A Hydrophilicity-Switchable, Self-Immobilizing Near-Infrared Photosensitizer for γ-Glutamyltransferase-Activated Precision Photodynamic Therapy.

Abstract

Photodynamic therapy (PDT) is a minimally invasive cancer treatment, but its clinical translation is limited by the intrinsic conflict between hydrophilicity for systemic delivery and hydrophobicity for cellular uptake and retention. Here, we report a γ-glutamyltransferase (GGT)-activatable, hydrophilicity-switchable, and self-immobilizing near-infrared photosensitizer, GGT-PS2. Initially hydrophilic and photoinactive, GGT-PS2 undergoes enzymatic cleavage by tumor-associated GGT, triggering a hydrophilic-to-hydrophobic transition and generating a reactive quinone methide intermediate for covalent immobilization. This process simultaneously activates near-infrared fluorescence and singlet oxygen production. In vitro studies demonstrate GGT-specific activation, efficient protein binding, and enhanced photodynamic performance compared to control analogs. In a HeLa tumor xenograft model, GGT-PS2 achieves selective tumor accumulation and prolonged retention, resulting in complete tumor regression after a single intravenous administration with light irradiation, without observable toxicity or recurrence. This "one-to-multi" design provides an effective strategy to overcome the solubility-retention trade-off, offering a promising platform for precision PDT.