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首页> 外文期刊>Acta biomaterialia >Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and in vivo siRNA delivery.
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Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and in vivo siRNA delivery.

机译：从mPEG-PCL-g-SS-PDMAEMA自组装的可聚阳离子分离的纳米颗粒，用于体内和体外siRNA递送。

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摘要

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.
机译：长循环，细胞内在化，内体逃逸和小干扰RNA（siRNA）释放到细胞质是siRNA传递载体的先决条件。本文中，通过使用细胞内活化的聚阳离子可分离共聚物（PECssD）制备了一种具有可胶束结构的siRNA传递的可脱落纳米颗粒（NPs），该聚合物是通过在PEG化聚己内酯（PCL）之间引入高度还原性的环境响应性二硫键而制备和接枝的聚阳离子，聚（甲基丙烯酸2-二甲基氨基乙酯）（PDMAEMA）。 PECssD自组装NP的体系结构包括可生物降解的疏水PCL核，PEG防护层和可分离的梳状聚阳离子表面。形成了PECssD NPs与siRNA的稳定纳米复合物，称为PECssD / siRNA胶束复合物，可以延长循环，改善肿瘤组织中的积累和保留，并有利于内在化。特别是，还证实了细胞内微环境中二硫键的裂解以及随后的PDMAEMA / siRNA复合物从PECssD / siRNA胶束复合物的PEG化PCL核中解离，这促进了内体逃逸和siRNA的有效释放。结果，增强了siRNA在细胞质中的分布，并随后提高了siRNA在基因沉默中的效率。此外，携带siPlk1（polo样激酶1特异性siRNA）的NP的系统性给药在HeLa-Luc异种移植鼠模型中诱导了肿瘤抑制作用。因此，聚阳离子可分离共聚物PECssD NPs的设计策略可以解决siRNA多步系统递送过程的要求。 PECssD / siRNA胶束复合物的疏水核心有望捕获抗肿瘤药物或其他用于联合疗法的治疗剂。

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