Near-infrared upconversion photosensitizer enabling photodynamic production and in situ dynamic monitoring of hydroxyl radical in live mice

Abstract

Upconversion photodynamic therapy (PDT), utilizing upconversion nanoparticles (UCNPs) to excite surface-anchored molecular photosensitizers, enables to treat deep-seated tumors using tissue-penetrating near-infrared (NIR) light. Yet, this technique was substantially limited by the O2 deficiency in solid tumors and the inability to visualize reactive oxygen species (ROS) for precise treatment. To address this challenge, we devised a neotype of multifunctional upconversion photosensitizer which not only efficiently generates hydroxyl radical (•OH) to induce cell apoptosis in hypoxic tumor, but also dynamically shows accumulated amount of radical •OH in situ in tumor. This photosensitizer consists of NaYbF4:Tm@NaYF4 upconversion nanoparticles (UCNPs) as the core, and mesoporous silica as the shell which was loaded with heterojunction Ag0-Ag2S quantum dots and IR 820 molecular probe on the surface. Under 980 nm NIR excitation, thulium ultraviolet and blue upconversion luminescence (UCL) excite spectrally overlapped Ag0-Ag2S, with metal-semiconductor heterojunction for enhanced electron-hole separation, to produce highly toxic •OH to induce cell death. While produced •OH can specifically degrade surface IR 820 dyes to remove luminescence resonant energy transfer from UCNPs to IR 820 dyes, this can turn on quenched UCL entailing dynamical observation of in situ generated •OH. Intravenous injection of the photosensitizers resulted in 8-fold tumor volume reduction as compared to control group, while dynamically showing accumulated production of •OH in hypoxic 4T1 tumor-bearing mice (Balb/c). These findings untap the use of upconversion photosensitizer for precise and visualized treatment of deep-seated hypoxic tumors in live mammals.