具有非靶区自身清除功能及改变肿瘤微环境的形变触发式释药系统的构建及其肿瘤穿透机制的研究

Tumor growth and progression are significantly influenced by the surrounding tumor microenvironment. It is important in anticancer therapy to change tumor microenvironment and enhance tumor penetration for drug carriers. Nano-carriers with large size may target tumor efficiently, however, they cannot penetrate tumor tissue as deeply as nano-carriers with tiny size. Unfortunately, the latter are easily trapped by normal “leaky” tissues. The absolute tumor targeting efficiency is less than 5% for targeted formulation with severe toxicity to normal tissues. To deal with these problems, a multi-functional combined drug delivery system (CDDS) will be constructed. In this CDDS, the primary carriers are hybrid liposomes with large size inside which tiny micelles are encapsulated as secondary carriers. Several strategies were employed including co-delivery and co-release drugs, enzyme degradation, structure remolding to irregular carriers, switch of particle size, and two-step biotin-avidin system to target tumor and change its microenvironment, penetrate tumor tissue and promote apoptosis of cancer cells layer by layer. Also, these drug carriers could eliminate themselves in non-targeting areas and avoid damage to normal tissues. The scientific significance of this research is to better understand a complete process for anticancer therapy. At the meantime, an effective evaluation system for tumor microenvironment will be established using a tumor model to investigate the key factors affecting tumor penetration for drug carriers. Also, this study will serve as a theoretical reference for transformable drug delivery system using combined carriers.

肿瘤部位的微环境对肿瘤细胞的生长调节起着至关重要的作用，如何克服肿瘤组织微环境并增加药物载体的渗透性是决定药效的关键；大粒径载体能够增加纳米载药系统的靶向效率却无法穿透肿瘤，小粒径载体可以有效穿透肿瘤却无法逃脱正常组织的截留；抗癌靶向制剂的绝对靶向效率尚不足5%，药物对正常组织的损伤仍普遍存在。针对以上问题，本课题设计一种多功能复合载药系统，以杂交脂质体为初级载体，小粒径载药胶束为次级载体，通过联合载药释药，酶降解作用，异型载体变构，粒径切换，以及生物素-亲和素系统的“两步法”等多个手段，靶向肿瘤组织，改变其微环境，深入穿透肿瘤，促进癌细胞层层凋亡，同时能够清除非靶区药物载体，避免对正常组织的损伤。本项目研究，将有助于进一步理解一个完整的抗肿瘤过程，并建立全面评价肿瘤微环境的细胞模型，探索实现肿瘤穿透的关键问题，同时也为复合型变构载药系统的研发提供前瞻性的成果借鉴。

本项目从载体的肿瘤穿透性以及安全性入手，设计以杂交脂质体为初级载体、小粒径载药胶束为次级载体的复合载药系统，通过联合载药释药，酶降解作用，异型载体变构，粒径切换，以及生物素-亲和素系统的“两步法”等多个手段，使载体携带药物靶向肿瘤组织，通过改变其微环境，深入穿透肿瘤递药，促进癌细胞层层凋亡，同时能够清除非靶区的药物载体，避免对正常组织的损伤。. 结果表明，所构建的复合载体粒径约为200nm，在肿瘤部位能够发生形态和粒径的切换，外膜变构成盘状载体，并释放出内部的小粒径胶束（约30nm），在完成肿瘤靶向后，可摆脱受-配体结合的束缚，实现对肿瘤组织的深层穿透。当生物素与亲和素的摩尔比为880:1时，肿瘤/血液内药物的浓度比最大，可达7.5，且在其他正常组织的分布量最小。与对照制剂及非亲和素清除的制剂相比，生物素修饰的复合载体在亲和素清除后，能够达到最佳的抗肿瘤药效和安全性。. 项目研究成果如下：. 1、已发表论文9篇，其中SCI论文6篇，中文期刊论文3篇；. 2、申请发明专利1项，已公开；. 3、主办或参与国际学术交流会议2次、国内学术交流会议7次，发表会议论文6篇。