增强肿瘤渗透性的智能化光响应性尺寸可变的纳米载药系统研究

The aim of antitumor drugs is to reach effectively the tumor site and kill tumor cells. However, multiple biological barriers hinder the diffusion of drug to the interior of tumor, which is difficult to reach the core region of tumor, inducing the survival of stem cells and tumor recurrence. The study is to design a kind of stimulus responsive nanodrug delivery system, which can be delivered to the tumor deep section by changing sizes to overcome physical obstacles based on near infrared (NIR) responsiveness. The initial sizes of intelligent core - shell drug carriers are 100-150 nm, which is benefit for the accumulation of carriers at the tumor targeting in the body. When arriving at tumor site, under NIR irradiation, the outer gold-shell of drug liposomes will burst and release the loading drug and inner drug - gold nanoparticles of 20-30 nm. Then the small inner-carriers will be delivered to the core of tumor and kill effectively the deep tumor cells through the synergy of chemotherapy and photothermal therapy. Meanwhile, the delivery rule and the related mechanism of drug delivery carriers entering tumor will be explored by regulating the drug carrier particle size, shape, surface functional groups and charges. Furthermore, the internal relations about transfer speed, depth and thermal efficiency of the system will be studied when the drug system enters the tumor tissue, and the related factors for influencing the carrier size change and release will be illuminated to realize the tumor complete cure.

抗肿瘤药物的目标是有效到达瘤内实现对瘤细胞的彻底杀伤。然而多个生物学屏障限制了药物在肿瘤内部的扩散，使药物难以到达肿瘤深部，导致深部的干细胞存活和肿瘤复发。本项目旨在设计合成一种刺激响应性的纳米载药系统，该系统通过对近红外光（NIR）响应性改变粒径以克服生理障碍，递送到肿瘤深部。该智能化的核-壳结构药物载体的初始粒径为100-150nm，利于载体在体内的肿瘤靶向聚集；到达肿瘤部位后经NIR照射，外层金球壳载药脂质体破裂，释放包载的药物和内核的20-30 nm药物-金纳米粒子，内核载体递送至肿瘤深部，通过化疗和光热治疗的协同作用实现对肿瘤深部细胞有效杀伤。在此过程中通过对药物载体的粒径、形状、表面功能基团和带电性调节，深入探究药物载体在肿瘤内部的递送规律及相关机制，研究载药系统在肿瘤组织内的传递速度、递送深度和产热效率的关系，以及影响载体尺寸改变和释放的相关因素，以实现肿瘤的彻底治愈。

抗肿瘤药物的目标是有效达到瘤内实现对肿瘤细胞的切底杀伤。然而多个生物学屏障限制了药物在肿瘤内部的扩散，使药物难以达到肿瘤的深层，进而导致肿瘤深层干细胞存活和肿瘤复发，这也是目前癌症治疗中的瓶颈问题。本项目通过多种方式使药物克服生理障碍，靶向递送至肿瘤深处，实现纳米药物治疗效果的强化。重要研究成果包括：（1）利用大尺寸纳米药物的肿瘤高度靶向与小尺寸纳米药物的深度渗透性能，设计合成基于尺寸变构型纳米药物，实现在肿瘤位点在近红外光响应下结构瓦解，从而提高纳米药物的渗透效率；其次，通过细胞的转胞吞作用，实现纳米药物的细胞内-细胞间的连续传递，通过细胞主动运输的方式将纳米药物递送至肿瘤深部，从而提高纳米药物的渗透效率；（3）由于肿瘤处淋巴回流缺失导致大量肿瘤间质液滞留，造成异常增高的肿瘤间质压力阻碍着药物的瘤内运输，项目利用化学能激发的光催化以及近红外光响应的热电催化分解肿瘤间质液中的水，使肿瘤间质液体积减少，从而降低肿瘤间质液压，从而提高纳米药物的瘤内渗透。本项目共发表SCI论文43篇，授权中国发明专利12项，培养人才16名；超额完成合同书规定的任务。