nano-in-micro多功能聚合物微球的可控制备及其在肝癌化疗栓塞疗法中药物可控释放研究

There are some shortcomings for the present transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma, such as uncontrollable embolization and drug release behavior, single drug and invisibility of embolic microsphere in the body. To enhance the efficacy of TACE therapy, a novel kind of monodispersed nano-in-micro polymeric microspheres with controllable diameter is proposed, which encapsulates superparamagnetic iron oxide (SPIO) and multiple drugs including free drugs and loaded drugs in a thermosensitive nano-carrier simultaneously. The main innovations of this proposal are as follows. The controllable nano-in-micro microstructure is obtained based on microfluidic emulsion technology and assembly technology. In addition, the encapsulated SPIO not only can enable magnetic resonance imaging detection, but also can generate heat under an alternating magnetic field due to the magnetocaloric effect to trigger the drug release from the thermosensitive nano-carries encapsulated in the microspheres, which achieve a programmable release and controllable release for drugs. As well, the generated heat can kill the adjacent tumor cells. Therefore, this nano-in-micro system combines multiple functions including embolization, chemotherapy and hyperthermia. The implementation of this proposal will develop various multifunctional polymeric microspheres, deepen the study on the micro/nano- structure and controllable release mechanism of multi-drugs. Thus, it possesses important scientific significance. Furthermore, the implementation of this proposal will provide a theoretical basis and design suggestion for the exploitation of novel TACE materials for hepatocellular carcinoma combined with embolization, chemotherapy and hyperthermia. Therefore, it also has great potential application value.

经导管肝动脉化疗栓塞（TACE）疗法中存在栓塞和释药行为不可控、药物单一、栓塞微球体内不可视等不足。本项目提出构建一种新型nano-in-micro聚合物微球，其粒径可控且单分散。同时负载超顺磁性氧化铁和多种药物如游离药物和温敏纳米药物，以改善TACE疗效。本项目主要创新点是：基于微流控乳化技术和组装技术，实现nano-in-micro微结构和组成的可控性。其次，包封的超顺磁性氧化铁不仅可增强磁共振成像，在交变磁场作用下其产生的热能还促发微球中温敏纳米载体中药物的释放，实现药物的程序释放和可控释放。同时，其产生的热能可直接杀死肿瘤细胞，具有热疗效果。因此，该体系兼具栓塞、化疗和热疗多重功能。本项目的实施将发展多种多功能聚合物微球、深化微纳结构和多药物释放调控机理研究,具有重要的科学意义；还对开发栓塞、化疗和热疗联合使用的新型肝癌TACE材料提供理论依据和设计方案，因此也具有重要的应用价值。

经导管动脉化疗栓塞（Transcatheter Arterial Chemoembolization，TACE）目前已被公认为是中晚期肝癌患者首选治疗方案。但存在化疗药物单一、药物释放不可控、疗效不佳、无法进行跟踪检测等缺点。本课题基于液滴型微流控可控制备技术和组装技术、聚合物链可作为无机纳米粒制备的模板效应，先后构建和可控制备了多种多功能的nano-in-micro聚合物栓塞微球，以改善上述不足。主要研究内容和进展如下：.（1）将多种抗癌药物共包封于栓塞微球中，实现多种药物的共输送，改善TACE治疗中化疗药物单一的缺陷，增强杀死肿瘤细胞的能力；.（2）在栓塞微球中包封温敏纳米凝胶、超顺磁性氧化铁纳米粒（NPs），改变这些纳米粒的用量和外加磁场来调控药物的释放，同时微球在磁共振(MR)下可视；.（3）基于热疗可直接杀死癌细胞并增敏化疗，构建并分别制备了原位包封四氧化三铁纳米粒、金纳米星、Bi2S3 纳米粒的nano-in-micro聚合物微球，实现磁控/光控药物释放、热疗联合化疗协同杀伤肿瘤细胞，改善治疗效果；.（4）一步制备原位包封Gd2O3 NPs或/和Fe3O4 NPs的聚乙烯醇微球，赋予微球多功能：栓塞、磁热、增强T1或/和T2-MR成像功能，实现热疗与TACE联用改善治疗效果、控制药物释放、微球在MR下可视等诊疗一体化； .（5）基于分子设计原理，制备了pH/温度/GSH响应的两性离子型纳米凝胶，克服纳米药物传输中对纳米载体物性的多个矛盾要求，实现胞内靶向释药。较高浓度的两性离子型温敏纳米凝胶在体温实现溶胶-凝胶相转变，与热疗联合使用，具有易于注射、可末端栓塞、抗蛋白吸附、可控释放、疗效高等优点。.这些研究为TACE治疗提供了新思路、新材料、新理论；为nano-in-micro杂化微球提供了简便、可控的制备方法；揭示了微球的微观组成和结构对药物释放的影响规律。目前已发表SCI研究论文6篇（包括Nano Lett, Nanomed Nanotech Biol Med, ACS Appl Mater Interfaces等），还有三篇论文在投稿中。申请中国发明专利4项，已授权一项。参加本领域国内学术会议6次，做了4次口头报告。参加国外学术交流和学术会议三次，做口头报告1次。培养硕士生5名，博士生1名。完成了研究目标。