Authors
Haowen Liu, Aoyun Cui, Kaikai Xu, Zhikang Song, Ke Wang, Shaohua Wei, Yongming M Deng, Lin Zhou
Published in
Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology. Jun 25, 2026. Epub Jun 25, 2026.
Abstract
Mitochondria are key targets in anticancer drug design owing to their central roles in cancer cell apoptosis and energy metabolism. In this study, we design and synthesize two triphenylphosphonium (TPP⁺)-modified zinc phthalocyanine (ZnPc) photosensitizers: ZnPc-O3-P(ph)3 linked by a polyethylene glycol (PEG) chain and ZnPc-C5-P(ph)3 linked by an alkyl chain. Subcellular localization studies show that ZnPc-O3-P(ph)3 precisely targets mitochondria, whereas ZnPc-C5-P(ph)3 unexpectedly accumulates in lysosomes. This finding overturns the conventional assumption that TPP⁺ confers universal mitochondrial targeting and reveals that linker structure critically governs TPP⁺-mediated subcellular localization. ZnPc-O3-P(ph)3 has a phototoxic index (PI, defined as the ratio of IC₅₀ in the dark to IC₅₀ under illumination) of 7.51 × 103, 544-fold higher than that of ZnPc-C5-P(ph)3 (PI = 13.8) and 10.4-fold higher than the clinical phthalocyanine photosensitizer photosens (PI = 725). In an orthotopic bladder cancer mouse model, ZnPc-O3-P(ph)3 exhibits therapeutic efficacy comparable to that of the first-line drug mitomycin C (MMC). This study demonstrates that linker design can dominate the subcellular fate of TPP⁺-conjugated agents, providing a new paradigm for targeted therapeutic development.
PMID:
42348102
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.
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