PAMAM Dendrimers Mediate siRNA Delivery to Target Hsp27 and Produce Potent Antiproliferative Effects on Prostate Cancer Cells
PAMAM Dendrimers Mediate siRNA Delivery to Target Hsp27 and Produce Potent Antiproliferative Effects on Prostate Cancer Cells
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DOI：
10.1002/cmdc.200900076
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发表时间：
2009-08-01
期刊：
影响因子：
3.4
通讯作者：
Peng, Ling
中科院分区：
文献类型：
--
作者：
Liu, Xiao-xuan;Rocchi, Palma;Peng, Ling
RNA干扰（RNAi）在治疗遗传性和获得性疾病方面具有很大的前景，前提是安全有效的递送系统可用。本文中，我们报告了结构灵活的三乙醇胺（TEA）核心PAMAM树枝状聚合物能够通过与siRNA形成稳定的纳米颗粒，保护siRNA纳米颗粒免受酶促降解，并增强siRNA的细胞摄取，有效地将Hsp 27 siRNA递送到前列腺癌（PC-3）细胞中。Hsp 27 siRNA导致热休克蛋白27的有效和特异性基因沉默，热休克蛋白27是去势抵抗性前列腺癌中有吸引力的治疗靶点。hsp 27基因的沉默导致诱导caspase-3/7依赖的凋亡和抑制PC-3细胞在体外的生长。此外，siRNA-树枝状聚合物复合物在用于siRNA递送的条件下是非细胞毒性的。总之，TEA核心PAMAM树枝状聚合物介导的siRNA递送）6与特异性靶向Hsp 27的RNAi组合，可能构成对抗去势抵抗性前列腺癌的有希望的方法，对于去势抵抗性前列腺癌没有有效的治疗。
RNA interference (RNAi) holds great promise for the treatment of inherited and acquired diseases, provided that safe and efficient delivery systems are available. Herein we report that structurally flexible triethanolamine (TEA) core PAMAM dendrimers are able to deliver an Hsp27 siRNA effectively into prostate cancer (PC-3) cells by forming stable nanoparticles with siRNA, protecting the siRNA nanoparticles from enzymatic degradation, and enhancing cellular uptake of siRNA. The Hsp27 siRNA resulted in potent and specific gene silencing of heat-shock protein 27, an attractive therapeutic target in castrate-resistant prostate cancer. Silencing of the hsp27 gene led to induction of caspase-3/7-dependent apoptosis and inhibition of PC-3 cell growth in vitro. In addition, the siRNA-dendrimer complexes are non-cytotoxic under the conditions used for siRNA delivery. Altogether, TEA core PAMAM dendrimer-mediated siRNA deliver)6 in combination with RNAi that specifically targets Hsp27, may constitute a promising approach for combating castrate-resistant prostate cancer, for which there is no efficacious treatment.