Key Takeaways & Executive Findings
- •• • Dual-lock activation: B-HCPP-RGD releases the type I PS HCEA only when both H2O2 and cathepsin B are present; ROS generation in solution is effectively suppressed in the absence of either stimulus. This prevents premature activation in circulation and reduces off-target phototoxicity, a persistent clinical liability of always-on PSs. • • Targeting specificity: covalent conjugation of cRGD confers specific recognition of αVβ3 integrin receptors overexpressed on tumor neovasculature and cancer cell membranes. In vitro, the conjugate exhibits almost no phototoxicity toward normal cells while producing significant phototoxicity toward tumor cells, widening the therapeutic window. • • Hypoxia tolerance: B-HCPP-RGD retains strong phototoxicity toward tumor cells even under hypoxic conditions, attributable to the type I ROS mechanism of the released HCEA. This addresses the oxygen-dependence bottleneck that limits conventional type II PSs in solid tumors. • • In vivo efficacy and safety: the conjugate actively targets tumor tissue and achieves a high tumor inhibition rate in vivo with high biosafety, supporting further preclinical development of dual-responsive peptide-PS conjugates for precision PDT.
Abstract
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.
1. Introduction
Clinical PDT remains constrained by the absence of tumor selectivity in conventional photosensitizers. Systemically distributed PSs accumulate in normal tissues, and illumination of the treatment field activates any PS within the light path, producing collateral phototoxicity. Ambient sunlight can also excite circulating PSs, creating a persistent risk of skin and ocular damage. Covalent attachment of tumor-homing peptides such as cRGD improves accumulation in αVβ3-overexpressing tumors, but targeting alone does not silence the PS en route; the molecule remains photoactive before it reaches the tumor.
Activatable PSs address the always-on problem by coupling ROS generation to tumor microenvironment (TME) stimuli. Single-response systems, however, are vulnerable to premature activation by a single aberrant cue, which is insufficiently tumor-specific. B-HCPP-RGD resolves this by requiring two orthogonal TME inputs: an H2O2-responsive 4-(bromomethyl)phenylboronic acid pinacol ester masks the hypocrellin-derived type I PS HCEA, and a cathepsin B-cleavable Gln-Val dipeptide linker tethers cRGD to the masked core. Only after both H2O2 and cathepsin B cleave their respective triggers is HCEA released. This dual-lock architecture suppresses ROS generation in solution, preserves type I activity under hypoxia, and confines phototoxicity to tumor cells, providing a modular route to safer, more precise PDT.
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MU Tong, ZHENG Xiuli, YUAN Yueke, WANG Yanping, LIU Tian, LI Hongxue, WU Jiasheng, LI Fan, ZHANG Wenjun, LEE Chun-Sing, LIU Weimin, WANG Pengfei (2025). Dual-Responsive Peptide-Photosensitizer Conjugate Based on a Hypocrellin Derivative for Tumor-Targeted Photodynamic Therapy. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3548-9
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Frequently Asked Questions
What prevents B-HCPP-RGD from being activated prematurely in circulation, where H2O2 and proteases are present at low levels?
Activation requires two independent inputs: cleavage of the H2O2-responsive 4-(bromomethyl)phenylboronic acid pinacol ester and cleavage of the cathepsin B-sensitive Gln-Val linker. In solution, ROS generation by B-HCPP-RGD is effectively suppressed, and the type I PS HCEA is released only when both H2O2 and cathepsin B are present. This AND-gate logic reduces the probability of activation by any single low-abundance circulating stimulus.
How does the construct perform under hypoxic conditions that impair type II photodynamic therapy?
B-HCPP-RGD maintains strong phototoxicity toward tumor cells even under hypoxic conditions. The released HCEA is a type I PS with a high ROS yield, and type I mechanisms are less dependent on molecular oxygen than type II pathways. This preserves efficacy in the hypoxic cores typical of solid tumors.
Does the cRGD targeting moiety compromise the selectivity of the dual-responsive activation?
No. cRGD binds αVβ3 integrin receptors overexpressed on tumor neovascular endothelial cells and cancer cell membranes, concentrating the conjugate at tumor sites. In vitro, B-HCPP-RGD exhibits almost no phototoxicity toward normal cells while showing significant phototoxicity toward tumor cells, indicating that targeting and dual-responsive masking act cooperatively rather than redundantly.
What is the in vivo evidence for tumor targeting and therapeutic efficacy?
In vivo studies confirmed that B-HCPP-RGD actively targets tumor tissue and achieves a high tumor inhibition rate. The conjugate also exhibits high biosafety in vivo, supporting its suitability for PDT. These results validate the dual-responsive, tumor-targeted design in an animal model.
What are the principal translational risks for this conjugate?
The synthesis requires sequential installation of an H2O2-responsive masking group, a cathepsin B-cleavable Gln-Val linker, and cRGD on the hypocrellin-derived HCEA core, which introduces manufacturing complexity and cost. Heterogeneity in tumor H2O2 and cathepsin B levels could produce variable activation, and the pharmacokinetics, biodistribution, and long-term toxicity of the conjugate require further characterization before clinical translation.
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