细胞膜包覆的共轭聚合物纳米粒构建及其肿瘤自主靶向光动力治疗研究

Photodynamic therapy (PDT) has garnered particular interest for cancer therapy, however, the therapeutic efficacy of photodynamic nanoparticles is limited due to easy recognition by the immune system, rapid clearance from blood circulation, and low accumulation in target sites. In this proposal, we aim to develop an organic phototherapeutic nanoagent that can biomimetically self-target to the inflammatory tumor for enhanced cancer photodynamic therapy. Such biomimetic nanoparticles comprise a near-infrared (NIR) absorbing semiconducting polymer nanoparticles (SPNs) coated with the cell membranes of neutrophils. The neutrophil membranes coated SPNs (Neutrophil-SPNs) could possess the associated membrane proteins, endowing the additional physiological features including immune escape and in vivo prolonged circulation time to nanoparticles. The chemotaxis of neutrophils and the photodynamic properties of SPNs could allow neutrophil-SPNs to actively target inflammatory tumor area, further leading to enhanced tumor accumulation after systemic administration in living mice. Therefore, the neutrophil-SPNs not only exhibit extended in vivo circulation time but also display the biomimetically self-targeting ability to tumor, ultimately leading to the enhanced cytotoxic singlet oxygen for photodynamic therapy. From this proposal, the development of an organic phototherapeutic nanoagent that biomimetically self-targets the tumor area for enhanced antitumor efficacy is expected to be achieved.

基于纳米材料的光动力疗法为癌症治疗提供了新的解决方案。然而，用于光动力治疗的纳米材料面临一系列难题：易被免疫系统识别，血液循环中被快速清除以及肿瘤富集量低等。本项目拟选用中性粒细胞与共轭聚合物制备具有良好生物相容性的中性粒细胞膜包覆的共轭聚合物纳米材料用于自主靶向的光动力治疗肿瘤。纳米材料表面修饰的中性粒细胞膜能够保留源细胞的抗原和相关膜功能，可以抑制体内的免疫清除，减少被巨噬细胞吞噬，增强纳米材料的体内循环时间。同时，利用中性粒细胞对炎症因子的趋向性和共轭聚合物的光动力特性的协同作用，可以通过引发肿瘤区域产生急性炎症，引导纳米材料自主靶向聚集到肿瘤，进一步增强纳米材料在肿瘤中的富集能力。通过本项目的研究，有望制备一种体内长循环兼具自主引导靶向肿瘤的共轭聚合物纳米材料用于光动力治疗，达到有效提高纳米材料的肿瘤富集量的目的，为癌症治疗的研究提供新的思路和方法。

增强纳米药物在肿瘤部位的富集对于肿瘤的治疗有着重要的意义。在项目的资助下，课题组成功设计了一种细胞膜包覆的仿生共轭聚合物纳米材料（SPNp），通过两阶段的激光操作使得纳米材料自主靶向肿瘤血管区域并实现了肿瘤血管的精准破坏。SPNp由半导体共轭聚合物纳米材料作为光热试剂内核，表面包覆一层有损伤血管靶向功能的血小板膜。在第一次激光照射时，SPNp产生的热量可以导致肿瘤血管出血，激活凝血级联反应，招募血小板富集到破损血管附近，使得更多的血小板膜包覆的SPNp自主靶向到肿瘤血管周围，这种自主靶向的性能显著增强了SPNp在肿瘤血管附近的富集，使得在第二次光照期间能够产生大量的热量有效破坏肿瘤血管，实现肿瘤的有效抑制。此外，这种光控精准血管损伤治疗策略通过减少髓源性抑制细胞，抑制了脾肿大现象，逆转了免疫抑制的肿瘤微环境。因此，本研究不仅阐明了一种光控自主靶向策略，增强了肿瘤治疗效果，而且还解释了肿瘤血管疗法引起的免疫治疗作用，为研究细胞膜仿生纳米材料的体内富集行为及其对肿瘤的治疗机制提供了理论基础。在本项目的资助下，课题组在三年内共发表SCI论文11篇。