Rationally Designed Ru(II) Complex with Dual Type I/II ROS Generation for Hypoxia-Tolerant Photodynamic Therapy in Melanoma

To overcome this challenge, a donor-π-acceptor (D-π-A) bis-terpyridine ruthenium(II) complex, Ru(tpy)₂TT, was rationally designed and synthesized to enable dual type I/II ROS generation. The ROS production efficiency was quantitatively evaluated in B16 murine melanoma cells, and the antitumor efficacy was assessed in a syngeneic C57BL/6N mouse melanoma model.

Upon photoactivation at 500 nm, Ru(tpy)₂TT efficiently generated both superoxide anion (type I ROS) and singlet oxygen (type II ROS). Intratumoral administration followed by localized irradiation resulted in an 80% reduction in tumor volume after 10 days, with no observed systemic toxicity or off-target effects. These findings demonstrate that Ru(tpy)₂TT circumvents hypoxia-induced PDT resistance in melanoma via hypoxia-tolerant and oxygen-dependent ROS pathways, establishing its potential as a targeted precision antitumor agent.