乏氧响应、多模式抗肿瘤的金属配合物研究

Cancer has evolved as one of the world’s deadliest diseases. A synergistic system with simultaneous therapeutic and diagnostic competencies (i.e., theranostics) is likely to actualize the early diagnosis of cancer, elevate the targeting extent of drugs, promote the therapeutic efficacy and relieve side effects, all of which contribute largely to the survival of patients. However, tumours are predominantly associated with hypoxic microenvironment which originates from the rapid proliferation of tumour cells and the unsound intra-tumour neovasculature system. It has been pointed out that hypoxia can fertilize the capability of chemo-resistance of cancer cells and facilitate their invasion and migration. In this context, cancer is unlikely to be cured by merely mono therapeutic regimen. In contrast, multi-modal therapy is an elegant and promising manner to eradicate cancer cells. In this proposal, we devise a series of heteronuclear metal complexes as hypoxia-stimulated multimodal theranostic prodrugs. The inclusion of an electron withdrawing azo group can deactivate the excited states of both metal centers by a photo-induced electron transfer (PET) mechanism, and thus the two metals can ''hide'' each other's photoactivity before being ''turned on'' by the target. Upon exposure to the hypoxic environment, the azo group will be reduced, the PET will be interrupted, and the photoactivities of Ir(III) and Ru(II) moieties will be restored. Ir(III) moiety can serve as a diagnostic probe as well as a photosensitizer. Guided by the emission signal of Ir(III), the selective excitation of Ru(II) can lead to a photo-activated chemotherapy (PACT) along with PDT of Ir(III). Meanwhile, the ligand exchange of Ru(II) complex leads to the release of the prodrug of CA-4 which can be degraded by ROS to CA-4 to inhibit tumor angiogenesis. Thus the tumour can be selectively imaged by virtue of its hypoxic attribute and selectively destroyed by a photo-activated multimodal therapy in an image-guided way.

癌症是威胁人类健康的主要疾病之一，抗癌药物的诊疗一体化不仅可以实现癌症的早期诊断，而且可以提高药物的靶向性，改善治疗效果并降低副作用，显著提高患者的存活机率。由于癌细胞的快速增殖以及肿瘤血管不健全，肿瘤普遍存在乏氧，这种微环境能促进癌细胞的耐药性与转移能力，仅靠单一模式治疗手段难以根除癌细胞。相比，具有多模式治疗效果的诊疗试剂具有广阔的前景。本项目拟设计一系列乏氧响应、多模式抗肿瘤的双异核金属配合物前药。该系列前药中的偶氮连接子能通过光致电子转移淬灭两种金属激发态，使其均处于失活状态。在乏氧环境中前药的偶氮基团能被选择性地还原活化，恢复铱(III)的发光与光动力治疗效果，利用铱(III)进行磷光引导的光治疗时，钌(II)能实现光活化化疗，在活化过程中激发配体交换，释放具有抑制肿瘤血管生成的康普瑞汀(CA-4)前药配体，该配体在活性氧下氧化分解，生成CA-4，实现磷光引导多模式抗肿瘤诊疗。

癌症是威胁人类健康的主要威胁之一，铂类抗肿瘤药物作为金属抗肿瘤药物的杰出代表，在抗癌药物中占据着重要地位。近年来，针对非铂类金属药物的研究日益增多，钌、铱等铂族金属由于具有良好的光物理性质与抗肿瘤生物活性而被广泛研究。光动力抗肿瘤治疗可以有效地克服耐药性的产生，是一种前景广阔的治疗手段。本项目基于钌、铱金属配合物，采用多光子激发技术，设计了多个具有肿瘤靶向、特殊细胞器聚集、激发光深层次组织渗透深度的从简单单分子到超分子结构的光敏剂，并采用从贴壁细胞到细胞球以及活体的多层次生物模型进行光动力治疗活性评估。本项目的执行将为多光子激发的非铂类金属光敏剂的可能的临床前研究提供基础。项目执行期间，期间累计发表SCI论文8篇。