超声/荧光/磁共振三模式成像探针的构筑及其对前列腺癌的增强光动力治疗

Currently, the technical difficulty of breakthrough theranostic of prostate cancer lies in the development of multi-modal diagnostic probes and efficient therapeutic agents. Nevertheless, the most theranostic reagents are not able to achieve accurate diagnosis and efficient treatment. Aiming at this problem, in this proposed study, we will synthesize a functional chain transfer agent with disulfide bond that can be self-polymerized, then reversible addition-fragmentation chain transfer (RAFT) reactive polymerization with poly(ethylene glycol) methacrylate (OEGMA), tetrafluoropropyl methacrylate (TFPMA) and methacrylate monomer with disulfide bond to prepare fluorinated water-soluble core cross-linked polymeric micelles, which are coupled with chlorin and paramagnetic gadolinium, and induce them self-assembly with perfluorohexane by solvent evaporation, then build an enhanced photodynamic therapy reagent of ultrasound, fluorescence and magnetic resonance trimodal imaging. The synthetic process, morphology and assembled mechanism are studied systematically. It is investigated that the promotion of diagnosis from fluorescence and magnetic resonance imaging enhancement effects under the condition of tumor high content glutathione and synergetic effect of trimodal imaging. Meanwhile, it is also studied that the efficacy and mechanism of enhanced photodynamic therapy for prostate cancer under the guidance of trimodal imaging. This project will promote the application of polymeric theranostic reagents in the diagnosis and treatment of prostate cancer.

目前突破前列腺癌诊疗的技术难点在于开发多模式诊断探针和高效治疗一体化试剂，然而现有的大多数诊疗试剂难于实现准确诊断和高效治疗的效果。针对此问题，本项目拟合成含有二硫键并可自聚合的功能链转移剂，与聚乙二醇甲基丙烯酸酯（OEGMA）、甲基丙烯酸四氟丙酯（TFPMA）、及含二硫键的甲基丙烯酸酯类单体等功能单体进行可逆加成断裂链转移（RAFT）活性聚合制备水溶性含氟核交联聚合物胶束，将该聚合物与二氢卟吩和顺磁性钆偶联，采用溶剂挥发诱导其与全氟己烷自组装，构建出一种在超声、荧光和磁共振三模式成像下的增强光动力诊疗试剂。系统研究诊疗试剂的制备工艺、形貌结构和组装机理。考察其在肿瘤谷胱甘肽刺激下的荧光/磁共振成像增强效果和三模式成像的协同效应对诊断的促进作用。同时也研究了诊疗试剂在三模式成像导向下对前列腺癌增强光动力治疗的效果和机理。本项目的研究将促进聚合物诊疗试剂在前列腺癌的诊断和治疗领域中的应用。

光动力治疗是在氧气存在下，依靠合适的激光激活光敏剂产生细胞毒性的活性氧自由基来实现肿瘤细胞的杀伤。然而缺氧是大多数实体瘤存在现象，进而降低了光动力的治疗效果，并且大多数肿瘤在治疗过程中缺少准确的诊断。针对以上问题本项目研究工作如下：（a）基于氟碳分子链的生物医学优势，通过RAFT活性聚合制备交联型和线形含氟两亲性聚合物，分别对光敏剂和全氟戊烷组装，考察了组装载体的光动力、光热治疗效果、体外荧光和超声成像特点。（b）将高含氧量的全氟己烷负载到蛋黄结构聚膦腈构筑复合纳米载体。研究其磁共振/超声/荧光三模式成像示踪作用，以及近红外辐射下对小鼠肿瘤表现出增强光动力和光热联合治疗。（c）基于上述蛋黄结构制备工艺，将具有生物催化特点的铂纳米粒子原位生成在蛋黄结构多巴胺载体，与肿瘤微环境的双氧水反应产生氧气，表现出增强光动力治疗效果，聚多巴胺的光热效应也能进一步提高治疗效果。结合载体的三模式成像指导作用，复合纳米载体对小鼠肿瘤表现出光热和增强光动力联合治疗。最后，基于活性氧对细胞的杀伤特点，本人开发了光催化产生活性氧的纳米粒子，例MoS2@ZIF-8、g-C3N4@ZIF-8、碳量子点等，考察光催化纳米粒子的抗菌作用，并进一步与水性聚氨酯、丙烯酸酯等乳液结合，研究复合涂层的抗菌、疏水、自清洁应用。综上所述，项目所研究复合纳米粒子在生物医学和功能涂层等领域展现良好应用前景。