自凝胶和自释放功能性纳米载体肿瘤定位持续释放siRNA与化疗药物

The co-delivery of siRNA and anticancer drug by nanotechnology is a promising approach to overcoming the multidrug resistance of cancer cells and enhancing chemotherapy efficiency. However, the lack of effective methods for sustained and targeted drug delivery to the tumor site is the major obstacle for the co-delivery of siRNA and anticancer drug in clinical application. The nanocarriers with targeted modification and long circulation could improve the tumor targeting transport efficiency at some extent by the blood circulation and EPR effect of tumor, but only less of drugs were targeted to tumors because of the fast clearance from the blood circulation and the unstability of the nanoparticles in blood.Tumor local injection of nanoparticles is an effective way to overcome the blood circulation obstacle, but the nanoparticles quickly outflow from the tumor site.This project plans to optimize the design of the nanocarriers with temperature-sensitive in situ gelation, which will transport and anchor the nanoparticles with high doses of siRNA and chemotherapeutic drugs to the tumor site. By means of dual drug controlled release mechanism of sustained release of nanoparticles from gel at the tumor site and tumor intracellular release of siRNA and drug from nanoparticles, the efficient and long-acting antitumor effect will be achieved. Using ovarian tumor as model, we will investigate the anchoring tumor co-delivery, antitumor effect and mechanism of siRNA and chemotherapy drugs at molecular, celluar and animal level via intraperitoneal injection of the nanoparticles with self-gelation function. As a result, the basis will be provided for siRNA, anticancer drug and their combination and intratumor therapy.

通过纳米载体共输送siRNA与化疗药物是克服肿瘤耐药性、提高化疗效果的有效途径，但如何连续靶向输送到肿瘤部位是问题的关键。靶向修饰及长循环型纳米载体经血液循环和肿瘤EPR效应能够提高靶向递送效果，但由于血液循环的快速清除作用和纳米粒的血液稳定性等问题，到达肿瘤组织的药物仍很少。肿瘤局部注射纳米粒是克服血液循环障碍的有效途径，但存在纳米粒很快从肿瘤部位流失等问题。本项目拟通过温敏原位凝胶性纳米载体的优化设计，把高剂量的siRNA 与化疗药物的纳米粒输送并锚固到肿瘤部位，通过肿瘤部位持续释放纳米粒和纳米粒在肿瘤细胞内释放siRNA 和药物的双重可控释放机制，达到高效、长效抗肿瘤效果。以卵巢癌为肿瘤模型，通过腹腔局部注射纳米粒自凝胶系统，在分子、细胞和模型动物水平上研究纳米载体对siRNA 和化疗药物的肿瘤定位输送功能、抗肿瘤效果与机理，为siRNA、化疗药物及其联合应用和肿瘤介入治疗提供依据。

预期目标：.（1）建立siRNA、化疗药物及共负载纳米粒可注射温敏原位凝胶给药系统和安全、可控的肿瘤定位给药技术，为高效、安全的肿瘤定位给药新剂型的开发奠定基础。.（2）在分子、细胞和模型动物水平上，初步揭示siRNA与药物共输送的纳米递送系统降低肿瘤耐药性、提高化疗效果的作用机理，为纳米载体共输送siRNA和药物、促进卵巢癌治疗效果提供理论依据。.（3）发表高水平论文6篇以上，申请及获得发明专利2项。.（4）培养材料学和生物医学领域的交叉性人才，培养青年科研骨干1名，博士研究生4名，硕士研究生2名。.完成情况：.主要根据肿瘤微环境的特点，从分子、细胞和模型动物水平上针对两亲性共聚物及其自组装核壳结构纳米粒进行结构设计、制备和功能性评价；研究了PECT纳米粒温敏凝胶的性能改善、化疗药物的共递送和腹腔注射给药；建立了一种siRNA、化疗药物共递送的载药纳米粒超分子水凝胶，初步揭示了siRNA与药物共输送的纳米递送系统降低肿瘤耐药性、提高化疗效果的作用机理，为高效、安全的肿瘤定位给药新剂型的开发奠定基础。.在Acta Biomater，ACS Appl Mater Interfaces，Biomater Sci-UK和Macromolecular Bioscience 等期刊上发表 SCI检索论文18篇；申报发明专利 4 项，其中2项获得授权。培养一位讲师晋升副教授。培养博士研究生 6名，其中毕业3名，培养硕士研究生11名，其中毕业9名。