Ruthenium Peptide Bioconjugates for Photoactivated Chemotherapy

目前抗癌化疗最严重的限制之一是毒性药物引起的严重副作用，不仅影响肿瘤，而且影响健康器官。通过肿瘤的光照射局部激活药物是控制毒性传递的有希望的方法。金属络合物非常适合于光活化化学疗法，但它们的活化波长通常太低而不能提供光的高组织穿透;而且，它们进入癌细胞的能力通常由亲脂性调节控制，这是非选择性的;最后，它们的光毒性通常依赖于氧依赖性机制，而许多肿瘤组织显示出低的分子氧浓度。该项目的目的是开发新的金属药物，这些药物可被红光或近红外光激活，通过受控机制进入细胞，并且在低氧条件下也向癌细胞传递强的光毒性。该设计基于将多个Ru（II）金属络合物连接到具有生物活性的抗肿瘤肽。钌络合物将具有调谐的配位环境以允许红光/近红外光活化;同时，肽将依赖于甲硫氨酸残基来配位钌，并允许前药受控地细胞摄取到癌细胞中。这两种成分在黑暗中会相互笼住，从而提供低毒性;而光诱导的硫醚键断裂会释放出两种生物活性成分，这将杀死癌细胞。该项目的新奇在于将联合收割机基于金属的光活化化学疗法与治疗肽结合，通过在两种光产物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，以及生物活性肽，这将提高癌细胞的吸收，该项目将提供关于肽与金属之间相互作用的新的基础知识，以及金属肽与细胞之间的相互作用。它将导致更接近癌症治疗的光疗的发展，大大减少副作用。

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.