新型靶向输送-光控释放抗癌前药模型的设计合成及荧光成像研究

The anticancer drugs which are used by now mostly have the disadvantage that they cannot be directionally transported to the cancer cells. There are serious side effects of chemotherapy for the treatment of cancer in the clinical treatment. They kill the cancer cells at the same time damnify the normal cells severely. Therefore, it is an important issue in medicine and pharmaceutics to develop new anticancer prodrugs, which are more active and specific in killing cancer cells. The new toxicity, high anti-cancer activity of new anticancer drugs have become the historic task and serious challenge to the field of biomedicine. There are two hot points of new anticancer drug development that are intelligent controlled drugs and targeted delivery. Based on my preliminary study, folic acid as the anticancer original drug targeting carrier has no immunity non-toxic and so on. This research is the first time that the use of folic acid cancer targeting positioning, combined with light controlled release characteristics of thiochromone derivatives photolabile protecting groups. On one hand, it is folic acid on cancer cells directed targeting. On the other hand, the photo-protective based directional light controlled release targeted delivery of anticancer drugs, in order to achieve the dual directional role. The novel original drugs are designed based on aza-anthraquinone anti-cancer drugs. The anticancer prodrugs model includes three functions that are targeted delivery, photo-controlled release, luorescent drug accumulation imaging. The self-developed photolabile protecting groups conclude optical response and can release potential fluorophores. The dual release of the original drug and fluorophores is 1:1. At the same time, the simulation vivo drug release will be achieved by cell fluorescence imaging. This feature is important to carry out quantitative substrate release study to further control the photo controlled-release drug. By now, there is no anticancer prodrug that can release the parent drug with thiochromone derivatives photolabile protecting group. In addition, although the prodrug design has been widely used, there is no report with these three parts: folic acid targeting, photolabile protecting groups, and the parent drug. For the sake of proving this concept quickly and availably, the anticancer prodrug model is designed and synthesized. This research will lay the theoretical foundation for the development of anti-cancer agents and experimental basis. This project will have a significant challenge, strong theoretical significance and significant value.

目前在癌症临床治疗的化疗过程中，因抗癌原药对癌细胞定向选择性差而导致的严重副作用，已成为制约癌症治疗效果的重要因素。为此，智能控制释放和原药靶向输送已成为新药研发中的两大热点。根据前期研究：1.独立研发的硫代色酮类光敏保护基具有既对光响应又能释放潜在荧光基团的特性，在光解离过程中释放的原药和荧光基团呈1：1的线性关系，在实现癌细胞荧光成像的同时可模拟生物体内药物释放，对于在生物细胞水平上开展药物定量释放研究和光控释药具有重要意义。2.叶酸作为原药的靶向载体具有无免疫性、性质稳定且无毒易得等特点。本课题首次探讨了具有双重定向功能的新型抗癌前药模型-即叶酸的靶向定位功能与光敏保护基的光控释药功能相结合。拟设计合成的新型抗癌原药模型集肿瘤靶向输送、光控释放、荧光药物积聚度成像三功能于一体，为抗癌新药研究提供实验依据和奠定理论基础，具有极大的挑战性、极强的理论意义和重大的应用价值。

光敏保护基是一类含有对光敏感的发色基团的保护基，可以在中性和无催化试剂的条件下进行光控释放脱保护反应。本课题依据Paternò–Büchi光反应机理，设计合成了系列新型硫代色酮类光敏保护基。成功应用于羟基、氨基、羧基、磷酸基、磺酸基、炔醇等常见官能团的保护和光解离脱保护。其光解离反应是以365nm长波紫外光作为激发光源，光解离脱保护反应迅速(<15分钟)，被保护底物脱保护收率高(>99％)，无任何副反应。可以通过1H NMR和HPLC以及荧光光谱对其光解反应进行监测。该类光敏保护基具有独特的既对光响应又能释放潜在荧光基团的特性，可成功实现光控释放原药和荧光基团的1：1双释放。利用靶向性叶酸对癌细胞的定位作用，以氮杂蒽醌类抗癌药物为原药模型，结合新型硫代色酮类光解保护基的光控释放特性，设计合成了集靶向输送、光控释放、荧光成像三功能于一体的抗癌前药模型。