Light-activated targeted degradation of VHL drug for selective tumor killing: A novel strategy for precision therapy of bladder cancer.

Photodegradation-targeting chimeras (PDTACs) addresses the off-target toxicity issues of proteolysis-targeting chimeras (PROTACs) in terms of technical principle; Difficulty in defining tumor boundaries and controlling light exposure increases the risk of damaging peritumoral tissues if light exposure oversteps the tumor. This study discovered that compared to SV-HUC-1 cells (normal cells), Von Hippel-Lindau (VHL) exhibits more active regulation of CDK2/4 in T24 cells (bladder cancer cells); Based on this, a series of PDTACs linking VHL ligands to photosensitizers were synthesized, and ZnPc-PEG2-VH032 was selected as the most potent antitumor compound. This compound degrades VHL upon light exposure and, when combined with photodynamic therapy (PDT), efficiently kills T24 cells with a phototoxicity index (PI) of 36,397. More importantly, after illumination, ZnPc-PEG2-VH032 exhibited a selectivity index (SI) of 749 for killing T24 cells versus SV-HUC-1 cells, achieving selective tumor cell targeting under light conditions and effectively mitigating the risk of damage to peritumoral tissues. This study demonstrates the potential of VHL as a precision therapeutic target for tumors and identifies the first PDTAC drug characterized by high PI and SI. It provides novel insights and structural references for developing drugs that selectively kill tumor cells.