Hypoxia active cyclometalated Ir(iii) Nile red triplet photosensitisers

Abstract

Cyclometalated Ir(III) compounds have gained increasing attention as promising photosensitisers for photodynamic therapy (PDT). Most photosensitisers exert their therapeutic effect by generating singlet oxygen through a light-activated reaction with molecular oxygen, which makes them less effective in treating hypoxic tumors. In this work, we report the synthesis, characterisation, photophysics, and biological studies of two novel, octahedral Ir(III) bis-cyclometalated photosensitisers, [Ir-2ENR]⁺ and [Ir-3ENR]⁺, featuring an extended Nile red (NR) chromophore. The absorption and emission spectra of the complexes and their excited states are largely governed by the NR chromophore and lie within the biological window (650–800 nm) for excitation and application in PDT. Overall, [Ir-3ENR]⁺ displays more attractive photophysical properties, which is reflected in its higher photodynamic activity in SKBR-3 cells compared to its 2ENR, and previously reported Ru(II), analogues. Further in vitro studies as reported here, using a MCF-7 cell line, examined the PDT effect under both normoxic and hypoxic conditions. The results revealed the excellent phototoxic activity of [Ir-3ENR]Cl (phototoxicity index = 179). This fluorescent mitochondria-accumulating complex, exerts its activity by combining type-I and type-II mechanisms and, more importantly, retains its cyto- and phototoxic activity under decreased oxygen concentrations. The data highlight how rational design can help overcome hypoxia limitation in conventional PDT and offer a promising approach to combat hypoxic solid tumors.