Dual-Responsive Peptide-Photosensitizer Conjugate Based on a Hypocrellin Derivative for Tumor-Targeted Photodynamic Therapy
Photodynamic therapy (PDT) is constrained by the absence of tumor selectivity in conventional photosensitizers (PSs), which produces phototoxicity in normal tissues and risks activation by ambient light. Covalent conjugation of PSs to targeting peptides improves accumulation but does not suppress off-target activation. This work reports B-HCPP-RGD, a single-molecule PS that integrates αVβ3 integrin targeting with dual responsiveness to H2O2 and cathepsin B. The hypocrellin-derived type I PS HCEA is masked by a 4-(bromomethyl)phenylboronic acid pinacol ester H2O2-responsive group and conjugated to cyclic Arg-Gly-Asp (cRGD) through a cathepsin B-cleavable Gln-Val dipeptide linker. ROS generation in solution is effectively suppressed until both H2O2 and cathepsin B are present, at which point HCEA is released. In vitro, B-HCPP-RGD shows negligible phototoxicity toward normal cells and pronounced phototoxicity toward tumor cells, including under hypoxic conditions. In vivo, the conjugate actively targets tumor tissue and achieves a high tumor inhibition rate with favorable biosafety. The results establish a modular design for dual-responsive, tumor-targeted PSs that improves the precision and safety of PDT.