A mono-substituted aluminum phthalocyanine photosensitizer with high phototoxicity index for effective bladder cancer treatment

Photosensitizers are central to the efficacy of photodynamic therapy (PDT) in cancer treatment. The phototoxic index (PI) defines the therapeutic window of a photosensitizer, with the clinically used Photosens® exhibiting a PI of 725. In our study, we observed that Zn(II) phthalocyanine mono-β-substituted with 4-carboxyphenoxy (ZnPc-COOH) displayed a phototoxic IC 50 in bladder cancer T24 cells at approximately 11.2 nM, yet its dark toxicity was notably high, yielding a PI of only 199. We hypothesize that the elevated dark toxicity is linked to mitochondrial localization. Rather than employing traditional side-chain substitution strategies to mitigate dark toxicity, we adopted a center metal substitution approach, synthesizing the first Al(III) phthalocyanine mono-β-substituted with 4-carboxyphenoxy photosensitizer (AlPc-COOH). Remarkably, AlPc-COOH localized to the lysosome, exhibited a phototoxic IC 50 of 1 nM, and showed a nearly 89-fold reduction in dark toxicity, achieving a PI of 223,700, which is 1000 times greater than ZnPc-COOH. In a murine orthotopic bladder cancer model, AlPc-COOH demonstrated therapeutic efficacy comparable to that of the clinically used chemotherapeutic agent mitomycin C (MMC). This study provides a crucial foundation for the design of optimized mono-substituted aluminum phthalocyanine-based photosensitizers.