红细胞膜修饰智能聚合物纳米囊泡的制备及其在肿瘤靶向热疗化疗与免疫联合治疗中的应用研究

The research of intelligent polymer nanocapsules has aroused wide attention. However, as an anti-tumor drug delivery system, its clinical applications still have problems, such as short blood circulation cycle, high side effect, low biology compatibility. Thus, the design of a novel tumor-targeted nano-based drug carrier has become an effective method to solve the bottleneck problem of anticancer drug delivery. Inspired by the natural biological properties of red blood cell membrane (CM), here a novel nano-based drug delivery system will be constructed based on the pH-responsive polymer nanocarriers (NC) coated with CM. This system can combine extraordinary mechanical stability, pH responsiveness in tumor microenvironment and targeted drug release of NC, and bionic camouflage and long circulation properties of CM. Furthermore, the immunotherapy antibodies and thermotherapy reagents will be introduced on the cell membrane surface to realize the dual targeting of tumor, have the synergistic anti-tumor efficacy of thermo-chemo-immunotherapy, improve the efficiency of tumor treatment and enhance the effect of combination therapy. More importantly, this project can not only provide new ideas for the development of intelligent polymer nanocapsules as drug carriers but also will provide the research basis for the application of tumor-targeted multi-combination therapy.

智能聚合物纳米囊泡的研究已经非常广泛，然而作为抗肿瘤药物输送系统的临床应用仍存在血液循环周期短、副作用大、生物相容性低等问题，设计构建新型高效的肿瘤靶向智能纳米药物载体成为当前解决抗癌药物输送瓶颈问题的一种有效方法。本项目拟利用红细胞膜天然生物特性，首创构建以pH响应型智能聚合物纳米囊泡为化疗药物载体，表面覆盖红细胞膜的新型智能纳米药物体系。该体系兼具了智能聚合物纳米囊泡的高稳定性、肿瘤微环境pH响应性、靶点定位释药的优势和红细胞膜的仿生伪装、长循环特性。同时在细胞膜表面引入免疫治疗抗体和热疗试剂，使其具有双重靶向性，发挥热疗化疗与免疫联合协同治疗作用，提高肿瘤治疗效率，增强联合疗法效果。本项目的研究成果将为智能聚合物纳米囊泡作为新型药物载体的研发提供思路，同时为肿瘤靶向多联合治疗的应用提供研究基础。

智能聚合物纳米囊泡作为抗肿瘤药物输送系统的临床应用存在血液循环周期短、副作用大、生物相容性低等问题，设计构建新型高效的肿瘤靶向智能纳米药物载体具有重要意义。本项目研究构建兼具智能聚合物纳米囊泡的高稳定性、肿瘤微环境pH响应性、靶点定位释药的优势和红细胞膜的仿生伪装、长循环特性的新型智能纳米药物体系。同时通过在细胞膜表面引入免疫治疗抗体和热疗试剂，使其具有双重靶向性，发挥热疗化疗与免疫联合协同治疗作用，提高肿瘤治疗效率，增强联合疗法效果。.选择合适的聚合单体、控制聚合物的链段长度和亲疏水比，研究合成pH响应型智能聚合物，NMR结果表明智能聚合物已成功制备。通过直接溶解法将智能聚合物自组装制得pH响应型智能聚合物纳米囊泡，DLS结果证明智能聚合物纳米囊泡具有良好的肿瘤微环境pH响应性。.通过将免疫治疗抗体和热疗试剂修饰的红细胞膜覆盖在聚合物纳米囊泡表面，构建具有良好的生物相容性、热疗化疗与免疫协同效应、肿瘤微环境pH敏感性的新型药物载体。DLS等结果表明纳米囊泡已成功包覆在细胞膜内。相比于纳米囊泡，红细胞膜修饰的纳米囊泡具有良好的血清稳定性。同时红细胞膜修饰的纳米囊泡具有良好的肿瘤微环境pH响应性，并对正常细胞没有明显毒性。另外，抗肿瘤活性实验结果表明，红细胞膜修饰的纳米囊泡则有着更高抗肿瘤活性，这是由于在细胞膜表面引入免疫治疗抗体和热疗试剂能够提高肿瘤治疗效率，能够发挥热疗化疗与免疫联合协同治疗效应，因此能够增强联合疗法效果。本项目研究为抗肿瘤新型药物载体的跨越式发展提供理论支撑和试验依据。.另外，在国内外高水平杂志上发表科研论文10余篇，其中标注本基金号的SCI论文4篇。培养硕、博士生9名，其中博士2名，硕士7名。