HMOX1靶向聚前药高分子胶束递送siRNA协同治疗耐药性脑胶质瘤

脑胶质瘤是中枢神经系统中最常见的恶性肿瘤。目前批准的唯一化疗药物替莫唑胺（TMZ）治疗中易产生肿瘤耐药性，临床上预后不佳。本项目拟针对血红素加氧酶1（HMOX1）在耐药性脑胶质瘤的高表达，开发一种特异性聚前药胶束高效共递送TMZ/siRNA，靶向协同治疗耐药性脑胶质瘤。该靶向递送系统通过聚前药和三重作用力（静电、氢键、疏水）稳定siRNA纳米粒子策略的联合使用，增加纳米药物的体内稳定性，提高TMZ/siRNA共递送效率。同时，利用瑞加德松短暂开启血脑屏障（BBB）及HMOX1靶向肽的导向作用，增加纳米药物在耐药性脑胶质瘤中的富集。当纳米药物进入靶细胞后，胞内谷胱甘肽酶将触发聚前药胶束解离，有效释放出TMZ和siRNA，并通过RNA干扰有效逆转脑胶质瘤的耐药性，提高TMZ的药物敏感性，最终实现对耐药性脑胶质瘤的精准靶向协同治疗。

Glioma poses as the most frequent malignant tumor in central nervous systems. Unfortunately, temozolomide (TMZ), the only clinical-approved chemotherapy drug, could easily induce drug-resistance in glioma, leading to unsatisfying therapeutic result. In this project, we constructed a heme oxygenas‐1 (HMOX1) specific polyprodrug polymeric micelle, to co-deliver TMZ and siRNA for synergistic therapy of glioma, by leveraging the overexpression of HMOX1 in the TMZ-resistant glioma. This targeted delivery system combines the polyprodrug and “triple-interactions” (i.e. electrostatic, hydrogen bond and hydrophobic) stabilization strategies to enhance the TMZ/siRNA codelivery efficiency, result from the improved in vivo stability of formulated nanomedicine. Moreover, the BBB transient opening mediated by lexiscan and the targeting ability of HMOX1 specific peptide, could enhance the administrated nanomedicine achieving potent tumor accumulation. When taken up by targeted cells, the glutathione in the cytoplasm would trigger the decomposition of polyprodrug micelle, leading to the release of siRNA and TMZ. Subsequently, the effect of RNA interference will be able to reverses the drug-resistance of glioma, improve the sensitivity of TMZ, and consequently accomplish the precise targeted synergistic therapy for glioma.