生漆是我国重要的林产品,生漆中漆酚具有抗肿瘤生物活性。由于漆酚易过敏、氧化和聚合,不饱和漆酚(USU)单体分离困难,限制漆酚药物开发应用。本研究以精制USU为原料，研究漆酚活性基团缩醛保护和D-A化学修饰机理,通过中压柱和逆流色谱分离邻苯二酚型USU丙烯酸酯。研究USU丙烯酸酯酰胺化和脱保护反应,以半乳糖(Gal)为靶向配体,通过改变PBAE和PEG分子量,调控疏水/亲水平衡比例,设计合成pH-响应USU-PBAE-PEG-Gal两亲聚合物,并通过两亲靶向配体TLS11a-C18和CendR-C18制备漆酚两亲聚合物胶束,研究其合成机理和结构特征,阐明漆酚两亲聚合物胶束负载DOX或紫杉醇等抗癌药体外药物缓控机理, 评价其药物负载能力和释放性能。对比分析不同胶束靶向载药体系的体内分布性能和体内抗肿瘤效果,阐明生漆不饱和烷基酚联合化疗药抗肿瘤减毒增效的机理,为漆酚抗肿瘤药物开发提供基础。

Raw lacquer is a kind of important forest products in China, its main active constituents of urushiol possess prominent antitumor biological activity. However, as urushiol can cause hypersensitive reaction, it is sensitive to oxidation and polymerization, and the separation of unsaturated urushiol (USU) monomers are difficult, so the application of urushiol in drug development will be limited. In this study the refined USU in raw lacquer will be used as raw material, we will study acetal protection and D-A chemical modification mechanism of active groups of urushiol, and separate catechol USU acrylic ester by medium pressure column and countercurrent chromatography. We will design and synthesize pH- responsed USU-PBAE-PEG-Gal amphiphilic polymers, by the amidation and deprotection of USU acrylic ester , with galactose (Gal) as targeting ligands, and by regulating the proportion of hydrophobic/hydrophilic balance via changing the molecular weight of poly amino ester (beta) (PBAE) and polyethylene glycol (PEG). Moreover, urushiol amphiphilic polymer micelle will be prepared with the amphiphilic targeting ligands of TLS11a-C18 and CendR-C18. Meanewhile, the synthesis mechanism and structure characteristics of amphiphilic polymer micelle will be studied, the in vitro slow control mechanism of urushiol amphiphilic polymer micelle loaded with anti-cancer drugs of DOX or paclitaxel will be clarified, and its drug loading capacity and release performance will be evaluated. We will comparatively analysize in vivo distribution performance and in vivo antitumor effects of different targeting drug system of micelle, in order to clarify mechanism of antitumor attenuated synergies of unsaturated alkyl phenol in raw lacquer combined with chemotherapeutic drugs, which will provides the basis for the antitumor drug development of urushiol.