环肽修饰竹红菌素衍生物的合成及光动力性质研究OA

Objective:Aiming to address the key limitations of insufficient cell targeting selectivity of traditional photosensitizers and restricted precision of photodynamic therapy(PDT),a cRGD peptide-modified hypocrellin derivative HCDS-RGD for the αvβ3 integrin receptor was designed and synthesized in this study.Methods:Using the hypocrellin derivative HCEA as the lead photosensitizer,the target product HCDS-RGD was obtained via covalent conjugation of HCEA to cRGD through a glutathione(GSH)-cleavable linker.The chemical structure,photophysical properties and GSH-responsive characteristics of HCDS-RGD were characterized by 1H NMR,ESI-MS and spectral assays.Its cellular uptake selectivity was verified by confocal laser scanning microscopy,and its photodynamic cytotoxicity under normoxic and hypoxic conditions was evaluated using the MTT assay.Results:The target photosensitizer HCDS-RGD was successfully synthesized through multi-step reactions.Upon cRGD modification,the reactive oxygen species(ROS)production yield of the photosensitizer was inhibited,while the highly active Type Ⅰ photosensitizer HCEA was released in a high-GSH microenvironment.Meanwhile,HCDS-RGD exhibited excellent tumor cell selectivity,with high cellular internalization efficiency in αvβ3 integrin-overexpressing tumor cells,and markedly reduced cellular uptake in αvβ3 integrin low-expressing cells.Under 635 nm laser irradiation,HCDS-RGD efficiently generated superoxide anion(O2·-)and hydroxyl radical(·OH)in HeLa cells,exerting potent photodynamic killing effect with a half-maximal inhibitory concentration(IC50)of 0.132±0.028 μM under normoxic conditions and 0.273±0.052 μM under hypoxic conditions(n=6).Conclusion:The prepared peptide-conjugated Type Ⅰ photosensitizer HCDS-RGD equipped with a tumor microenvironment-cleavable linker endows the photosensitizer with excellent tumor cell selectivity while well preserving its photodynamic activity.Furthermore,its intrinsic Type Ⅰ photodynamic mechanism can circumvent the limitation of the hypoxic tumor microenvironment.This study provides a novel strategy for solving the core problems of traditional photosensitizers,including insufficient targeting capacity and compromised therapeutic efficacy under hypoxic conditions.