Redox-Sensitive PEG鈥揚olypeptide Nanoporous Particles for Survivin Silencing in Prostate Cancer Cells

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• 作者：Francesca Cavalieri ; Giovanni L. Beretta ; Jiwei Cui ; Julia A. Braunger ; Yan Yan ; Joseph J. Richardson ; Stella Tinelli ; Marco Folini ; Nadia Zaffaroni ; Frank Caruso
• 刊名：Biomacromolecules
• 出版年：2015
• 出版时间：July 13, 2015
• 年：2015
• 卷：16
• 期：7
• 页码：2168-2178
• 全文大小：574K
• ISSN：1526-4602

文摘

We report the engineering of intracellular redox-responsive nanoporous poly(ethylene glycol)鈥損oly(l-lysine) particles (NPEG鈥揚LLs). The obtained particles exhibit no toxicity while maintaining the capability to deliver a small interfering RNA sequence (siRNA) targeting the anti-apoptotic factor, survivin, in prostate cancer cells. The redox-mediated cleavage of the disulfide bonds stabilizing the NPEG鈥揚LL鈥搒iRNA complex results in the release of bioactive siRNA into the cytosol of prostate cancer PC-3 cells, which, in turn, leads to the effective silencing (鈭?9 卤 8%) of the target gene. These findings, obtained under optimal conditions, indicate that NPEG鈥揚LLs may protect the therapeutic nucleic acid in the extracellular and intracellular environments, thus preventing the occurrence of competitive interactions with serum and cytosolic proteins as well as degradation by RNase. The intracellular trafficking and final fate of the NPEG鈥揚LLs were investigated by a combination of deconvolution microscopy, fluorescence lifetime imaging microscopy, and super-resolution structured illumination microscopy. A significant impairment of cell survival was observed in cells concomitantly exposed to paclitaxel and siRNA-loaded NPEG鈥揚LLs. Overall, our findings indicate that NPEG鈥揚LLs represent a highly loaded depot for the delivery of therapeutic nucleic acids to cancer cells.