Ruthenium Peptide Bioconjugates for Photoactivated Chemotherapy

用于光激活化疗的钌肽生物缀合物

• 批准号: 495675456
• 负责人: Dr. Irene Regeni
• 金额: --
• 依托单位: Leiden Institute of Chemistry
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/495675456?language=en
• 关键词: Ruthenium; Peptide; Bioconjugates; Photoactivated; Chemotherapy

One of the most severe limitations of current anticancer chemotherapy are the serious side effects caused by toxic drugs affecting not only tumors but also healthy organs. Local activation of drugs by light irradiation of the tumor is a promising approach to control where the toxicity is delivered. Metal complexes are well suited for photoactivated chemotherapy, but their activation wavelength is often too low to afford high tissue penetration of light; also, their ability to enter cancer cells is often controlled by lipophilicity tuning, which is unselective; finally, their phototoxicity often relies on oxygen-dependent mechanisms, while many tumor tissues show low dioxygen concentrations.The aim of this project is to develop new metallodrugs that are activated by red or near-infrared light, enter cells by controlled mechanisms, and deliver strong phototoxicity to cancer cells also under low oxygen conditions. The design is based on connecting multiple Ru(II) metal complexes to a biologically active antitumoral peptide. The ruthenium complexes will have a tuned coordination environment to allow red/near-IR light activation; meanwhile, the peptides will rely on methionine residues to coordinate ruthenium, and allow controlled cellular uptake of the prodrug into cancer cells. Both components will cage each other in the dark, thus affording low toxicity; while light-induced cleavage of the ruthenium-thioether bonds will release two bioactive components, which will kill cancer cells.The novelty of this project is to combine metal-based photoactivated chemotherapy with therapeutic peptides to enhance phototoxicity by creating synergies between both photoproducts. By combining light activation, resulting in timely- and spatially-resolved toxicity release, and bioactive peptides, which will improve uptake in cancer cells, this project will deliver new fundamental knowledge on the interaction between peptides and metals, and between metallopeptides and cells. It will lead closer to the development of phototherapy for cancer treatment with drastically reduced side effects.

目前抗癌化疗最严重的局限性之一是有毒药物引起的严重副作用，不仅影响肿瘤，还影响健康器官。通过肿瘤的光照射来局部激活药物是控制毒性传递到哪里的一种很有前途的方法。金属络合物非常适合于光激活化疗，但它们的激活波长往往太低，无法承受高强度的光穿透；此外，它们进入癌细胞的能力往往受亲脂性调节的控制，这是非选择性的；最后，它们的光毒性往往依赖于氧依赖机制，而许多肿瘤组织表现出低氧浓度。本项目的目的是开发新的金属药物，这些药物可以被红光或近红外光激活，通过受控的机制进入细胞，并在低氧条件下对癌细胞产生强烈的光毒性。该设计是基于将多个Ru(II)金属配合物连接到具有生物活性的抗癌多肽上。Ru络合物将具有一个可调的配位环境，以允许红色/近红外光激活；同时，多肽将依赖蛋氨酸残基来协调Ru，并允许受控的细胞摄取前体药物进入癌细胞。这两种成分都会在黑暗中相互笼子，从而提供低毒性；而光诱导的Ru-硫醚键的裂解将释放两种生物活性成分，从而杀死癌细胞。本项目的新颖之处在于将金属基光活化化疗与治疗性多肽相结合，通过在两种光产品之间产生协同作用来增强光毒性。通过结合光激活，导致及时和空间分辨的毒性释放，以及生物活性多肽，将提高癌细胞的摄取，该项目将提供关于多肽与金属之间以及金属多肽与细胞之间相互作用的新的基础知识。它将进一步推动光疗法在癌症治疗中的发展，并大大减少副作用。