氮掺杂石墨烯量子点双光子光敏剂的制备及其光动力学抗肿瘤应用

Photodynamic therapy has been recognized as one potential cancer therapeutics because it has some advantages, such as good selectivity, less invasiveness, and low systemic toxicity as compared with three traditional therapeutics including operation, radiotherapy and chemotherapy. As one of the essential elements in photodynamics, photosensitizer (PS) plays an important role in the photodynamic therapy for cancer. After decades of efforts, the performance of the PS has been greatly elevated. However, some disadvantages such as limited photodynamics activity, poor water solubility and targeting ability still exist among the PS of the clinical used and studied and thus hindering their further application. To address these problems, a novel PS system composed of the nitrogen-doped graphene quantum dots (N-GQDs) and the RGD modified-zinc porphyrin (ZnP)-contained cytochrome C will be designed and synthesized. By using the N-GQDs complexed with ZnP as the two-photon photosensitizer, and the soluble cytochrome C and RGD peptide as the drug carrier and target molecule, respectively, we can achieve the two-photon photodynamic therapy with high efficiency and selectivity. The project can provide new evidence for the development of novel PS for the most effecitive and safest cancer therapy.

相比于三大传统疗法，化疗、放疗和手术治疗，光动力学治疗具有选择性较好、创伤小、毒性低等优势，被认为是一种非常有前景的肿瘤治疗方法。作为光动力学的核心要素之一，光敏剂在肿瘤的光动力学治疗过程中发挥着重要的作用。经过几十年的努力，光敏剂的性能已经在有了很大的提高。但是，目前临床使用和进入临床研究的光敏剂依然存在着光动力学活性不足、水溶性差、肿瘤靶向性欠佳等问题。针对上述问题，本项目拟设计合成氮掺杂石墨烯量子点和短肽RGD修饰的含锌卟啉的细胞色素C复合物作为光敏剂。通过氮掺杂石墨烯量子点和锌卟啉的复合引入双光子光动力学活性，水溶性的细胞色素C作为的载体，RGD提供肿瘤靶向作用，实现高效、高选择性的双光子光动力学治疗。本项目为发展新型的高效安全的光敏材料提供了新的实验依据。

作为光动力学的三大核心要素之一，光敏剂在肿瘤的光动力学治疗过程中发挥着重要的作用。为了解决常规光敏剂光动力学活性不足、水溶性差等问题，我们展开了构建新型双光子光敏剂及其光动力学活性分析的研究工作。首先，我们将具有很强的双光子响应的氮掺杂石墨烯量子点和常规光敏剂竹红菌甲素进行复合。复合物相比于单独的竹红菌甲素在水溶性和生物缓冲液环境下的稳定性有了显著的提高。光谱学分析结果表明，氮掺杂石墨烯量子点和竹红菌甲素之间能够发生荧光能量共振转移作用。电子顺磁显示，复合物持续产生单线态氧的能力相对于竹红菌甲素也有一定的提高。此外，该复合物在单光子和双光子的条件下都能实现光动力学作用。最后，细胞学分析表明，复合物能够被肿瘤细胞高效的摄取，在双光子光动力学作用下，肿瘤细胞活力得到了有效的抑制。其次，在合作条件下，我们将氮掺杂石墨烯量子点和常规光敏剂玫瑰红通过亲水的衔接物共价的连接，该复合物具有较好的水溶性，在双光子的激发条件下，通过荧光能量共振转移机制，实现双光子光动力学作用，最后表现出对肿瘤细胞的活力抑制和小鼠微血管的封闭效果。本研究为发展基于荧光共振转移的双光子光敏剂提供了基本理论依据。