光热-化疗一体化逐级靶向多重响应性递药系统的构建及其在耐药结肠癌口服高效精准治疗中的应用基础研究

结肠癌发病机制复杂，传统化疗难以取得高效的口服治疗效果。光热-化疗联合治疗（PTT-CT）是突破此瓶颈的新兴手段，然而胃肠道环境复杂，如何使药物和光热载体在空间上精准定位至靶点，在时间上辅以靶点微环境响应性释放，并逆转多药耐药，是实现口服结肠癌高效精准治疗亟待解决的关键问题。因此，本课题拟构建聚多巴胺覆膜纳米金刚石（PNDs）多功能纳米载体，在赋予体系光热和肿瘤微环境多重响应性释放特性的同时，确保高载药量；在PNDs表面修饰线粒体靶向配体三苯基膦，从多通路逆转载体的多药耐药，进一步提升PTT-CT精准治疗效果；以结肠葡聚糖酶特异性敏感的硬脂醇改性交联葡聚糖作为结肠定位材料包裹载药内核，有效避免药物的靶前泄漏，得到一种逐级靶向多重响应性光热递药系统，以解决结肠癌口服高效精准治疗的难题。本课题将从细胞、组织和动物多层次阐明载体的作用机制，为结肠癌口服PTT-CT协同递药系统的研究提供理论支撑。

The pathogenesis of colon cancer is complex, so it is difficult to achieve effective oral treatment effect with traditional chemotherapy. Photothermal-chemo combined therapy (PTT-CT) is an emerging approach to break through this bottleneck. However, the gastrointestinal environment is complex. How to precisely locate the drug and the photothermal carrier to the target in space, accompany microenvironment responsive release in time, and to reverse the multidrug resistance, are the key problems to be solved urgently for realize efficient and precise orally PTT-CT treatment of colon cancer. Therefore, this project intends to construct polydopamine coated nanodiamond (PNDs) multifunctional nanocarrier to ensure high drug loading capacity while endowing the tumor microenvironment/photothermal multiple responsive release characteristics of the system. Mitochondrial targeting ligand triphenylphosphine will be modified on the surface of PNDs to reverse the multidrug resistance of the carrier from the multipathway and further improve the precision therapeutic effect of PTT-CT. Colonic glucanase specific sensitive stearyl alcohol modified cross-linked dextran is used as colonic localization material to protect the drug loaded core in order to effectively avoid the drug leakage before reaching the target. Then a hierarchical targeted multiple response photothermal drug delivery system will be obtained, so as to solve the problem of highly effective and accurate oral treatment of colon cancer. The project will elucidate the mechanism of the carrier from multiple levels of cells, tissues and animals, and provide theoretical support for the study of oral PTT-CT synergistic drug delivery system for colon cancer.