微环境调控协同层次化“靶向-释药”策略促中药脂质体肿瘤深层递送研究

项目名称： 微环境调控协同层次化“靶向-释药”策略促中药脂质体肿瘤深层递送研究

项目编号： No.81503264

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 瞿鼎

作者单位： 南京中医药大学

项目金额： 18万元

中文摘要： 抗乳腺癌脂质体具有显著降低包埋药物的毒性、提高瘤内滞留的优势，但在改善患者生存时间上依然存在局限。基于以往对抗肿瘤药物瘤内递送规律深入研究发现，肿瘤微环境异常致使药物难以被递送至肿瘤深层是脂质体疗效不佳的主要原因。针对上述问题，本项目引入活血化瘀中药成分丹参酮IIA作为“微环境调控剂”，以雷公藤红素作为抗肿瘤成分，借助分级装配技术构建一种可层次化“靶向-释药”的脂质体。该递药系统在肿瘤外周一级释放丹参酮IIA修复肿瘤微环境，改善药物递送环境；在肿瘤深层二级释放雷公藤红素精确杀伤肿瘤细胞，提高抗肿瘤疗效。同时，采用3D瘤球模型、瘤内逐层扫描和激光共聚焦等技术评价该脂质体瘤内渗透和抗肿瘤疗效。本项目在中医药理论的指导下，整合活血化瘀中药和抗肿瘤中药的优势，构建了兼具“肿瘤深层渗透”和“肿瘤精确递送”特性的脂质体，为治疗乳腺癌寻求新突破点，也为中药多组分抗肿瘤脂质体智能化递送提供新思路和新方法。

中文关键词： 肿瘤深层渗透；脂质体；微环境调控；层次化“靶向-释药”

英文摘要： Anti-breast cancer lipsomes are capable of reducing cytotoxicity of drug and enhancing tumor-site retention greatly, however, there are still big challenges in curative effect. Based on the our previous research of anticancer drug delivery in tumor, the poor therapy effect was attributed to abnormal tumor microenvironment and consequent failure to deep penetration. Therefore, a sequential trageting-release lipsome was developed by hierarchical assembly technology using tanshinone IIA, capable of promoting blood circulation for removing blood stasis, as microenvironment regulator, and celastrol as anticancer component in this study. On the initial stage, such drug delivery system releases tanshinone IIA to modulate microenvironment and improve drug delivery at superficial tumor tissue; on the subsequent stage, it releases celastrol at deep tumor to enhance anticancer effect. In addition, 3D tumor sphere model, intratumoral layer by layer scanning and confocal laser scanning microscopy were used to evaluate the penetration and pharmacodynamics. In summary, we fabricate a “deep and accurate” tumoral delivery lipsome by integrating the superiorities of tanshinone IIA and celastrol under the guidance of traditional Chinese medicine (TCM) theory. It can not only help us to find a new breakthrough in breast cancer treatment, but also provide a novel strategy and technology to smart TCM-lipsome tumor delivery.

英文关键词： tumoral deep penetration;lipsome;microenvironment regulation ;sequential trageting-release