生物素介导靶向光动力治疗-化疗联用抗癌药物的合成及构效关系研究

项目名称： 生物素介导靶向光动力治疗-化疗联用抗癌药物的合成及构效关系研究

项目编号： No.21471033

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 环境科学、安全科学

项目作者： 刘见永

作者单位： 福州大学

项目金额： 80万元

中文摘要： 提高光敏剂的靶向性和增强光动力治疗与化疗的协同作用是光动力治疗领域研究的焦点。本项目拟通过Cu（I）催化的点击化学将化疗药物香豆素和靶向配体生物素逐步共价键连到双炔基功能化的酞菁环上，制备一系列兼具靶向、光动力治疗、化疗特性的轭合物。该轭合物中的生物素基元能与肿瘤细胞表面过度表达的生物素受体强烈作用，从而实现药物在肿瘤组织中的特异性摄取，同时提高光动力治疗和化疗的选择性，并增强二者之间的协同作用，以达致提高治疗效果，降低副作用的目的。研究这些轭合物在水溶液中的基本光物理化学性质，包括光学稳定性﹑聚集状况和产生单线态氧的能力，探索这些轭合物对人癌细胞HepG2﹑HT29、MCF-7、Hela、A549和正常细胞HELF的摄取率﹑体外抑制活性。分析比较这些数据，将能揭示这些轭合物的构效关系。该研究将为开发高效、低毒抗癌药物提供新的思路，具有十分重要的理论指导意义和实际应用价值。

中文关键词： 光动力治疗；酞菁；抗肿瘤；生物素；香豆素

英文摘要： Recently, there has been considerable interest in the development of targeted photosensitizers and combining photodynamic therapy with anticancer chemotherapy. Both aims to enhance therapeutic efficacy, and reduce side effect and retarded drug-resistance problem. In this project, a series of biotin-phthalocyanine-coumarin conjugates will be synthesized by treatment of a zinc(II) phthalocyanine derivative bearing two acetylene groups with azide-substituted coumarins and biotins via click chemistry catalyzed by Cu(I). The resulting conjugates containing biotin moieties can strongly interact with biotin receptors overexpressed in the tumor cells, leading to their specific localization on the tumor cells. As a result, the conjugates will exhibit a highly selective treatment to tumor tissue over normal tissue and a synergistic effect of combination of photodynamic therapy and chemotherapy will be observed. The basic photo-physical and -chemical properties of these conjugates, including optical stabilities, aggregation behaviors and singlet oxygen generation efficiency will be investigated in aqueous solution. The cellular uptakes and photodynamic activities of all these conjugates on HepG2, HT29, MCF-7, Hela and A549 cancer cells, and HELF normal cells will also be explored. The structure-activity relationships of these anticancer drugs will be revealed by analysis and comparison of all these data. By this study, it is expected to establish the methods of synthesis and purifications for biotin-phthalocyanine-coumarin conjugates; it is also expected to offer a paradigm for both targeted treatment and combination of photodynamic therapy and chemotherapy, which is very significant for both theoretical study and practical application.

英文关键词： PDT;phthalocyanine;antitumor;biotin;coumarin