新型还原响应型硅酞菁类光敏剂的制备及其在肿瘤靶向诊疗中的应用研究

Photodynamic therapy (PDT) is a newly emerging cancer treatment modality that has been successfully applied in clinics. In PDT, the interplay of a photosensitizer, oxygen, and light of appropriate wavelength generates reactive oxygen species (ROS), such as singlet oxygen, superoxide anion radical, and hydroxyl radical, which in turn damages tumor cells. In comparison with surgery, chemotherapy, and radiotherapy, PDT is considered to be a clinical treatment with higher safety and fewer side effects. However, poor tumor selectivity of photosensitizers limits the wide clinical applications of PDT. In order to improve the specific anti-tumor efficacy of photosensitizers, this object decides to design and prepare a dual-functional photosensitizer based on the silicon(IV) phthalocyanine. This new photosensitizer is composed of a folate group for targeting tumor cells with overexpression of folate receptors, and a quencher moiety that can be cleaved upon encountering glutathione. The dual-functional characteristics makes the PDT effect of this new photosensitizer only available in the intracellular reductive microenvironment of tumor cells, which can effectively improve the PDT efficacy against tumor cells and lower the phototoxicity toward normal cells. The fluorescence of the photosensitizer is also recovered in response to glutathione, which means this new photosensitizer can also serve as a fluorescence probe for early diagnosis of cancers. This work will provide a promising guideline for the development of new effective PDT theranostic drugs.

光动力疗法是近年来迅速发展的一种癌症新兴治疗方法，它利用光、氧气和光敏剂共同作用产生活性氧物种，实现对肿瘤细胞的杀伤。与传统治疗方法相比，光动力疗法具有副作用小、安全性高的优点。然而，由于常规光敏剂缺乏肿瘤靶向性，在一定程度上限制了光动力疗法的临床应用。为了提高光敏剂对肿瘤组织的靶向杀伤能力，本课题拟设计合成一种兼具肿瘤特异性靶向和还原环境响应能力的双功能硅酞菁类光敏剂。这一光敏剂以叶酸基团为靶向基团，有助于增强该光敏剂在叶酸受体过表达的肿瘤细胞中特异性富集，同时联合一个可被谷胱甘肽切断的猝灭基团，使其光动力活性只在肿瘤细胞内还原环境中被激活，有效提高光动力疗效并降低其对正常细胞的光毒性。同时借助于光敏剂的还原响应荧光增强特性，也可以对肿瘤进行荧光成像，有效提高早期诊断水平。该项研究有望为新型光动力诊疗药物的研发提供新思路。

光动力疗法是一种新兴的肿瘤治疗方法。本项目旨在开发高效光敏剂以提高光动力疗法的疗效。主要研究内容如下：.（1）通过在硅酞菁中引入六甘醇（PEG6）以及生物素，设计合成了水溶性生物物受体靶向硅酞菁光敏剂。细胞以及动物实验证实，光敏剂具有优异的肿瘤靶向能力和光动力疗效。.（2）设计合成了谷胱甘肽响应型5-氨基酮戊酸(5-ALA)衍生物，该光敏剂不但克服了5-ALA类光敏剂生理条件下稳定性差的问题，也显著增强了光敏剂的靶向性。.（3）在谷胱甘肽响应型5-ALA工作的基础上，设计了一系列多功能5-ALA衍生物，它们具有生物素受体靶向以及GSH响应双靶向能力，更进一步提高了光敏剂的靶向性。此外，它们也可在胞内耗竭GSH，有效增强了PDT的疗效。.这些研究成果为设计高效光敏剂提供了理论依据和实验基础。在该项目资助下，发表了5篇SCI论文；申请了2项国家发明专利，已有一项获得授权；协助培养了一名硕士研究生。