The use of photodynamic therapy (PDT) against cancer has received increasing attention over recent years. However, the application of the currently approved photosensitizers (PSs) is limited by their poor aqueous solubility, aggregation, photobleaching and slow clearance from the body. To overcome these limitations, there is a need for the development of new classes of PSs with ruthenium(II) polypyridine complexes currently gaining momentum. However, these compounds generally lack significant absorption in the biological spectral window, limiting their application to treat deep-seated or large tumors. To overcome this drawback, ruthenium(II) polypyridine complexes designed in silico with (E,E′)-4,4′-bisstyryl-2,2′-bipyridine ligands show impressive 1-and 2-Photon absorption up to a magnitude higher than the ones published so far. While nontoxic in the dark, these compounds are phototoxic in various 2D monolayer cells, 3D multicellular tumor spheroids and are able to eradicate a multiresistant tumor inside a mouse model upon clinically relevant 1-Photon and 2-Photon excitation.

A novel unique arch-bridge-like stator, after the rigidification of rotor 1 by intramolecular H-bonding, afforded two classes of solution and solid dual photoluminescence (PL) molecules.

Despite the clinical success of photodynamic therapy (PDT), the application of this medical technique is intrinsically limited by the low oxygen concentrations found in cancer tumors, hampering the production of therapeutically necessary singlet oxygen (1O2). To overcome this limitation, we report on a novel mitochondria-localized iridium­(III) endoperoxide prodrug (2-O-IrAn), which, upon two-photon irradiation in NIR, synergistically releases a highly cytotoxic iridium­(III) complex (2-IrAn), singlet oxygen, and an alkoxy radical. 2-O-IrAn was found to be highly (photo-)­toxic in hypoxic tumor cells and multicellular tumor spheroids (MCTS) in the nanomolar range. To provide cancer selectivity and improve the pharmacological properties of 2-O-IrAn, it was encapsulated into a biotin-functionalized polymer. The generated nanoparticles were found to nearly fully eradicate the tumor inside a mouse model within a single treatment. This study presents, to the best of our knowledge, the first example of an iridium­(III)-based endoperoxide prodrug for synergistic photodynamic therapy/photoactivated chemotherapy, opening up new avenues for the treatment of hypoxic tumors.

A glutathione (GSH)-activatable ruthenium(ii)-azo photosensitizer was prepared. The complex had low toxicity towards cells under dark conditions. It exhibited excellent phototoxicity under two-photon excitation (810 nm) and thus was developed as a two-photon photodynamic anticancer agent for cancer therapy.

The efficacy of photodynamic therapyi st ypically reliant on the local concentration and diffusion of oxygen. Due to the hypoxic microenvironment found in solid tumors, oxygen-independent photosensitizers are in great demand for cancer therapy. We herein report an iridium(III) anthraquinone complex as am itochondrion-localized carbon-radical initiator.I ts emission is turned on under hypoxic conditions after reduction by reductase.F urthermore,i ts two-photon excitation properties (l ex = 730 nm) are highly desirable for imaging.U pon irradiation, the reduced form of the complex generates carbon radicals,l eading to al oss of mitochondrial membrane potential and cell death (IC 50 light = 2.1 mm,IC 50 dark = 58.2 mm,P I= 27.7). The efficacy of the complex as aP DT agent was also demonstrated under hypoxic conditions in vivo. To the best of our knowledge,i ti st he first metal-complexbased theranostic agent which can generate carbon radicals for oxygen-independent two-photon photodynamic therapy.