Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and in vivo siRNA delivery

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• 作者：Daoshu Lin ; Qian Jiang ; Qiang Cheng ; Yuanyu Huang ; Pingsheng Huang ; Shangcong Han ; Shutao Guo ; Zicai Liang ; Anjie Dong
• 关键词：Reduction-sensitive ; Disulfide ; Polycation-detachable ; Nanoparticles ; siRNA delivery
• 刊名：Acta Biomaterialia
• 出版年：2013
• 出版时间：August, 2013
• 年：2013
• 卷：9
• 期：8
• 页码：7746-7757
• 全文大小：2358 K

文摘

Long circulation, cell internalization, endosomal escape and small interfering RNA (siRNA) release to the cytoplasm are the prerequisite considerations for siRNA delivery vectors. Herein, a kind of sheddable nanoparticles (NPs) with micelle architecture for siRNA delivery were fabricated by using an intracellular-activated polycation-detachable copolymer (PECssD), which was prepared by introducing highly reducing environment-responsive disulfide linkages between PEGylated polycaprolactone (PCL) and the grafted polycation, poly(2-dimethylaminoethyl methacrylate) (PDMAEMA). The architecture of PECssD self-assembled NPs includes a biodegradable hydrophobic PCL core, a PEG shield and a detachable comb-like polycation surface. The stable nanosized complexes of PECssD NPs with siRNA, termed PECssD/siRNA micelleplexes, were formed, which could prolong circulation, improve accumulation and retention in tumor tissue, and be favorable for internalization. In particular, the cleavage of the disulfide linkages in the intracellular microenvironment and the subsequent dissociation of the PDMAEMA/siRNA polyplexes from the PEGylated PCL cores of PECssD/siRNA micelleplexes were also confirmed, which facilitated the endosomal escape and the efficient release of siRNA. As a result, the distribution of siRNA in cytoplasm was enhanced and subsequently promoted the efficiency of siRNA in gene silencing. Furthermore, systemic administration of the NPs carrying siPlk1 (polo-like kinase 1 specific siRNA) induced a tumor-suppressing effect in the HeLa-Luc xenograft murine model. Therefore, the devised strategy of the polycation-detachable copolymer PECssD NPs could address the requirements of the multistep systemic delivery process of siRNA. The hydrophobic core of the PECssD/siRNA micelleplexes is expected to entrap antitumor drugs or other therapeutic agents for combined therapies.