肿瘤坏死组织靶向性双蒽核蒽醌的发现、合成、构效关系及其在肿瘤诊治上的应用研究

Tumor necrotic tissue is the common characteristics of malignant solid tumor and an excellent target of tumor targeted therapy and diagnosis. Our previous work revealed that hypericin belonging to anthraquinone could be targetedly distributed to the necrotic tissue. The radioactive drug with hypericin as a carrier is effective in the treatment of solid tumor, and its gamma rays can be used for tumor imaging. Previous work has proved that double-anthracene nucleus is a necessary structure for necrosis-targeting agents, and both stereostructure and substituent are closely related to the necrosis avidity. In search for lead compounds with effective targetability and good druggability, this project intends to build a library of natural product analogues of such compounds by further isolation and structure modification; to investigate the necrosis targeting property by using isotope tracer method on tumor necrosis model, meanwhile to explore structure-activity relationship, binding configuration, stereostructure, substituent group and the position of double-anthracene nucleus anthraquinone relative to their targetability. In addition, targeted radioactive drugs will be prepared with lead compounds and their anticancer effects will be studied. Furthermore, we will combine this unique targeting principle with nuclear imaging technology to explore the differencial diagnosis betweent inflammation and malignancies, which in combination with other imaging methods will further improve cancer diagnosis. The project will provide scientific background for promoting the development of the necrosis targeting drugs and clinical translational research.

坏死组织是恶性肿瘤共有的特点，也是肿瘤靶向治疗和诊断的理想靶标。课题组发现蒽醌类化合物金丝桃素能靶向分布于肿瘤内坏死组织，以金丝桃素为载体制备放射性药物，可有效治疗实体瘤，同时利用其射线对肿瘤成像。前期工作证实双蒽核结构是蒽醌类化合物具有坏死组织靶向性的必要条件，空间结构和取代基与其靶向性关系密切。为寻找高靶向性和成药性的肿瘤坏死组织靶向先导化合物，本项目拟进一步分离、半合成双蒽核蒽醌，构建化合物库；在肿瘤坏死模型上利用同位素示踪方法考察其坏死组织靶向性，研究双蒽核蒽醌的连接方式、立体结构、取代基团及其位置与靶向性之间的构效关系；选择先导化合物制备放射性靶向药物，研究其对肿瘤治疗效果，并利用其独特的靶向成像原理，结合核医学成像技术，探索其诊断区别肿瘤和炎症的应用价值，综合应用其它影像方法提高肿瘤诊断率。本项目研究将为促进肿瘤坏死组织靶向药物的开发、临床转化研究提供科学依据。