番荔枝内酯防治肿瘤的关键科学问题及纳米靶向制剂成药性研究

项目名称： 番荔枝内酯防治肿瘤的关键科学问题及纳米靶向制剂成药性研究

项目编号： No.U1401223

项目类型： 联合基金项目

立项/批准年度： 2015

项目学科： 管理科学

项目作者： 王向涛

作者单位： 中国医学科学院药用植物研究所

项目金额： 243万元

中文摘要： 番荔枝是我国具有丰富资源的岭南药材，番荔枝内酯是其特有的一类长链脂肪酸内酯化合物，其强效抗肿瘤活性、独特的机理（作用于线粒体呼吸链）、能逆转多药耐药等特性，使其一度成为国内外抗肿瘤药研究热点。但其水不溶、成分复杂、含量测定困难等特点，尤其是药效太强而带来难以接受的毒副作用，使进一步研究开发陷入困境。本项目针对番荔枝内酯成药性中存在的这些关键科学问题，对总内酯有效部位，拟通过纳米技术、被动靶向、主动靶向、荧光探针示踪等加以解决；而对总内酯中药效强、含量较高的成分，分离出单体，尝试制备更高靶向治疗作用的抗体偶联药物。本项目还首次提出了“抗体结合药物”的研究设想，借助于番荔枝内酯与β-环糊精较强的包合作用，尝试通过接枝在单抗上的环糊精的物理包合作用将番荔枝内酯单体甚至总内酯有效部位“结合”到单抗上。利用纳米靶向给药对难溶性中药有效部位减毒增效，提高成药性，类似研究鲜有报道。

中文关键词： 番荔枝内酯；抗肿瘤；纳米粒；靶向给药；抗体

英文摘要： Annona squamosa is resourceful medicinal materials in Lingnan Region in south China. Annonaceous acetogenins (AAGs) are long chain fatty acid lactone unique in Annonaceae plants. Due to their potent anti-tumor activity, unique mechanism of targeting at mitochondrial respiratory chain, the ability to reverse multi-drug resistance and the absence of mutagenesis, AAGs have once been the research focus for anti-tumor drugs. However the further R & D is deeply beset with their water insolubility, complex components, difficulty in quantitative determination as the result of very low UV absorbance, especially the unacceptable serious adverse effect accompanied with their potent efficacy, Aiming at these key druggability issues for AAGs, such technologies as drug-loading nanoparticles, passive tumor-targeting, active tumor-targeting and fluorescence probing are proposed to tackle these problems. As for the very potent compound further isolated from AAGs, antibody-drug conjugate (ADC) is proposed as a strategy to further enhance its tumor-targeted therapeutic efficacy. Inspiring by the concept of antibody-drug conjugate, a new concept of antibody-drug complex is conceived, for which drug is linked to antibody based on physical interaction by the help of the strong β-cyclodextrin inclusion of long fatty chain AAG(s) while the β-cyclodextrin molecules have been conjugated to antibody in advance. Using nano- and targeted drug delivery systems to reduce adverse effect, enhance therapeutic efficacy and improve the druggability for the effective fraction of Chinese medicinal herbs which contains multiple components, is the characteristic feature of this proposal and similar research has been seldom reported.

英文关键词： Annonaceous acetogenins;anti-tumor;nanoparticles;targeted drug delivery;antibody