Targeting Hypoxic Deep-Seated Tumours with Ru(II)-Rhodamine Complexes via Sonodynamic Therapy

Objective

Sonodynamic therapy (SDT) is emerging as a promising alternative to conventional chemotherapy and light-activated therapies. Unlike other approaches, which often suffer from limited tissue penetration or severe systemic toxicity, SDT capitalizes on the unique properties of ultrasound to activate specialized compounds known as sonosensitizers. Upon exposure to ultrasound (up to 10 cm depth), these sonosensitizers generate reactive oxygen species (ROS) through cavitation-driven processes, thereby initiating localized oxidative stress and subsequent cancer cell death. Despite these advantages, several critical challenges remain. One of the most significant obstacles is the hypoxic nature of deep-seated tumours. To address this limitation, new sonosensitizers must be specifically designed to favor oxygen-independent pathways, particularly through Type I mechanisms involving electron-transfer reactions. This project seeks to address this issue thrugh the rational design, synthesis, and biological evaluation in different cancer cell models of a new class of Ru(II)-rhodamine sonosensitizers. The innovation rests on a dual-component strategy: rhodamine-based moieties are incorporated for their ability to respond efficiently to cavitation events induced by ultrasound, while a strategically tailored Ru(II) metal fragment serves as an electron-transfer center. Following ultrasound irradiation and cavitation, excitation of the rhodamine unit promotes charge transfer to the Ru(II) center, enabling Type I ROS generation even under hypoxic conditions. Beyond their therapeutic potential, these Ru(II)-rhodamine complexes will be rigorously characterized at both the physicochemical and biological levels, providing value insights into their properties and their induced therapeutic effect. Ultimately, this projects will create solid knowleadge for the rational development of next-generation sonosensitizers active under hypoxic conditions.