Recent Approaches towards the Development of Ru(II) Polypyridyl Complexes for Anticancer Photodynamic Therapy

Abstract

Photodynamic therapy (PDT) is a remarkable alternative or complementary technique to chemotherapy, radiotherapy or immunotherapy to treat certain forms of cancer. The synergistic effect of light, photosensitizer (PS) and oxygen allows for the treatment of tumours with an extremely high spatio-tumoral control, therefore minimizing the severe side effects usually observed in chemotherapy. The currently employed PDT PSs based on porphyrins have, in some cases, some limitations, which include a low absorbance in the therapeutic window, a low body clearance, photobleaching, among others. In this context, Ru(ii) polypyridyl complexes are interesting alternatives. They have low lying excited energy states and the presence of a heavy metal increases the possibility of spin-orbit coupling. Moreover, their photophysical properties are relatively easy to tune and they have very low photobleaching rates. All of these make them attractive candidates for further development as therapeutically suitable PDT PSs. In this review, after having presented this field of research, we discuss the developments made by our group in this field of research since 2017. We notably describe how we tuned the photophysical properties of our complexes from the visible region to the therapeutically suitable red region. This was accompanied by the preparation of PSs with enhanced phototoxicity and high phototoxicity index. We also discuss the use of two-photon excitation to eradicate tumours in nude mice. Furthermore, we describe our approach for the selective delivery of our complexes using targeting agents. Lastly, we report on our very recent synergistic approach to treat cancer using bimetallic Ru(ii)-Pt(iv) prodrug candidates.

Polymeric Nanosystems Applied for Metal-Based Drugs and Photosensitizers Delivery: The State of the Art and Recent Advancements

“…Furthermore, beyond acting as classical chemotherapeutic agents, metal-containing compounds have also been investigated as photosensitizers for photodynamic therapy (PDT) [ 25 ]. PDT is a promising and less invasive method for treating cancer and other diseases, which is based on the use of a PS and visible light irradiation to produce reactive oxygen species (ROS) [ 26 , 27 ].…”

Ruthenium(II) Polypyridyl Complexes Containing Simple Dioxo Ligands: a Structure‐Activity Relationship Study Shows the Importance of the Charge

“…As mentioned above, we recently described how cis-locked Ru(II)-DMSO precursors with dioxo ligands can be exploited for the efficient microwave-assisted synthesis of bis-heteroleptic polypyridyl compounds [36]. Ruthenium(II) complexes 3 -8 were obtained as intermediates following this novel approach, as exemplified in Figure 3 for a neutral (6) and a cationic (7) complex. Compounds 3 -8 are all soluble in DMSO, chloroform, and in aqueous media containing 1% of DMSO.…”

“…Inert Ru(II) polypyridyl complexes hold tremendous potential as chemotherapeutic agents against cancer, both in the presence of visible light – i. e., as photosensitizers for photodynamic therapy (PDT) – and in its absence. [ 1 , 2 , 3 , 4 , 5 , 6 ] The spearhead among metal complexes investigated as potential PDT agents is TLD‐1433, a bis‐heteroleptic Ru(II) polypyridyl complex that is in phase II clinical trial against high‐risk non‐muscle invasive bladder cancer (NMIBC), [7] and is being also investigated against other cancer types. [8] On the other hand, Ru(II) polypyridyl complexes have been studied for several years as cytotoxic agents for anticancer therapy.…”

Steric hindrance, ligand ejection and associated photocytotoxic properties of ruthenium(II) polypyridyl complexes

“…The increasing interest in the possible use of photoresponsive, metal-based anticancer drugs stems from the highly promising properties of TLD-1433, a polypyridyl Ru(II) complex reported by McFarland, Lilge and co-workers [1], which has entered Phase II clinical trials for the treatment of non-muscle invasive bladder cancer (NMIBC) [2]. Hence, numerous transition-metal-containing photosensitizers have been described in the literature for potential utilization in photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) [17][18][19].…”