基于肿瘤微环境响应性光敏剂制备近红外光调控的诊疗一体化高分子纳米药物载体

Tumor-environment responsive amphiphilic polyprodrug-based polymeric nanoparticles are widely used as anti cancer drug delivery carriers due to their elongated circulation in the bloodstream and site-specific release of active drugs. However, not like light-responsive drug carriers, tumor-environment responsive nano-carriers could easily lead to futile treatment or unnecessary treatments owing to the lack of enough controllability. The use of light as an external stimulus is a very appealing tool for the spatio-temporal release of active drugs. Current light responsive drug delivery vehicles mainly rely on o-benzyl that could be cleaved upon irradiation of UV light. Nevertheless, the general requirement of UV light is a significant limitation due to associated toxicity and poor tissue penetration. By contrast, light between 650 and 900 nm, often referred to as the near-IR window, is cytocompatible and has significant tissue penetration. In this proposal, we will design NIR light-responsive drug delivery carriers by taking advantage of the unique reaction of singlet oxygen that can be generated by the combination of photosensitizer and low energy light. Spontaneous cleavage of beta-enamino esters leads to the site-specific release of active anti-cancer drugs. It should be noted that the designed difunctional photosensitizers would be activated only in the presence of tumor specific enzymes or overexpressed biomolecules, concomitant with the fluorescence emission that can lighting up the cancer tissue for guiding light-controlled therapy. Moreover, a apoptosis probe that covalently linked to the the hydrophilic segment of the amphiphilic polymers can assess the therapy efficacy in situ. The research will explore the laws of NIR lght-responsive nano-theranostics with tumor-microenvironment activable photosensitizers, and provide a novel concept in the field of anticancer nano-theranostics and precise medicine.

基于肿瘤微环境响应性聚合物前药设计的纳米药物载体有着体内长循环及定点控制释放等优点，然而相对于光这种外源性调控的药物载体，其由于缺乏可控性容易导致无效治疗或过度治疗。目前光控纳米药物载体多依赖于邻硝基苄基作为光响应基团，其所需的紫外光源容易损伤健康细胞，且较短的波长限制了其组织穿透深度。本项目拟基于光敏剂在光照条件下产生单线态氧的性质，并结合单线态氧诱导的断键化学设计并制备近红外光触发的高分子纳米药物载体。该近红外光敏剂被设计成仅被肿瘤标志物选择性开启，且整合了荧光探针的功能，同时，在亲水链中共价修饰了细胞凋亡探针，这两种探针分别用于指导光照的始点和终点，并提供光照位点及早期疗效评估，预期会有效规避脱靶治疗，无效治疗以及过度治疗，使得抗肿瘤治疗可以做到有的放矢和收放自如，有望为癌症的个性化治疗甚至精准治疗提供一条新的策略。

利用高分子组装体调控光学成像基元和光控基元的协作，为疾病治疗同时提供了高时空分辨率的影像指导和操控，为癌症的个体化治疗和精准治疗提供了一种有效方案。本项目从设计可视化荧光探针这一关键功能模块入手，建立了多种制备高性能荧光探针的分子策略，为纳米药物所需的光学影像指导和疗效实时监控提供了可视化工具。同时，开发了一种合成激活型光敏剂的通用策略，并以此制备了多种肿瘤标志物响应的光敏剂用于光响应模块。最后，通过聚合物自组装将各种光功能模块巧妙的装配在一起，开发了多种诊疗一体化纳米药物，有效提升了肿瘤治疗的精准性。研究成果共发表论文8篇（IF>10的5篇），申请国家发明专利8项。