新型高渗透性温敏纳米凝胶载药系统对胃癌的协同靶向治疗评价

Liver, abdominal lymph metastasis and abdominal cavity implantation metastasis are important causes of death for advanced gastric cancer. However, present treatment are not effective enough due to insufficient targeting, penetrating or sustained release pattern. Based on our previous work on the preparation of gelatinases dual-targeted miR-200c/DOC loaded nanoparticles, this program is aimed at the promotion of the effectiveness of the nanoparticle by the involvement of tumor penetrating peptide and thermosensitive hydroxypropyl cellulose hydrogel. The obtained drug loaded hygrogel will be used as an jnjectable local drug delivery system for gastric cancer treatment, especially for metastatic cancer.This study is focusing on the sustaninable and high drug concentrations in tumors as well as the synergic effect of miR-200c and DOC on the inhibition of cancer stem cells and tumor cells at the proliferative stage. We believe that our research will provide scientific evidence to develop new targeted drug carriers and transit them to clinical application.

进展期胃癌常发生肝、腹腔淋巴结和腹腔种植等局部或区域性转移，危及生命。然而局部或区域性药物治疗因药物的靶向性、穿透性和缓释性等因素影响，迄今尚无理想的治疗技术。本项目在国家自然基金前期资助发现miR-200c抑制肿瘤干细胞、增敏多西紫杉醇（DOC）的基础上，采用最新研究发现的肿瘤高渗透肽修饰miR-200c/DOC明胶酶靶向双药纳米粒子，提高药物在肿瘤组织和细胞的穿透性，并将该双靶向双药粒子载入可注射温敏羟丙基纤维素水凝胶中，得到温敏双药双靶向纳米微球水凝胶，通过肿瘤局部或区域性给药方式，研究该纳米载药体系对胃癌生长抑制作用，重点探讨该载药体系在持续性提高肿瘤内药物浓度、miR-200c与DOC对肿瘤干细胞和处于增殖期的肿瘤细胞的双重抑制效果，明确其作为一种新型的协同靶向药物控释体系在胃癌治疗中的价值，为其在临床应用提供科学依据。

在该项目中，我们首先成功制备了负载miR-200c/多西紫杉醇的双药明胶酶靶向纳米粒子，其对荷人胃癌裸鼠的抗肿瘤效果优于单药纳米粒子及裸药，对肿瘤干细胞具有一定抑制作用；最后成功构建了兼具肿瘤双靶向性和高穿透性的纳米粒子-可注射温敏羟丙基纤维素水凝胶复合给药系统，通过近红外荧光成像证实了靶向纳米粒子的高渗透性和肿瘤靶向性，是一种肿瘤局部或区域性给药模式，明显抑制胃癌的生长。本课题共发表SCI收录论文7篇，其中3篇影响因子>5.0，参加国内外学术会议3次，并获得2015年江苏省科学技术奖和江苏省医学科技奖。本项目成功构建的兼具肿瘤靶向与高穿透性的纳米载药系统在胃癌治疗中具有一定的价值与优势，为我国潜在自主知识产权的新型靶向载体药物的研制及向临床应用的过渡提供科学依据。