Interaction with a Biomolecule Facilitates the Formation of the Function-Determining Long-Lived Triplet State in a Ruthenium Complex for Photodynamic Therapy

in: Journal of Physical Chemistry A (2022)
Chettri, Avinash; Cole, Houston; Roque, John III; Schneider, Kilian R.A.; Yang, Tingxiang; Cameron, Colin G.; McFarland, Sherri A.; Dietzek-Ivanšić, Benjamin
TLD1433 is the first ruthenium (Ru)-based photodynamic therapy (PDT) agent to advance to clinical trials and is currently in a phase II study for treating nonmuscle bladder cancer with PDT. Herein, we present a photophysical study of TLD1433 and its derivative TLD1633 using complex, biologically relevant solvents to elucidate the excited-state properties that are key for biological activity. The complexes incorporate an imidazo [4,5-f ][1,10]phenanthroline (IP) ligand appended to á-ter- or quaterthiophene, respectively, where TLD1433 = [Ru(4,4′- dmb)2(IP-3T)]Cl2 and TLD1633 = [Ru(4,4′-dmb)2(IP-4T)]Cl2 (4,4′-dmb = 4,4′-dimethyl-2,2′-bipyridine; 3T = á-terthiophene; 4T = á-quaterthiophene). Timeresolved transient absorption experiments demonstrate that the excited-state dynamics of the complexes change upon interaction with biological macromolecules (e.g., DNA). In this case, the accessibility of the lowest-energy triplet intraligand chargetransfer (3ILCT) state (T1) is increased at the expense of a higher-lying 3ILCT state. We attribute this behavior to the increased rigidity of the ligand framework upon binding to DNA, which prolongs the lifetime of the T1 state. This lowest-lying state is primarily responsible for O2 sensitization and hence photoinduced cytotoxicity. Therefore, to gain a realistic picture of the excited-state kinetics that underlie the photoinduced function of the complexes, it is necessary to interrogate their photophysical dynamics in the presence of biological targets once they are known.

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