Conventional anticancer therapies suffer from severe side effects due to their lack of selectivity, often damaging healthy tissues alongside tumours. A promising strategy to overcome this limitation is photoactivated chemotherapy (PACT), in which prodrugs remain inactive until triggered by light at the tumour site, thereby achieving spatial and temporal control over toxicity. Metal complexes, particularly polypyridyl-ruthenium (Ru(II)) compounds, are well-suited for this approach due to their ability to undergo ligand exchange upon irradiation. However, challenges remain, including insufficient light penetration, reliance on oxygen-dependent mechanisms, and non-selective cellular uptake. To address these issues, this proposal introduces a novel multimetallic Ru(II)-peptide bioconjugate strategy that integrates the benefits of metal-based PACT with the biological activity of anticancer peptides (ACPs).
The core innovation of pepRu4PACT lies in coordinating one or multiple Ru(II) complexes to methionine residues of biologically active peptides. This dual-component system enables mutual caging in the dark, minimizing off-target toxicity, while light activation cleaves the Ru-thioether bond(s), simultaneously releasing both cytotoxic components, i.e. the ruthenium fragment and the ACP. By leveraging red or near-infrared light, which penetrates more deeply into tissues, this approach ensures effective activation even in hypoxic tumour environments where conventional photodynamic therapy (PDT) is less effective. Additionally, peptide-based targeting enhances selective cellular uptake through receptor-mediated pathways, further increasing therapeutic precision.
In order to achieve our general goal, intermediate objectives had to be established first: (a) tuning the coordination sphere of Ru(II)-polypyridyl complexes bound to thioethers to achieve light activation in the red or near-IR spectral region; (b) synthesize and characterize these Ru(II)-peptide conjugates; (c) validate their activation by red/near-infrared light; and (c) assess their combined phototoxic effects in cancer models. This work will provide fundamental insights into peptide-metal interactions while paving the way for more effective, side-effect-free chemotherapies.
