Tumor-Microenvironment-Responsive Nanoconjugate for Synergistic Antivascular Activity and Phototherapy

Insufficient oxygen supply (hypoxia), short half-life (<40 ns) of singlet oxygen, and up-regulation of the heat shock protein expression in solid tumors impede the photodynamic and photothermal therapeutic efficacy. Herein, a near-infrared carrier-free nanoconjugate direct-acting antiviral (DAA) with synergistic antivascular activity and pH-responsive photodynamic/photothermal behavior was designed and synthesized to improve cancer treatment efficacy. Obtained by the self-assembly approach, the biocompatible DAA nanoparticles (NPs) displayed amplifying pH-responsive photodynamic/photothermal performance in an acidic tumor microenvironment due to the protonation of diethylaminophenyl units. Most important, the antivascular agent 5,6-dimethylxanthenone-4-acetic acid, targeting the vascular endothelial growth factor, can be smartly released from the pro-drug DAA via ester bond hydrolysis at the subacid endocytosis organelles in the endothelial cells, which can effectively destroy the vascular region to prevent tumor proliferation and metastasis. Hence, DAA NPs can specifically target vascular endothelial cells and tumorous lysosomes with desired cellular damage properties in vitro. Therefore, the tumors can be ablated completely with no recurrence and side effects in vivo, which implies that DAA NPs provide a promising approach for cancer treatment via synergistic antivascular activity and photodynamic/photothermal therapy.