Thiochromenocarbazole imide-based photosensitizers decorated with carbonic anhydrase inhibitors for the targeted treatment of hypoxic tumours

Abstract

PDT has gained growing interest as a prospective approach for cancer therapy, thanks to its minimal invasiveness and low systemic toxicity, making it a promising therapeutic option. Nevertheless, type II PDT is significantly influenced by the oxygen levels in the tumoral microenvironment. Consequently, the weak oxygen pressure encountered in hypoxic regions of solid tumours poses a significant challenge in cancer treatment. In this case, PDT efficiency is reduced and the existing hypoxia is intensified by oxygen consumption and vascular closure, activating the angiogenic factors and thus, potentially leading to cancer recurrence and progression. We describe here a series of thiochromenocarbazole imide (TCI) photosensitizers featuring carbonic anhydrase inhibitors (CAi) of the sulfonamide, coumarin and sulfocoumarine type, designed to alleviate the consequences of PDT-induced hypoxia by merging the advantages of hCA IX knockdowns with PDT. TCIs with coumarin and sulfocoumarin moieties showed selective inhibition against tumour-associated hCA IX and hCA XII, while TCI incorporating benzenesulfonamide moieties also showed activity against the off-target hCA II. In biological assays, the TCI photosensitizer incorporating coumarin-based CAi demonstrated minimal dark toxicity and showcased strong imaging and photodynamic therapy (PDT) effects in both in vitro and in vivo settings.