Synthetic ease and exceptional in vivo performance of pyrazole-based cyclometallated iridium complexes

Abstract

Two luminescent cyclometallated Ir^III complexes of the type [Ir(C^N)₂(N^N)]^x (X = 0 (1), and X = +1 (2)) were prepared using methyl 2-phenylquinoline-4-carboxylate as C^N ligands and either a deprotonated or protonated 3-(2-pyridyl)pyrazole as the N^N chelate. The synthesis followed a well-established and straightforward procedure. Photophysical analysis unveiled their remarkable properties, featuring phosphorescent red and orange emissions attributed to ³MLCT and ³LLCT transitions, with high emissive quantum yields in degassed DMSO solutions. Importantly, these complexes exhibited dual functionality as potent chemotherapeutic agents and photosensitisers, with their effectiveness tailored to specific cancer cell lines. Phototherapeutic treatment was particularly effective against lung cancer A549 cells, while a chemotherapeutic approach yielded superior results against breast cancer 4T1-luc2 cells. Both complexes primarily targeted lysosomes, leading to cell death through apoptotic pathways, with IC₅₀ values in the nanomolar range. Importantly, they demonstrated no cytotoxicity against lymphocytes, mimicking the behaviour observed in healthy cells. Encouragingly, 1 and 2 exhibited minimal in vivo toxicity. The most striking finding was the exceptional chemotherapeutic efficacy of complexes 1 and 2 against 4T1-luc2 cells in BALB/c mice. These complexes surpassed the performance of the clinically employed 5-fluorouracil, especially at early tumor stages, significantly retarding 4T1-luc2 proliferation. Further investigations at vascularised and organised tumor stages revealed that complex 1 could reduce tumor size by half compared to untreated mice, which was also confirmed through tumoral weight analysis. While these findings are preliminary, the outstanding performance of these complexes at early tumor stages against breast cancer 4T1-luc2 in vivo, their selective therapeutic feasibility (chemotherapy vs. PDT) tailored to specific cancerous cell lines, and their straightforward synthetic design make them highly attractive candidates for cancer treatment.