Tuning the phototherapeutic activity of Pt(iv) complexes for bladder cancer via modification of trans N-heterocyclic ligands

Abstract

Bladder cancer is a common cancer globally that suffers from expensive treatment, drug and hypoxia resistance, and high recurrence rate. A series of six novel diazido Pt(IV) complexes with the general formula trans, trans, trans-[Pt(N₃)₂(OH)₂(L)₂] and various equatorial N-heterocyclic amine ligands (L = pyridines: 1 and 3–6; or imidazole: 2) have been synthesised and characterised, including their X-ray crystal structures, and their photoactivation investigated. The L-substituents modify the photocytotoxicity of these complexes towards bladder cancer cells significantly. In general, strong electron-withdrawing substituents result in higher photocytotoxicity compared to unsubstituted trans, trans, trans-[Pt(N₃)₂(OH)₂(py)₂] (FM190) and enhanced photocytotoxicity under hypoxia than normoxia, but higher dark cytotoxicity as well. Among them, the nitroimidazole complex 2, trans, trans, trans-[Pt(N₃)₂(OH)₂(1-methyl-5-nitroimidazole)₂], exhibits low dark cytotoxicity and promising photocytotoxicity with blue-light irradiation IC₅₀ values < 5 μM towards a series of bladder cancer cell lines under both normoxia and hypoxia. Notably, its green-light photocytotoxicity was significantly enhanced (>15×) under hypoxia compared to normoxia. Low cytotoxicity (IC₅₀ 14.4–100 μM) was observed towards normal bladder cells, even upon irradiation. Although photoinduced ROS generation, apoptosis and lipid peroxidation were observed for 2 under normoxia rather than hypoxia, high nuclear Pt accumulation, increased photoactivation in the medium, significantly enhanced cellular Pt accumulation and mitochondrial membrane potential changes upon irradiation under hypoxia were observed. These results suggest different mechanisms of action for 2 under normoxia and hypoxia. In addition, 2 exhibited high liver microsomal dark stability and photo-enhanced Pt accumulation in rat bladder. Based on these results, complex 2 is a promising candidate for phototherapeutic bladder cancer treatment.