石墨烯基仿生光控递药体系的构建及其在肝癌多模式治疗中的应用

Liver cancer was known as "King of the cancer", which has a high degree of malignancy, a rapid development and a poor efficacy of mono-therapy mode, so multi-modal therapy has become a trend in the treatment of liver cancer. The project intends to build a new bionic drug delivery system, setting targeted delivery property, light-controlled drug release performance and photo-thermal therapy efficacy as a whole. Specific ideas are as follows. (1) the preparation of reduced graphene oxide (rGO) via light reduction and the use of it as a drug delivery matrix and a photo-thermal media; (2) the use of phospholipid as the membrane, to improve the dispersion of the drug delivery system under physiological conditions on the one hand, and to endow the drug delivery system temperature-sensitive drug release performance on the other hand; (3) the connection of rGO with small molecule ligands to achieve targeted delivery to liver cells; (4) the use of near-infrared laser as the remote-contol media, to regulate drug release via the changes of the permeability of the lipid membrane trigged by the photo-thermal effect of graphene on the one hand, and to kill cancer cells via its photo-thermal effect on the other hand. The system integrates the high drug loading capacity of graphene and good compatibility of liposome, meanwhile takes the advantages of both strong photo-thermal effect of graphene and good temperature-sensitive controlled release performance of liposome, which is expected to achieve efficient inhibition of hepatocellular carcinoma. This paper will study the building of the drug delivery, evaluate the in vitro and in vivo mechanism of the carrier systems, and study the laser-trigged drug release patterns and anticancer mechanism of the drug delivery system. The aim the study is to clarify the relationship between the components of system and their efficacy to liver cancer, meanwhile to build the relationship between laser irradiation and the anti-cancer effect of the drug delivery system. The study will provide a theoretical basis and experimental evidence for laser-controlled multi-mode liver tumor treatment.

肝癌素有“癌中之王”称号，其恶性程度高，扩散快，单一治疗模式疗效差，因此多模式治疗成为发展趋势。本项目拟构建新型仿生光控递药体系，集靶向递送、光控释药和光热抗癌为一体。具体思路：（1）采用液相光照法还原制备还原氧化石墨烯（rGO），作为递药基体和光热介质；（2）以仿生磷脂为膜材，既改善载药rGO在生理条件下的分散性，又能够赋予体系温敏释药性能；（3）引入小分子靶向配体修饰，实现递药体系的靶向传递；（4）利用光照对治疗进行远程调控，一方面利用rGO光照产热触发磷脂膜通透性增加及药物释放，另一方面利用其热能杀伤癌细胞，协同抗癌。该体系集成了rGO载药量大、光致发热效率高和磷脂膜生物相容性好、热敏控释性能佳的优势，有望实现光控热疗-化疗协同作用，高效抗癌。本项目将研究体系的构建方法，评价其体内外疗效，阐明体系的光触释药规律及光控抗癌机理，以期为肝癌的光控多模式治疗提供理论基础和实验依据。

恶性肿瘤发生发展迅速，且癌细胞易对化学药物产生多重耐受，致使单一的化疗往往不能满足肿瘤治疗需要，多种治疗手段联合应用成为发展趋势。本项目成功制备得到少层小尺寸（片层厚度1-2 nm、片径400 nm以下）、高分散性的氧化石墨烯纳米材料，为其生物应用提供了条件；引入脂质体包裹，构建了仿生递药体系（GO-lipo），有效改善了GO及载药材料在生理条件下的分散性能；考察了复合递药体系的药物释放行为及入胞能力、抗癌疗效等，完成了实验的既定目标。.. 在此基础上，为了进一步增强GO材料的光热性能，实现化疗和光热治疗的协同，在GO表面引入金纳米粒修饰和超顺磁纳米粒修饰并采用脂质体包裹，分别构建了两个在生理条件下能够稳定分散的体系（GO-Au/lipo和mGO-lipo）。评价了复合递药体系的药物释放行为及入胞能力、抗癌疗效等，并着重考察了体系的光照升温能力和体内外光照肿瘤消融效果。此外，构建小鼠肿瘤模型，考察了复合材料的体内分布和近红外光照射下瘤内升温能力。研究表明，脂质体包裹不仅能够增强层状二维材料的分散性能，减少团聚，还能促进材料的瘤内分布，实现了光热疗-化疗协同作用，增强了抗肿瘤疗效。上述研究为本课题研究目标的延伸。.. 此外，研究在成功制备小尺寸GO的基础上，还围绕GO材料的层层自组装修饰展开。利用层层自组装技术成功制备了一系列天然高分子聚合物非共价修饰的氧化石墨烯基复合材料（GO-CS/SA、GO-CS/DEX、GO-PRM/SA等），有效改善了载药体系生理条件下的稳定性。进一步引入超顺磁纳米粒修饰，制备得到GO-IONP- CS/DEX、mGO-CS/SA等复合材料，实现了复合体系的磁靶向递送及光热疗-化疗协同作用。该研究系本课题的有益扩展，拓宽了GO基材料的生物应用。