Focusing on electronic properties of ruthenium polypyridyl complexes for anticancer therapy: computational rationalization of photoinduced cytotoxicity

Due to the urgency for new anticancer strategies able to overcome the well-known drawbacks of the actually adopted therapies admitted to clinical practice, including those employing transition metal complexes, special attention of scientists has been focused on light-driven photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) due to their spatial and temporal resolution. The main difference between these treatments is the limited application of PDT in cases of low cellular oxygenation, which is typical of cancerous cells. PACT is able to overcome this drawback as it works independently of the presence of oxygen. However, compared to PDT, PACT is stoichiometric due to the irreversibility of the reactions occurring under light irradiation, while PDT is catalytic due to the reversibility of the processes of excitation and relaxation to the ground state. In this framework, Ru(II) polypyridyl complexes have emerged as very promising systems to be used in both therapies thanks to their versatile chemical-physical properties. The most recent tendency is to try to combine PDT and PACT to overcome the limitations and exploit the advantages of each of them. In this perspective the photophysical properties and light-driven reactivity of Ru(II) polypyridyl complexes proposed as PDT, PACT and dual PDT/PACT agents have been examined through the lens of quantum-mechanical DFT computational approaches that enable the detailed characterization of electronic excitations, intersystem crossing processes, and excited-state reaction pathways and provide mechanistic insights that can support the rational design of Ru(II) complexes with optimized photosensitizing or photoreleasing properties.