还原敏感触发式纳米Pickering乳递药系统的构建及靶向肝癌的研究

Hepatocellular carcinoma (HCC) is one of the most common malignancies with the lowest sensitivity to chemotherapy. Since chemotherapy is a general method for treating the HCC.However,some chemotherapy drugs such as docetaxel could provide effects for several hepatocellular carcinoma cells in vitro, the clinical tests don't show satisfactory effectson patients due to lack of specificity, damage to normal hepatic tissues and drug resistance. Therefore, it is so crucial to develop a new therapeutic strategy for the HCC. A new challenging task in treatment of the HCC with the chemotherapy is to provide a HCC-targeted drug delivery system, and enhance the sensitivity of conventional chemotherapeutic agents.In our previous studies, a stable nanoscale Pickering emulsion was developed through assembling highly deformable and amphipathic nanogels at spatially confined O/W interfaces, breaking through the micrometer scale limitation of the Pickering emulsion;the excellent ability for delivery of paclitaxel was provided; advantages of sustained release, enhancement of cytotoxicity, and prolonged plasma half-life were presented; meanwhile, the tissue distribution and the antitumor efficacy studies showed that the nanoscale Pickering emulsion could induce a higher drug accumulation at the tumor site and enhance the tumor growth inhibition. According to the previous research, we will provide a new nanoscale Pickering emulsion in the study based on the highly deformable and amphipathic nanogels,which should been prepared by the miniemulsion copolymerization of monomethyl oligo(ethylene glycol) acrylate (OEG) and allylamine, bis(2-acryloyloxyethyl) disulfide (BADS)is adopted as a crosslinker.In addition, for specifically targeting to ανβ3 receptors on hepatocellular carcinomacells and neovascular endothelial cells, cyclic pentapeptide RGD is adopted as the targeting ligand to modify the system to further increase the antitumor activity. Furthermore, reduction-cleavage of the disulfide bonds of the nanoges at nanoscale Pickering emulsion interfacescanfurther promote the intracellular drug release.Thus, the targeted and reduction-responded nanoscale Pickering emulsion provided by the study can enhance drug targeting ability for the hepatocellular carcinoma cells, control drug releasing in suit,and aid better antitumor effect in vivo with low systemic toxicity for the treatment of HCC.

肝癌是化疗敏感性最差的恶性肿瘤之一，以改善肝癌的治疗现状为目标研究肝癌靶向给药系统，增加抗肿瘤药物对肝癌的敏感性已成为肝癌治疗的主要研究方向。前期工作中我们采用两亲性、可变形纳米凝胶在油水界面组装获得稳定的纳米Pickering乳，突破了Pickering乳从微米到纳米尺度的限制，同时体现出良好的药物传输性能。针对目前肝癌药物靶向递送系统尚需解决的问题（肝肿瘤靶向特异性、靶部位定位释药、复杂体内环境下的稳定传递），本项目拟通过将还原敏感型连接臂双硫键和靶向分子cRGD肽引入至可生物降解的纳米凝胶活性位点，构建一种功能性纳米凝胶组装的纳米Pickering乳递药体系，该体系将进一步提高这种新型纳米复合系统在抗肝癌药物传递中的靶向性和在靶部位的控制释药能力，实现抗肝癌药物的安全、高效递送，改善肝癌药物治疗效果。

本项目发表SCI论文6篇，中文核心论文1篇，申请发明专利1项，已经完成预定目标2-3篇论文的研究任务；本项目培养硕士研究生4名（胡婷、胡利修、蔡萌和尚星星），其中胡婷获湖北省优秀硕士论文，2位本科生参与项目获湖北省优秀学士论文（易慧兰、张恒）；本项目针对目前抗癌药物靶向递送系统尚需解决的问题（肿瘤靶向特异性、靶部位定位释药、复杂体内环境下的稳定传递），构建靶向分子cRGD 肽修饰的还原响应型纳米Pickering乳和还原响应性的壳交联SMA聚合物胶束纳米靶向药物递送系统，提高这两种纳米复合体系在抗癌药物传递中的靶向性和在靶部位控制释药能力，实现抗癌药物的安全、高效递送，改善抗癌药物治疗效果。