化疗药物和siRNA“离子对复合物”及其非阳离子型高分子纳米载体研究

As a new biotechnology drugs, the clinical application of small interfering RNA (siRNA) is limited by the delivery systems. Among the current siRNA delivery systems, the cationic materials were the main component, including cationic liposome, water-soluble cationic polymers, and positively charged polymeric nanoparticles. These delivery systems were capable of absorbing siRNA via electrostatic interactions, and further loaded drugs to achieve co-delivery of both drug and siRNA for cancer therapy. However, the preparation process was complicated, and the potential toxicity of positively charged material restricts clinical application of siRNA. Recently, we found that the cationic chemotherapy drugs DOX and anionic siRNA was capable of form hydrophobic complex DOX&siRNA by “hydrophobic ion pair” method. The obtained hydrophobic complex DOX&siRNA could be encapsulated into the clinically approved non-positively charged PEG-PLA nanoparticles, and efficiently down-regulated the gene expression and synergistically kill tumor cells. In this project, we will expand the species of chemotherapy drugs, which could form hydrophobic complex drug with siRNA. Furthermore, we will develop the non-positively charged polymeric nanocarriers to efficiently encapsulate and deliver the hydrophobic complex drug. Meanwhile, we will investigate the circulation, tissue distribution, cell internalization, and intracellular release of the hydrophobic complexes drug loaded polymeric nanocarriers. Moreover, the synergistic tumor suppression effect following the intravenous administration of polymeric nanoparticles will be examined. This project can provide novel and effective strategy for co-delivery of chemotherapy drugs and siRNA.

小干扰RNA（siRNA）作为一种新型生物技术药物，其应用瓶颈在于体内递送载体。现有递送载体主要利用阳离子型材料吸附带负电的siRNA，并可进一步负载化疗药物，实现了化疗药物和siRNA的共输送；但这类体系制备过程较难控制，且正电荷材料容易带来的潜在毒性。本项目前期研究发现，带正电荷的化疗药物阿霉素（DOX）与siRNA通过“疏水性离子对”方法，形成疏水性复合药物，并可物理包埋于两亲性高分子纳米载体，实现两种药物共输送。本项目拟在此基础上，一方面研究能与siRNA形成“疏水性离子对”的化疗药物或其衍生物，获得不同结构的疏水性“离子对复合物”；另一方面发展有效负载这些“离子对复合物”的非阳离子型高分子载体，实现两种药物共输送。项目将系统研究包载疏水性“离子对复合物”的非阳离子型高分子纳米体系的体内生物学过程，研究其抗肿瘤药效，为发展共输送化疗药物和siRNA药物的高分子纳米载体提供新策略。

本项目拟系统研究siRNA与盐酸盐型化疗药物的相关作用以及其形成疏水性“离子对复合物”的机理；并通过非阳离子型高分子纳米体系实现其体内共递送。主要成果包括：（1）阐述了不同小分子化疗药物和siRNA的形成疏水复合物的机理，并通过高分子材料mPEG-PLA纳米体系对疏水复合物体内共递送，协同增效；（2）发展了基于DOX前药和siRNA的自组装纳米体系，实现化疗与免疫检查点疗法联合；（3）基于siRNA和米托蒽醌盐酸盐的相互作用，开发了siRNA辅助的亲水化疗药共递送体系，增强巨噬细胞对肿瘤细胞的吞噬，提高抗肿瘤疗效。本项研究的成果申请发明专利7项，授权2项；以通讯作者在ACS Nano、Nano Letters、Advanced Functional Materials、Biomaterials、Small等期刊发表SCI研究论文25篇。