酶催化合成多重刺激响应型聚酯作为索拉非尼/miR-122联合输送载体的研究

Hepatocellular Carcinoma (HCC) remains one of the primary disease that threaten human lives in the world, the traditional chemotherapy generally have a limited therapeutic efficacy. Recently, the development of the technological advances and comprehensive cognition of tumorigenesis and progression have led to the more efficient discoveries and development of new therapeutic methods for HCC treatment. With better understanding the properties of the both chemotherapy and gene therapy, using novel multifunctional carriers to combinatorially deliver chemotherapeutic drugs and genes has garnered more attention as a method for maximizing therapeutic efficiency. The key point to successfully combine drugs and genes within a single delivery platform is that the co-delivery system should have the ability to simultaneously load and deliver the therapeutic drugs and genes to the target tumor cells, however, the application and the development of such co-delivery system was limited due to the highly requirement of the materials design, the complexity of the materials synthesis, strict reaction condition and the difficulty of duplication. Therefore, on the basis of a large number of research experience on enzymatic polymer synthesis, we are aiming to develop a drug and gene co-delivery system using enzymatic synthesized polyesters. By taking advantage of the lipase-catalytic polymerization, we plan to synthesize a series of novel polyesters with controllable structures, tunable characteristics, which possesses pH, redox and/or ROS dual- or multi-responsive properties. Based on the development of these stimuli-responsive polyesters, we should be able to establish and optimize a safe and efficient co-delivery system for Sorafenib and miR-122 co-delivery, and explore the relationship between material structure and stimuli-responsive behaviors. Ultimately we can obtain an efficient co-delivery system to achieve better therapeutic effect for both in vitro and in vivo, which will provide us important theoretical and technical guidance for the development of the stimuli-responsive drug and gene co-delivery system.

肝癌目前仍是威胁人类健康最主要的疾病之一，传统的药物化疗往往治疗效果有限。近年来随着对肝癌发生和发展机制的不断研究发现分子靶向药物和相关基因联合治疗能实现更好的治疗效果，而其中关键在于将药物和基因同时高效的输送到靶细胞中并发挥作用，但由于联合输送载体对材料设计要求高、合成复杂、条件严苛且不易重复，因此大大限制了它的发展和应用。为此，本课题在申请人前期大量的酶催化合成材料工作基础上提出利用生物酶催化特有的反应活性和优点，合成一系列结构可控、性能可调、同时具有pH、氧化、还原双重或多重响应性能的新型聚酯材料，构建能够同时包载索拉菲尼和miR-122的多重刺激响应型纳米输送体系用于肝癌治疗，并深入探索载体环境刺激响应行为和材料结构组分之间的关系，获得载体材料结构与输送效率之间的规律性理解，最终实现更高效的多靶点药物联合治疗，为推动刺激响应型载体与联合输送体系的发展提供理论依据和技术指导。

传统化疗的癌症治疗效果有限且具有较大的毒副作用。智能响应型纳米载体可将药物递送至病灶部位，并根据刺激进行动态反应实现靶向递送和肿瘤部位“定点、按需”药物释放，相比传统化疗具有精准和高效等优势，成为了肿瘤治疗领域的研究热点和前沿。功能性聚酯材料具有生物可降解、化学性质可调节等优点，作为纳米药物载体具有极大的发展前景。我们利用酶催化合成方法引入单个或多个响应性组分，可使聚酯材料具备单重或多重刺激响应能力，通过调整单体比例，可调节聚酯材料的响应程度，制备出结构与分子量可控的刺激响应型聚酯材料。我们通过一步法合成具有pH和还原双重响应的PEG-PPMD/PEG-PCMD和PEG-PMT智能输药载体系统，并取得了较好的体内外治疗肿瘤治疗效果；利用酶催化法合成了具有pH和ROS双重响应的PEG-PPMT材料用于肿瘤微环境响应型药物递送，并实现了较好的肿瘤生长抑制效果；为了改进对治疗区域的响应性，利用MMP-2敏感的底物肽连接疏水链段PPMT和亲水链段PEG，合成PEG-M-PPMT两亲性聚合物，同时负载疏水分子靶向药物索拉非尼和光敏剂二氢卟吩e6，实现化疗-光动力联合肿瘤治疗，大幅度提高肿瘤抑制效果；为了解决激光深度的问题，利用酶催化法合成了具有pH，ROS和GSH三重响应的PEG-PPMDT材料用于肿瘤微环境响应型药物递送，为肿瘤化疗/声动力学治疗提供一种有前景的综合治疗策略；除此还开展了索拉非尼和miR-122基因共载的工作，并获得了较好的协同抑制肿瘤生长的效果。综上，我们设计了多重刺激响应型纳米输送体系用于肿瘤治疗，并深入探索载体环境刺激响应行为和材料结构组分之间的关系，获得载体材料结构与输送效率之间的规律性理解，最终实现更高效的多靶点药物联合治疗，为推动刺激响应型载体与联合输送体系的发展提供理论依据和技术指导。