载基因纳米胶束治疗雄性激素非依赖性前列腺癌的机理

miRAN can effectively inhibit the growth of androgen-independent prostate cancer (AIPC), however, its therapeutical application in vivo need urgently the effective delivery of carrier. For this,on the basis of Natural Science Foundation of China (Young Foundation), we design and synthesize PEI-PBA and PEI-Aco-C225 polymer based on the PEI polymer, and construct PEI-PBA-miR-146a/PEI-Aco-C225 micelle with these properties of targeting to UD145 AIPC, endosome escape, cytoplasm responsive release, and etc, and using miR-146a as therapy gene. Subsequently, we research these properties of PEI-PBA-miR-146a/PEI-Aco-C225 micelle for loading or releasing miR-146a, and research the influence and mechanism of PEI-PBA-miR-146a/PEI-Aco-C225 micelle for cell cloning, cell migration and invasion, endosome escape, cytoplasm responsive release, and etc. We then further investigate the targeting distribution property of PEI-PBA-miR-146a/PEI-Aco-C225 micelle in DU145 AIPC-bearing mice, the therapy efficiency and mechamism for UD145 AIPC and its toxicity in vivo are also explored. This study contribute to solve the bottleneck problem for curing AIPC.

miRNA被证实可有效抑制雄性激素非依赖性前列腺癌细胞生长，但其体内治疗需载体的有效递送才能实现；为此本研究在前期国家自然科学基金（青年基金）的基础上，基于PEI设计合成聚乙烯亚胺-苯基硼酸（PEI-PBA）和聚乙烯亚胺-乌头酸酐-Cetuximab（PEI-Aco-C225）聚合物载体，并以有效抑制DU145雄性激素非依赖性前列腺癌细胞生长的miR-146a为治疗基因，构建具有能靶向雄性激素非依赖性前列腺癌、内涵体逃逸和细胞质响应性释放特性的PEI-PBA-miR-146a/PEI-Aco-C225纳米胶束；研究纳米胶束荷载及释放miR-146a特性；研究纳米胶束的细胞克隆形成、迁移和侵袭、内涵体逃逸、细胞质响应性释放等特性及机理；研究纳米胶束在荷UD145前列腺癌裸鼠体内靶向分布、对前列腺癌治疗效率及机理和纳米胶束毒性。本研究有助于解决治疗雄性激素非依赖性前列腺癌无效的瓶颈问题。

本项目基于PEI设计合成聚乙烯亚胺-苯基硼酸（PEI-PBA）和聚乙烯亚胺-乌头酸酐-Cetuximab（PEI-Aco-C225）聚合物载体，并以有效抑制DU145雄性激素非依赖性前列腺癌细胞生长的miR-146a为治疗基因，通过层层组装构建具有能靶向雄性激素非依赖性前列腺癌纳米胶束（PEI-PBA-miR-146a/PEI-Aco-C225）。该纳米胶束可有效避免miRNA的降解，从而被前列腺癌细胞有效摄取，并通过细胞内的Ph值响应来逃逸内涵体，通过肿瘤细胞内的ATP响应释放miRNA，从而有效抑制前列腺癌细胞的增值、迁移和侵袭。动物实验也证实该纳米胶束能有效抑制前列腺癌的增长，且动物体内主要器官无明显毒性损伤，证实了PEI-PBA-miR-146a/PEI-Aco-C225纳米胶束用于雄性激素非依赖性前列腺癌治疗的有效性。