光诱导诊疗联用肿瘤诊治前药的构建与应用研究

The fusion of diagnostics and therapy for optimizing efficacy and safety of antitumor drug ,which is a growing direction of tumor therapy that is paving the way towards the goal of personalized medicine for the benefit of patients. Driven by this need,the purpose of this project is to gain the ability to image and monitor the diseased tissue,delivery kinetics, and drug efficacy with the long-term hope of gaining the ability to tune the therapy and dose with heretofore unattainable control. Herein we will design and synthesis of a theranostic prodrug based on‵folate -antitumor drug-NIR(near infrared) cyanine dyes′with cell-specific,light activat -able photoacid and pH-responsive release antitumor drug. The title prodrug also will be studied following parts: prodrug synthesis,the optimization of the photoreaction conditions and technological parameters, in vitro drug release study for kill cancer cell,and in vitro activation of a prodrug for imaging.Therefore, our research are expected to have significant impact on future personalized strategy for tumor treatment,and to improve the tumor treatment effect,enhance the tumor patients′quality of life and prolong the survival period, relieve their economic burden.

高效、安全和经济的具诊断与治疗功能的抗肿瘤药物是未来个性化肿瘤治疗的发展方向。为发展一种具有药物靶向传递和药物剂量控制及肿瘤诊断与治疗于一体的个性化诊治联用前药，本项目从分子设计层面出发，基于叶酸偶联药物能被叶酸受体(FR)特异性表达于肿瘤细胞膜表面、花箐染料分子的荧光成像与光致酸、C=N官能团易受酸断裂释药特性。拟通过花箐近红外荧光染料为分子骨架，构建"叶酸-抗肿瘤前药-荧光染料分子"的具有细胞特异选择性--光激活释酸--酸响应释药的诊疗联用肿瘤诊治前药。并通过前药研制、光控释酸与释药条件考察、荧光成像性能、体外药效学评价对目标前药进行研究。本项目的开展对个性化肿瘤防治策略的发展，改善肿瘤治疗效果，减轻患者经济负担，提高患者生存质量具有重要意义。

单分子具有诊断和治疗性能的抗肿瘤前药备受关注。为此，本项目将化学治疗、光动力治疗与荧光成像诊断、MRI成像诊断整合与一个分子中并开展了体内外性能研究。先后构建了花箐染料偶联氮芥化疗药物、罗丹明衍生物与氮芥、Gd-DTPA与5-氟尿嘧啶偶联物偶联物以及4-氨基喹唑啉氮芥偶联物系列工作。将上述获得的先导化合物先后进行了光激活体外释放药物、光刺激与光动力效能、体内外成像诊断性能、体外靶向性能、生物相容性、药效学等方面的研究。经上述研究发表研究论文10篇，被SCI收录5篇，获得授权发明专利1项，获得成果奖2项。项目的开展对将来的个性化肿瘤治疗策略的发展、改善肿瘤治疗效果，对于减轻患者经济负担，提高患者生存质量具有十分重要意义。