铂类-黄酮类药物-药物共晶设计及其协同增效机理研究

Malignant tumor is a kind of common disease which seriously threatens the life and health of human. Platinum-based drugs are commonly used to treat malignant tumors. Platinum drugs are mainly administered via intravenous injection, and prone to serious side effects and drug resistance, which seriously limit their clinical application. Development of novel and oral platinum drugs with high efficiency and low toxicity is an important research direction in the development of platinum drugs and also the need of national health. At present, the new types of platinum drugs are mainly modified by chemical structure modifications, but few studies on its synergistic effect have been conducted. Based on this, this research project intends to take satraplatin as the research object, constructing novel platinum-flavonoid (drug-drug) cocrystals with anti-tumor flavonoid compounds. Based on the differences in the properties of flavonoid ligands, the platinum-flavonoid cocrystals with different properties will be prepared through the high throughput screening. The physicochemical properties of platinum-flavonoid cocrystals and their anti-tumor activities in vitro and vivo will be investigated to obtain the optimized platinum-flavonoid cocrystals with synergistic effect. The relationship among properties of flavonoid ligands, physicochemical properties, and antitumor activities of platinum-flavonoid cocrystals will be studied, which can help to explore the synergistic mechanism of platinum-flavonoid cocrystals and find rules to design the platinum-flavonoid cocrystals with adjustable physicochemical properties and cytotoxicity. The study will provide the theoretical support and basic data for the design and application of the platinum drug cocrystals. Constructing platinum-flavonoid cocrystals is expected to behave as a complementary method of building platinum-based drug complex.

恶性肿瘤是一类严重威胁人类生命健康的常见病，铂类药物是常用的治疗恶性肿瘤药物。铂类药物主要采用滴注给药，且易产生严重的毒副作用和耐药性，严重限制了其临床应用。高效低毒可口服的新型铂类药物是铂类药物发展的一个重要研究方向，也是国民健康需求所在。目前新型铂类药物主要通过化学结构修饰改造，但对其协同增效研究较少。基于此，本课题拟以赛特铂为研究对象，将其与黄酮类抗肿瘤化合物构建新型铂类-黄酮类药物共晶复合物。基于黄酮类配体的性质差异，高通量制备性质差异化的铂类-黄酮类药物共晶复合物。考察铂类-黄酮类共晶的理化性质和其体内体外抗肿瘤活性，优选得到协同增效的铂类-黄酮类共晶。研究黄酮类配体性质与药物共晶理化性质和体内外抗肿瘤活性的影响关系，探索其协同增效机理，并以此来寻找理化性质和细胞毒活性可调的药物共晶设计规律，为铂类药物共晶的设计和应用推广提供理论依据和基础数据，丰富铂类复合物的构筑手段。

恶性肿瘤是一类严重威胁人类生命健康的疾病，铂类药物是常用的治疗恶性肿瘤药物。铂类药物主要采用滴注给药，且易产生严重的毒副作用和耐药性，严重限制了其临床应用。高效低毒可口服的新型铂类药物是铂类药物发展的一个重要研究方向。基于此，本课题以二价铂类药物奥沙利铂（OXA）、基于奥沙利铂的四价铂Pt（IV）前药为研究对象，考察铂类药物共晶的理化性质及其抗肿瘤活性，优选得到协同增效的铂类药物共晶。研究配体性质与药物共晶理化性质和抗肿瘤活性的影响关系，探索其协同增效机理，并以此来寻找理化性质可调的药物共晶理性设计，丰富铂类复合物的构筑手段。.将OXA与黄酮类抗肿瘤化合物构建新型铂类-黄酮类药物共晶复合物，成功制备了奥沙利铂-黄芩素(OXABAI)、奥沙利铂-柚皮素(OXANAR)两种药物药物共晶，并解析了其晶体结构。OXABAI、OXANAR降低了OXA的溶解度和溶出速率，改善了其在溶液中的稳定性。黄酮类配体的抗肿瘤性质不但改善了铂类药物共晶的理化性质，同时增强了其体外抗肿瘤活性，并降低了对正常细胞的毒性，具有协同增效的效果。通过共晶晶体结构的分析与相互作用的量化计算，得到了二价铂类药物共晶理化性质调控的设计规律，为铂类药物共晶的设计和应用推广提供理论依据和基础数据。.将奥沙利铂基Pt (IV)配合物DHOXA与苯甲酸(BA)、水杨酸(SA)、对苯二酚(HYD)、3,5-二氟苯甲酸(3,5- da)、3-羟基-2-萘酸(3H2NA)和草酸(OA)制备共晶，对其进行了系统的固态化学表征，并解析了晶体结构。基于配体性质的差异，得到溶解性、溶液稳定性和还原性不同的药物共晶，可以实现四价铂类前药的理化性质调控。DHOXA-HYD-DH共晶的形成增强了铂类药物在强酸溶液中的稳定性，具有潜在的口服给药应用。细胞毒性研究表明DHOXA-HYD-DH共晶的两个组分产生协同作用，通过共晶技术初步实现了四价铂类抗肿瘤前药的高效、低毒的协同作用。.本课题的完成为铂类药物共晶的实验研究提供可靠的理论方法支持，为铂类药物共晶的设计和应用推广提供理论依据和基础数据，具有较高的应用前景和良好的社会效益。