB005683-02, NS050660]
- DOD [BC053471]
- Nebraska Health and Human Services [2007-41]
- UNMC Eppley Cancer Center
- UNMC Predoctoral Fellowship
- Nebraska Research Initiative (NRI)
- Nebraska Center for Virology
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Polymer-siRNA complexes (siRNA polyplexes) are being actively developed to improve the therapeutic application of siRNA. A major limitation for many siRNA polyplexes, however, is insufficient mRNA suppression. Given that modifying the sense strand of siRNA with 3' cholesterol (chol-siRNA) increases the activity of free nuclease-resistant siRNA in vitro and in vivo, we hypothesized that complexation of chol-siRNA can increase mRNA suppression by siRNA polyplexes. In this study, the characteristics and siRNA activity of self assembled polyplexes formed with chol-siRNA or unmodified siRNA were compared using three types of conventional, positively charged polymers: (i) biodegradable, cross-linked nanogels (BDNG) (ii) graft copolymers (PEI-PEG), and (iii) linear block copolymers (PLL10-PEG, and PLL50-PEG). Chol-siRNA did not alter complex formation or the resistance of polyplexes to siRNA displacement by heparin but increased nuclease protection by BDNG, PLL10-PEG, and PLL50-PEG polyplexes over polyplexes with unmodified siRNA. Chol-CYPB siRNA increased suppression of native CYPB mRNA in mammary microvascular endothelial cells (MVEC) by BDNG polyplexes (35%) and PLL10-PEG polyplexes (69%) over comparable CYPB siRNA polyplexes but had no effect on PEI-PEG or PLL50-PEG polyplexes. Overall, these results indicate that complexation of chol-siRNA increases nuclease protection and mRNA suppression by select siRNA polyplexes. These results also suggest that polycationic block length is an important factor in increasing mRNA suppression by PLL-PEG chol-siRNA polyplexes in mammary MVEC. (C) 2010 Elsevier Ltd. All rights reserved.
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