基于微流控技术的复合结构栓塞微球的设计制备及用于肝癌的多模式介入诊疗研究

As one of the most malignant tumors, hepatic carcinoma is mainly treated by transarterial chemoembolization (TACE) currently, which still cannot fulfill long-term survival completely. With clinical trial and development of magnetic hyperthermia and photothermal therapy, magnetic nanomaterials with outstanding magnetic hyperthermia ability and graphene-based nanocomposites with outstanding photothermal ability show great potential in biomedicine, especially clinical multimodal therapy for hepatic carcinoma. The applicant has extensive experience of the synthesis, assembly and biomedical research of magnetic nanomaterials and graphene-based nanocomposites, while major participants have extensive clinical TACE experience. Thus, in this project we propose to choose a series of pharmaceutic excipients as structure support, and combine microfluidics with supercritical carbon dioxide drying to fabricate inorganic nanomaterials based multifunctional and hierarchical structural microspheres. Furthermore, we propose to integrate magnetic materials with great magnetic hyperthermia/MR properties and graphene composites with great photothermal performance into transarterial embolizing microspheres, which has a great potential to achieve synergistic therapy effect including embolization of tumor blood vessels, chemotherapy drug elution, photothermal therapy and magnetic hyperthermia all in a single transarterial interventional treatment, under the guidance of multimodal imaging. This project shows important scientific significance and clinical potential, which could serve as a novel multimodal integrated theranostic treatment of hepatic carcinoma.

肝癌是一种恶性程度极高的肿瘤，经动脉介入栓塞化疗（TACE）作为当前的主要治疗手段仍不能满足肝癌临床治疗的需求。随着磁热疗和光热疗技术在临床上的开展，具有良好的磁热和磁共振性能的磁性纳米材料和具有良好的光热性能的石墨烯纳米复合物在肝癌的综合治疗中展现出极大的临床应用潜力。基于申请人在磁性纳米材料和石墨烯纳米复合物制备、组装及其生物医学应用方面的研究基础，以及项目主要成员丰富的肝癌介入栓塞化疗临床经验，本项目拟通过微流控技术与超临界干燥技术的联用，以多种药用辅料聚合物为结构模板，构建基于无机纳米生物材料的复合功能多级结构微球。通过将磁性纳米材料和石墨烯复合物与药物缓释型的介入栓塞微球复合，实现在磁共振成像和CT成像多模式造影的引导下，通过一次肝脏动脉栓塞介入治疗即可达到肿瘤血管物理栓塞、化疗药物缓释、光热治疗和磁热治疗多种手段的协同效果，将有望成为新型的肝癌一体化综合治疗方案。

肝癌是一种恶性程度极高的肿瘤，经动脉介入栓塞化疗作为当前的主要治疗手段仍不能满足肝癌临床治疗的需求。随着磁热疗和光热疗技术在临床上的开展，具有良好的光热和磁共振性能的磁性纳米材料和具有良好的光热性能的纳米复合物在肝癌的综合治疗中展现出极大的临床应用潜力。本项目基于项目组成员在磁性纳米材料和石墨烯纳米复合物等的制备、组装及其生物医学应用方面的研究基础，以及项目主要成员丰富的肝癌介入栓塞化疗临床经验，研发了多种光热杀伤肿瘤的新型制剂，以及多种可用于肿瘤磁共振诊断和磁热杀伤的磁性纳米生物材料，为结合光热和磁热的栓塞材料的设计制备提供了新型的功能基元。进一步通过微流控技术与超临界干燥技术的联用，以壳聚糖等药用辅料聚合物为结构模板，构建基于无机纳米生物材料的复合功能多级结构微球，并初步验证了其用于肝癌栓塞的可行性。同时基于复合物的构效关系优化设计了新型无机功能性纳米材料与壳聚糖等天然高分子之间的结构，提出了界面作用力优化和仿生合成设计两种策略，为进一步的功能性栓塞微球的制备提供了必要的结构设计参考。本项目在无机-有机复合生物材料与肝癌等恶性肿瘤诊疗特别是介入治疗方向取得一系列研究成果，其中本课题主持人作为共同第一作者发表自然子刊论文一篇Nature Biomedical Engineering，并被Nature Biomedical Engineering以News&Views形式全文点评。项目执行过程中，项目主持人作为共同通讯作者在生物医学和生物材料领域发表上述研究方向的SCI论文17篇，包括Nature Communications 1篇，Angewandte Chemie International Edition 1篇，ACS Nano 1篇，Materials Horizons 1篇，Biomaterials 1篇，Chemical Science 1篇， ACS Applied Materials & Interfaces 3篇，Nanoscale 2篇，Biomaterials Science 2篇。申请中国发明专利8项，其中4项授权，相关工作展现出良好的应用转化潜力。