化疗药物、基因共递送的新型MRI可视栓塞化疗系统的构建及其在耐药肝癌TACE治疗上的应用

Recently transcatheter arterial chemoembolization (TACE) has been becoming an effective treatment for inoperable hepatic tumors. However, the occurrence of multidrug resistance leads to unsatisfactory efficacy of mid-and-long term of TACE treatment. Commercial ion-exchange microspheres are widely used in the interventional therapy of hepatic carcinoma. Nonetheless this kind of embolic agents is not visible in the current imaging modalities. The lack of non-invasive tracking and mapping the fate of embolic agents has restricted the development and further application of TACE therapy. In addition, this kind of embolic agents can just load positively-charged drugs. Novel ion-exchange microspheres (HAMs) with hydroxyethyl-methacrylate (HEMA) and acrylic acid (AA) as monomers have already been successfully synthesized and have been proved possessing excellent properties as embolic material in our previous experiments. Based on it, this study aims to further synthesize MRI-visible ion-exchange embolic microspheres (MDHAMs). Meanwhile, the complex nanoparticles (CNPs) loading with DOX and P-gp siRNA to reverse drug resistance of hepatic carcinoma will also be prepared. Then MDHAMs can accomplish loading CNPs by ionic adsorption, forming novel MRI-visible chemoembolic system to co-deliver chemotherapy drug & gene. This novel system can block the blood supply of tumor, as well as facilitate accumulation of CNPs in tumor via enhanced permeability and retention (EPR) effect, to improve anti-tumor effect and reduce multidrug resistance. In this study, the visualization of embolic material of HAMs is first performed, and then nanotechnology is involved, which can be beneficial to enlarging the drug-loading range of ion-exchange microspheres, and reversing multidrug resistance and significantly improving controllability and effectiveness of chemoembolization for multiresistant hepatic carcinoma.

经动脉化疗栓塞（TACE）已成为肝癌重要治疗手段。肝癌耐药，TACE治疗中长期效果欠佳。商业化离子交换微球广泛用于肝癌的介入治疗，但在影像设备下不可视缺点使行栓塞术中监控及术后复查困难；另此类微球仅能负载荷正电的药物。前期研究我们首次制备了新型甲基丙烯酸羟乙酯-丙烯酸（HEMA-AA）离子交换微球，表现出优良的性能。本项目拟在此基础上，针对其不可视问题继续合成MRI可视HEMA-AA微球（MDHAMs）；同时制备载DOX和P-gp siRNA的复合纳米粒（CNPs），逆转肝癌耐药提高化疗效果。然后通过离子吸附，MDHAMs负载CNPs，构建化疗药物、基因共递送的新型MRI可视栓塞化疗系统，阻断肿瘤血供同时，CNPs通过EPR效应在肿瘤部位富集。本项目将离子交换微球可视化，并与纳米技术结合，实现多种类型药物的负载与共递送，逆转肝癌耐药的同时提高TACE治疗的可控性和有效性。

经导管的动脉化疗栓塞（TACE）是不可切除肝细胞癌（HCC）的一种行之有效的治疗方法。本研究通过反相悬浮聚合法制备了新型的栓塞制剂—聚（甲基丙烯酸羟乙酯-丙烯酸）离子交换微球（HAMs）及其磁共振成像可检测的聚（甲基丙烯酸羟乙酯-丙烯酸）离子交换微球（MDHAMs）。然后对两种微球进行了一系列的表征与评价，包括：形态，粒度，含水量，弹性和粘弹性，导管输送能力，细胞毒性，载药释药及血管栓塞性能，并对MDHAMs进行了包载铁的表征、铁含量测定及体内外的MRI可视特性考察。实验证实，HAMs及MDHAMs均具有优良的载药释药能力和血管栓塞性能，有望不久的将来用于肝癌的TACE治疗。MDHAMs还可以用于MRI介导的TACE术及术后的MRI复查。