增强组织渗透和细胞内吞的靶向抗肿瘤高分子纳米药物的研究

Five main bottlenecks, including in vivo circulation, enrichment in tumor tissue, penetration into tumor tissue, tumor cell uptake and drug release in tumor cell, hamper the clinical application of polymeric nanomedicines. Presently, most of the polymeric nanomedicines focus on only part of problems, and the integrated programs for overcoming all the limitations are rare. Based on the biological characteristics of tumor tissue and cell, the project will prepare a series of polymeric nanomedicines with various targeting strategies through the electrostatic or hydrophobic interactions among block copolymers, tumor cell inhibitor loaded nanogels and tumor vascular inhibitor. These will be used to comprehensively solve the critical issues of drug delivery in vivo with polymeric nanocarriers. The polymeric nanomedicines exhibit the capabilities of tumor tissue (vascular) or cell targeting, progressive "on-demand" release of tumor vascular and cell inhibitors, and release of the drug loaded nanogels with enhanced tumor tissue penetration and endocytosis, and intracellular reductive drug release. The successful implementation of the project will broaden the ideas and approaches for the exploitation of novel antitumor nanomedicines, and lay the experimental and theoretical bases for the acquisition of ideal smart nanomedicines with independent intellectual property rights.

体内循环、肿瘤组织富集、肿瘤组织渗透、肿瘤细胞摄取和肿瘤细胞内药物释放是高分子纳米药物临床应用的5个主要瓶颈。目前，大部分高分子纳米药物往往顾此失彼，综合克服药物传输屏障的方案匮乏。本项目以肿瘤组织和细胞的生物学特性为基础，拟通过嵌段共聚物、负载肿瘤细胞抑制剂的纳米凝胶与肿瘤血管抑制剂之间的静电或疏水相互作用，制备一系列具有不同靶向策略的高分子纳米药物，用于综合解决高分子纳米载体在生物体内传输抗肿瘤药物的关键问题。该高分子纳米药物具有肿瘤组织（血管）或肿瘤细胞靶向，可以实现肿瘤血管抑制剂和肿瘤细胞抑制剂的逐级"按需"释放，且在肿瘤组织"释放"出的载药纳米凝胶具有增强组织渗透和细胞内吞以及细胞内还原响应性释放的能力。本项目的成功实施将拓宽研发新型抗肿瘤纳米药物的思路和方法，并为获得具有自主知识产权的理想的智能纳米药物奠定实验和理论基础。

目前，临床上广泛使用的大部分抗肿瘤药物为小分子化合物，存在水溶性差、选择性不足、生物利用度低、对正常组织毒副作用大且治疗效果差等问题。为了解决上述问题，本项目以肿瘤组织和细胞的特殊微环境为基础设计并制备了一系列pH响应性、还原响应性、pH与还原双响应性的智能高分子纳米药物载体，以增强药物在肿瘤组织的渗透、提高肿瘤细胞摄取并实现细胞内高选择性药物释放。经过系统的体外和体内实验证实本项目所开发的智能高分子纳米载体可显著降低小分子药物的毒副作用，并提高治疗效果。本项目已完成了预定的研究目标。在本项目的资助下，我们在国际知名学术期刊上发表研究论文49篇、撰写邀请综述9篇、撰写专著章节2篇、申请中国发明专利20项，其中授权5项。