Red‐Light Activation of a Microtubule Polymerization Inhibitor via Amide Functionalization of the Ruthenium Photocage

Photoactivated chemotherapy (PACT) is a promising cancer treatment modality that kills cancer cells via photochemical uncaging of a cytotoxic drug. Most ruthenium‐based photocages used for PACT are activated with blue or green light, which penetrates sub‐optimally into tumor tissues. Here, we report amide functionalization as a tool to fine‐tune the toxicity and excited states of a terpyridine‐based ruthenium photocage. Due to conjugation of the amide group with the terpyridine π system in the excited state, the absorption of red light (630 nm) increased 8‐fold, and the photosubstitution rate rose 5‐fold. In vitro, red light activation triggered inhibition of tubulin polymerization, which led to apoptotic cell death both in normoxic (21 % O2) and hypoxic (1 % O2) cancer cells. In vivo, red light irradiation of tumor‐bearing mice demonstrated significant tumor volume reduction (45 %) with improved biosafety, thereby demonstrating the clinical potential of this compound. Methylamide functionalization of a green light‐sensitive photoactivated chemotherapy agent based on ruthenium fine‐tuned its excited states, dramatically improving red light absorption. The new prodrug inhibited microtubule polymerization under red light activation, efficiently killing cancer cells in vitro. In vivo, red light activation shrank non‐melanoma skin tumors in mice, while in the dark the prodrug showed improved biosafety.