新型多功能磁性纳米光敏剂的构建及光动力治疗肝癌性能研究

Photodynamic therapy (PDT) have been recognized as a promising strategy for the treatment of liver cancer. However, its clinical application can be ineffective or limited by the satisfactory outcomes because of the off-targeted properties, hypoxia circumstances and side effects. Herein, we employed Janus magnetic mesoporous silica nanoparticles (M-MSNs) as a nanocarrier to load photosensitizers, developing multifunctional nano-photosensitizers to solve these shortcomings of PDT and confer upon characteristics of the effective tumor-targeting, on-demand release of photosensitizers, multi-modal therapy and real-time monitoring the fate and therapeutic effect. Aiming at improving the therapeutic effect of advanced liver cancer though the above-mentioned strategy, we design and prepare a biomimetic nano-photosensitizer (M-MSNs/HPD@LCM) composed of Hiporfin (HPD)-loaded Janus magnetic mesoporous silica nanoparticles (M-MSNs) as the inner cores and liver cancer cell membranes (LCM) as the outer shells. The M-MSNs/HPD@LCM perfectly utilize the LCM with the passive and homotypic targeting and immune escape properties and M-MSNs with the high loading capacities and tumor-responsively photosensitizer release behavior, magnetic resonance imaging (MRI) contrast, as well as the increased micro-environmental oxygenation induced by magnetothermal effect. These project systematically investigate the targeted endocytosis, on-demand photosensitizer release and immune escape of the nano-photosensitizer, the tumor-targeting and the synergetically therapeutic effect as well as bio-safety and bio-distribution evaluation in vitro and in vivo. Meanwhile, MRI is employed to real-time monitor the in vivo fate therapeutic efficacy and optimize the procedure for the sequential therapy integrate photodynamic/magnetothermal therapy. Taken together, our project addresses and develops the new strategy and materials for that combination of photodynamic therapy and magnetothermal therapy for hepatocellular carcinoma.

研发高疗效的新型多功能纳米光敏剂是推动光动力治疗癌症进程亟待解决的科学难题。本项目拟以Janus型磁性介孔二氧化硅纳米粒子为担载剂，开发靶向性强、可控释药、多模式治疗且可实时监控疗效的多功能纳米磁性光敏剂。利用具有肝癌靶向和免疫逃逸特征的肝癌细胞膜包裹多功能磁性纳米光敏剂，提高肿瘤靶向能力；利用肿瘤微环境的弱酸性特性建构pH响应体系，实现光敏剂的响应释放；利用磁热治疗方法，在缩小瘤体同时提高肿瘤微环境氧含量，提高光动力治疗效果；利用分子影像学等手段实时监测纳米光敏剂输送过程、肝癌微环境氧含量变化和治疗效果，系统研究纳米光敏剂的肝癌协同及靶向治疗、可控释药及实时监控疗效作用，阐明多功能纳米磁性光敏剂对光动力治疗的重要性，为肝癌的临床综合治疗提供新方法和新材料。

光动力治疗是一种极具潜力的肿瘤治疗新途径，但由于光敏剂存在靶向性差、激活特异性不好以及乏氧条件下效率低等缺点导致治疗效果不佳、副作用大，从而限制了其临床进一步应用。本项目采用Janus型可降解磁性介孔二氧化硅纳米粒子担载光敏剂，开发靶向性强、可双重响应肿瘤微环境（pH/还原性）的可控释药、“磁热+光动力+免疫检查点抑制剂”多模式治疗功能且可实时监控疗效的多功能纳米光敏剂。利用肿瘤细胞膜的肿瘤靶向和免疫逃逸等特征，构筑出肿瘤细胞膜包裹的多功能磁性纳米光敏剂，提高其同源靶向能力；利用肿瘤组织弱酸性及还原性的微环境，设计并合成特异性的pH/还原性响应体系，实现光敏剂的肿瘤微环境可控释放；利用磁热治疗，实现肿瘤组织的整体杀灭并提高肿瘤微环境氧含量，辅助以高效的光动力治疗杀灭残存的肿瘤细胞，在此基础上，继续联合免疫检查点抑制剂来实现抗肿瘤免疫性，从而实现肿瘤的“磁热+光动力+免疫检查点抑制剂”序贯治疗。利用核磁成像等分子影像学手段实时监测纳米光敏剂输送过程、肿瘤微环境氧含量变化和治疗效果，系统研究纳米光敏剂的肿瘤靶向、微环境释药、免疫逃逸的作用，评价序贯治疗的有效性和安全性，阐明序贯治疗肿瘤的机理，为肿瘤的临床综合治疗提供新策略和新材料。