具有长波敏化功能的竹红菌甲素靶向载药体系的构建及其光敏抗肿瘤活性

Hypocrellin A is an effective photosensitive anti-cancer drug in the field of photodynamic therapy. However, it can only be used in superficial disease and there are three reasons hampering its application to treat soid tumor. The first reason is hypocrellin A is hydrophobic, and therefore, preparation of pharmaceutical formulations for parenteral administration is highly hampered. The second reason is it don't have cancer targeting ability. And the third reason is its low absorption in the photodynamic window. To solve above problems, a new drug delivery system was designed by simultaneously encapsulating hypocrellin A and upconversion nanocrystal into tumor targeting molecules modified core-shell silica nanoparticles. When excited by an 980nm infrared source, strong visible bands appear around 470nm to excite hypocrellin A to generate reactive oxygen species. And finally, we will get a multi-function system of hypocrellin A, which can be effectively delivered in blood,active target to tumor and sensitized using infrared source. In this project, the sensitized process and mechenisms of upconversion nanocrystals to hypocrellin A wiil be deeply reserched. Beside, the influence of encapsulation effect by silica nanoparticle preparation way, the in vivo tumor targeting ability and solid tumor treating effect will be discussed. All the research results would greatly improve the clinical application of hypocrellin A to treat solid tumor in the field of photodynamic therapy.

竹红菌甲素是一类光敏化活性高、可用于新型肿瘤治疗手段- - 光动力疗法的天然光疗抗癌药。针对其靶向性差、无法直接静脉注射给药及与其相匹配的470 nm治疗光源组织穿透深度浅等三个制约其临床应用进程的关键问题，本项目设计并构建出同时装载竹红菌甲素和上转换晶体、并在载体表面修饰肿瘤靶向分子的核壳结构纳米二氧化硅给药体系；探索与竹红菌甲素敏化需求相匹配的上转换晶体的影响因素与规律，确立980nm近红外光源激发装载体系中的上转换晶体敏化竹红菌甲素（所需470nm可见光敏化）的效率及机制；得到在血液内有效传输且靶向肿瘤组织、近红外光源激发并敏化的载药体系。总结出纳米载药体系的构建条件及载体结构与其光敏抗肿瘤活性间的关系，筛选得到具有治疗体内实体肿瘤活性的竹红菌甲素纳米载药体系。本项目的开展将推动竹红菌甲素光动力治疗体内实体肿瘤的临床应用进程。

光动力疗法是一种新型肿瘤治疗手段，竹红菌甲素是一种抗肿瘤活性很高的光疗药物。但因其水溶性差，无法直接静脉注射给药、肿瘤靶向性差及与其匹配的470 nm治疗光源组织穿透深度浅等问题，无法用于体内实体肿瘤的治疗。为在同一系统内同时解决上述瓶颈问题，本项目设计构建了同时装载竹红菌甲素及上转换晶体的核壳结构纳米二氧化硅载体，并在上述体系中加入叶酸及Fe3O4纳米粒子，使体系具有肿瘤靶向及核磁成像的同步诊疗功能，叶酸通过与肿瘤细胞表面高表达的叶酸受体结合而实现肿瘤靶向功能。Fe3O4纳米粒子不仅能够提供体系的磁靶向功能，还能在治疗的同时进行T2核磁造影成像，实现体内实体肿瘤的同步诊疗。体内及体外研究表明，体系具有良好的实体肿瘤靶项功能，使用980 nm激光激发后，体系可有效产生活性氧杀灭肿瘤细胞。此外，在项目的资助下，项目组还开展了上转换纳米材料与生物大分子的相互作用研究、基于环糊精主客体相互作用的新型自组装长波敏化体系及针对上转换纳米材料特性进行的新型光敏药物设计合成等研究。