Ultrasound‐Activated Oxygen and ROS Generation Nanosystem Systematically Modulates Tumor Microenvironment and Sensitizes Sonodynamic Therapy for Hypoxic Solid Tumors

Abstract

Sonodynamic therapy (SDT) is noninvasive and possesses high bodypenetration depth, showing great potential for the treatment of deep-seated solid tumors. The efficacy of SDT, however, is limited by widespread hypoxia in solid tumors. Given this, an ultrasound-activated nanosystem is developed by integrating ferrate(VI) and protoporphyrin IX into biodegradable hollow mesoporous organosilica nanoplatforms, followed by assembling a phasechange material of lauric acid. The ferrate(VI) effectively reacts with water as well as overexpressed hydrogen peroxide and glutathione (GSH) in tumor cells, leading to tumor-microenvironment-independent oxygen production and in situ GSH depletion in tumors. More importantly, significant reactive oxygen species (ROS) overproduction is simultaneously achieved by protoporphyrin-augmented SDT and intracellular Fenton chemistry. Furthermore, the mild hyperthermia induced by ultrasound can trigger the phase change of lauric acid, achieving ultrasound-responsive control over the release of oxygen and ROS, and the depletion of GSH. The simultaneous oxygen generation, in situ GSH depletion, and ROS overproduction play a synergetic role in sensitizing SDT toward hypoxic solid tumors, which is verified by the remarkable improvement of hypoxic environments and more significant growth inhibition of SDT against osteosarcoma both in vitro and in vivo, showing promising application in hypoxic solid tumor treatment.

Perfluoropolyether Nanoemulsion Encapsulating Chlorin e6 for Sonodynamic and Photodynamic Therapy of Hypoxic Tumor

“…In addition, ultrasound has the ability to remarkably promote the release of oxygen to the tumor site from perfluorocarbon-based nanostructures like Ce6-P/W NE, as is intensively reported in previous studies [ 41 , 71 ]. The released oxygen contributes to the modulation of tumor hypoxia.…”

GSH‐Depleted Nanozymes with Hyperthermia‐Enhanced Dual Enzyme‐Mimic Activities for Tumor Nanocatalytic Therapy

“…**p < 0.01, ***p < 0.001. highly quenched by O 2 . [21] As shown in Figure 3d, the intracellular fluorescence of [Ru(dpp) 3 ] 2+ Cl 2 in the presence of PEG/Ce-Bi@DMSN nanozymes with the 1064 nm laser irradiation was remarkably quenched and was weaker than that without the irradiation of the 1064 nm laser. This was attributed to the hyperthermia-augmented CAT-mimic catalytic activity for O 2 generation and was confirmed by the normalized intracellular fluorescence intensity of [Ru(dpp) 3 ] 2+ Cl 2 ( Figure S10, Supporting Information).…”

Ultrasound‐Activated Sensitizers and Applications

“…In addition, it has found widespread applications in biomedicine because of its biodegradability, high biocompatibility, physiological stability. In addition, Si‐based NPs such as porous silicon have been developed as sonosensitizers for SDT . Sviridov et al.…”