基于聚吡咯有机“可视化光热剂”的制备及MRI/CT双模态诊断、引导光热治疗的研究

Combining medical imaging with photothermal therapy together to achieve “visible photothermal therapy” is an inevitable tendency of developing theranostic technology for cancer treatment, and the building of “visible photothermal agent” (“VPTA”) has become a crucial technique in the field. Though polypyrrole stands out from numerous photothermal agents, but the development and clinica application of based polypyrrole “VPTA” might be limited due to the chemical inertness of polypyrrole. In this project, the polymerizable functional complex containing gadolinium (Gd) and iodine (I) are designed and synthesized firstly, and then copolymerized with pyrrole monomer in aqueous phase to built the polypyrrole based organic “VPTA”, which could be served as theranostic agent for T1-MRI/CT dual-modality imaging and imaging-guided photothermal therapy. Facile preparation progress will be explored to overcome the shortages of multistep preparation, and single-modality imaging of those polypyrrole based “VPTA” have been reported. The controlling technique and condition for the structure, morphology and property of “VPTA” will be investigated. Furthermore, the morphological regulation and targeting modification will be conducted to enhance tumor cells uptake of the “VPTA”, the interactions between “VPTA” with cancer cells and cell damaged mechanism will be studied. We will investigate and optimize the results of T1-MRI/CT dual-modality imaging and imaging-guided photothermal therapy, summarize the internal relations between the compositions, structure, morphology of “VPTA” with the results of tumor diagnosis and imaging-guided photothermal therapy. The application of “VPTA” in theranostic technology for cancer diagnosis and treatment will be grasped to provide innovative substances and theoretical basis for the development of “visible photothermal therapy”.

医学成像与光热治疗相结合而实现“可视化光热治疗”是肿瘤诊疗一体化发展的必然趋势，构建“可视化光热剂”成为该领域的技术关键。聚吡咯在众多光热剂中脱颖而出，但化学惰性导致聚吡咯基“可视化光热剂”的发展与临床应用受限。本项目拟合成含钆、碘功能配合物，再与吡咯在水相中进行共聚，构建具有T1-MRI/CT双模态成像、引导光热治疗的有机“可视化光热剂”；探索简单易行的聚吡咯基“可视化光热剂”制备方法，解决目前制备工艺复杂、成像模式单一等问题；探讨“可视化光热剂”结构、形貌、性能调控的技术、条件。通过形貌调控、靶向修饰，提高肿瘤细胞对“可视化光热剂”的摄取量，并研究与肿瘤细胞的相互作用及杀伤机理；考察、优化肿瘤组织的MRI/CT双模态诊断、引导光热治疗效果，总结“可视化光热剂”组成、结构、形貌和诊断、引导光热治疗效果的关系；掌握其在肿瘤诊疗一体化中的应用，为“可视化光热治疗”的发展提供新的物质和理论依据

将医学成像技术与新型肿瘤治疗技术结合具有重要意义。项目以钆离子作为中心离子，选用吡咯-1-丙酸、泛影酸、1-氨基邻菲罗啉作为主要配体制备可聚合功能配合物。调控功能单体与无机纳米粒子，通过聚合、组装及生物矿化等制备技术，制备出多功能成像引导治疗的“可视化光热剂”，探索出简单易行的制备技术，探究了它们与细胞的相互作用、生物相容性；研究了其在肿瘤诊断、治疗等方面的应用，并取得优良效果。重要研究结果如下：.1.制备出具有荧光、CT造影双功能配合物，通过乳液聚合法制备具有双层核壳结构的磁性MRI、荧光和CT造影三重功能生物医用微球，平均粒径132nm，具有优良的MRI、CT和荧光造影成像效果。.2.将聚多巴胺作为光热剂，与近红外荧光染料IR780在碱性条件下组装制备出复合纳米粒子，生物相容性好，具有荧光成像诊断能力和光热光动协同治疗作用。.3.用中-四（4-羧基苯基）卟吩和FeCl3·6H2O，一锅法合成了棒状Fe(Ⅲ) MOF，长度约为400 nm，生物安全性良好，具有良好的成像能力，纵向弛豫率为3.15 mM-1s-1，表现出优异的体内光动力治疗效果。.4.以聚多巴胺纳米粒子作为MnO2的载体，络合IR780，巧妙地构建了以pH刺激响应释氧的磁共振成像引导光热/光动力协同治疗的纳米粒子，粒径约为240 nm，纵向弛豫率为4.58mM-1s-1，表现出良好的体内光热/光动力（CDT/PDT）治疗效果。.5.通过络合、包裹复合方法制备了pH刺激响应的磁共振成像引导光热/药物协同治疗的纳米粒子。纳米粒子尺寸均一，约为130 nm，可在肿瘤酸性微环境释放抗癌药物，形成光热治疗与化疗相结合的协同治疗体系。体内体外MRI显示出良好的成像性能，其纵向弛豫率为10.06 mM-1s-1。.6.将牛血清蛋白作为吡咯聚合的稳定剂，将纺锤状羟基氧化铁纳米粒子（FeOOH NSs）作为吡咯聚合的纳米模板，制备了纺锤状FeOOH@PPy复合纳米粒子，平均粒径100 nm，可吸收808 nm的近红外光，并将其转化为足够的热量，使肿瘤细胞凋亡。.7.利用NH2-MIL101(Fe)负载光敏剂Ce6，并在外层包覆MnO2，制得粒子粒径为300 nm，MnO2在肿瘤微环境中生成O2，改善肿瘤部位的乏氧状态，粒子发生类芬顿反应，可以杀死肿瘤细胞，有效地进行CDT/PDT联合治疗。