仿血小板纳米粒联合BQ123通过自放大靶向效应增强肿瘤光热治疗的研究

Photothermal therapy (PTT) with high specific, minimally invasive, high efficient treatment characteristics, is one of the current research hotspots. However, the disadvantages of photothermal nanomaterials are poor tumor targeting, non-uniform intratumoral distribution, high clearance rate, accumulation in normal tissues, which affect the tumor killing effect and limit the further clinical application. Accordingly, we established a PTT strategy by self-amplified targeting systems of platelet-mimicking nanoparticles with the aid of tumor vascular dilation in this project. A new kind of biomimetic long-circulation nanoparticles such as gold nanorods and polydopamine nanoparticle enclosed in the plasma membrane of human platelets were synthesized. The cutaneous squamous cell carcinoma was chosen as a tumor model. The endothelin A receptor antagonist BQ123 could regulate tumor microenvironment, induce tumor vascular relaxation, increase blood flow perfusion, which was helpful for photothermal nanomaterials to enhance the penetration and uptake of tumor. A large number of platelet-mimicking nanoparticles targeted to microthrombosis that formed after tumor vascular injury by photothermal damage. Repeated laser exposure induced more microthrombosis formation and targeting aggregation of platelet-mimicking nanoparticles in tumor vascular. As a result, photothermal effect was enhanced, the tumor was eventually killed. Through our strategy, the nanomaterials concentration and distribution in the tumor were improved, and the multiple heat treatment was achieved with low dose and long-circulation biomimetic nanomaterials combined with BQ123 administration. This project provided a reference for the exploration of new-type photothermal nanomaterials and the development of tumor therapy strategy.

肿瘤光热治疗具有可控、微创、高效优势，是当前研究热点之一，但目前还存在纳米材料的肿瘤靶向性较差、瘤内分布不够均一、易血液清除和正常组织大量蓄积等问题，影响肿瘤杀灭效果，限制其进一步临床应用。据此，本项目提出一种仿血小板纳米粒联合肿瘤血管扩张剂通过自放大靶向效应增强肿瘤光热治疗的新策略。该策略采用血小板膜包被光热纳米材料（如金纳米棒和聚多巴胺纳米球），构建一类新型长循环仿生纳米粒；以皮肤鳞癌为肿瘤模型，采用内皮素A受体拮抗剂BQ123特异性扩张肿瘤血管，提高仿生纳米粒瘤内穿透和均匀分布；通过仿生纳米粒光热损伤肿瘤血管，诱导瘤内微血栓形成，吸引大量仿生纳米粒靶向结合在微血栓处；重复光照，诱导更多微血栓形成和仿生纳米粒靶向聚集，瘤内光热效应进一步增强，最终杀灭肿瘤。通过上述策略，有望实现低剂量单次给药多次热疗，显著提高肿瘤治疗效果。本项目研究为发展新型光热纳米材料增强肿瘤光热治疗提供参考。

本项目针对目前肿瘤光热治疗领域中，纳米光热材料的肿瘤靶向性较差、瘤内分布不够均一、易血液清除和正常组织大量蓄积等问题，发展了一种仿生纳米粒联合肿瘤血管扩张剂通过自放大靶向效应增强肿瘤光热治疗的新策略。通过红细胞膜和红细胞与血小板杂合膜包覆光热纳米材料的策略，制备长循环纳米粒，并采用内皮素A受体拮抗剂BQ123特异性扩张肿瘤血管，提高仿生纳米粒的瘤内穿透和均匀分布；再经低温光热刺激仿生纳米粒热损伤肿瘤血管，诱导瘤内微血栓形成，以此吸引大量仿生纳米粒靶向结合在微血栓处，提高靶向聚集效应，进一步增强瘤内光热效果，最终更好杀灭肿瘤。研究中我们发现，细胞膜包覆方法存在繁琐的细胞提取、分离、膜纯化等步骤，规模化制备较难且会有免疫排斥等缺点，对此我们进一步对膜层进行研究，构建一种人造细胞膜，将两性离子聚合物包裹在纳米光热材料表面，制备长循环性能更好，无免疫原性可规模化生产的仿细胞膜光热纳米材料，体内外研究证实全方位优于细胞膜仿生策略，为今后可能的光热纳米制剂的临床转化奠定了前期研究基础。