肿瘤组织内可自渗透增强的聚合物前药纳米给药系统的设计与制备

The complex microenvironment in tumor tissue can not only improve tumor invasion, metastasis and immune evasion, but also suppress the accumulation and penetration of chemotherapeutics and nano-sized chemotherapy drugs in tumor severely and probably induce drug resistance. Therefore, an appropriate intervention of tumor microenvironment may be a new chemotherapy strategy. In this project, in order to deal with the barriers of drug delivery in tumor microenvironment such as viscous extracellular matrix and high tumor interstitial fluid pressure, we plan to synthesize a kind of novel polymeric prodrugs capable of stimuli-responsive properties to encapsulate microenvironment-regulating agents. By virtue of them, we may construct a polymeric prodrug-based drug delivery system with combination of tumor-microenvironment-induced penetration, targeted accumulation and triggered drug release. Through in vitro and in vivo assays, we further investigate the influence of tumor microenvironment modulators on the penetration and accumulation of nanodrug in tumor, study the inner relationship between the components of the co-delivery nanoparticles and the therapeutic effect. By means of these researches, we proposed to find an efficient drug delivery strategy to improve the accumulation and penetration of antitumor agents and kill tumor cells, especially those far from the vasculature.

肿瘤组织内复杂的微环境不仅能促进肿瘤的浸润、转移及免疫逃避，而且还会严重阻碍化疗药物，包括纳米化疗药物在瘤内富集、渗透，甚至诱发肿瘤细胞耐药性。因此，对肿瘤微环境进行适当干预成为提高化疗效果的一个新途径。本申请针对肿瘤组织内粘稠的细胞外基质和高肿瘤间质压等药物传输屏障，设计合成一类新型的具备刺激响应功能的高分子前药用以包覆肿瘤微环境调节剂，以此构建肿瘤微环境诱导下可渗透增强、靶向富集及触发给药一体化的聚合物前药纳米给药系统，使之克服普通纳米载药粒子瘤内渗透差的缺点。通过体外实验与体内动物试验考察肿瘤微环境调节剂对纳米化疗药物在瘤内的渗透、肿瘤细胞里的富集及药物释放的影响，研究材料的结构、性能及药物的组成关系与治疗效果之间的内在关联，探索提高瘤内药物浓度、改善瘤内药物渗透、摧毁肿瘤细胞特别是肿瘤深处细胞的有效途径。

基于肿瘤内部环境特征（如：pH、还原环境等）制备的智能纳米载体，可以通过刺激响应的结构转变实现对纳米载体的尺寸及药物释放进行有效调控，有助于提高纳米载体的肿瘤内渗透增强和给药效率。此外，纳米药物载体可同时负载多种不同作用机制的抗肿瘤药物，并通过内涵体转运的方式进入肿瘤细胞，不仅能克服肿瘤细胞的多药耐药，而且还能增强抑制肿瘤的效果。基于此目的，我们设计制备了一系列刺激响应性高分子和小分子前药，并以此制备了纳米药物载体。利用肿瘤内部微环境的改变实现载体的尺寸缩小和药物释放；通过不同作用机制药物的联合释放，实现损伤肿瘤细胞的DNA结构、微管结构和线粒体结构或诱导铁死亡的效果。