Glutathione/Glucose-Depleting Nanoparticles with NO Generation for Ferroptosis/Starvation/NO-Induced Cancer Therapy

Abstract

Depleting intracellular glutathione (GSH) has emerged as a potent strategy to combat cancer. However, the existing GSH-depleting agents are too toxic or ineffective and standalone GSH depletion fails to yield a satisfactory curative effect. Herein, we present an intelligent nanoparticle that possesses GSH depletion, glucose consumption accompanied with H2O2 production, and NO generation properties for multimodal cancer therapy. The nanoparticle is constructed by synthesis of tetrasulfide bond-doped mesoporous silica nanoparticles followed by conjugating glucose oxidase (GOx) on the surface and loading l-arginine (l-Arg) into the mesopores. In this nanoparticle, the doped tetrasulfide bonds can quickly deplete GSH, which increases the cellular reactive oxygen species concentration to induce ferroptosis and meanwhile triggers particle biodegradation to expose the loaded l-Arg. Moreover, the elevated H2O2 level activates l-Arg to release NO for NO therapy. GOx consumes glucose to initiate starvation therapy and simultaneously produces a large amount of H2O2. Importantly, the produced H2O2 can not only potentiate ferroptosis but also promote NO release to enhance NO therapy. Besides, NO could in turn improve the efficacy of starvation therapy by damaging the mitochondria to block energy supply. In vitro and in vivo studies demonstrate that the nanoparticles show a great synergistic effect of ferroptosis/starvation/NO therapy, which can significantly kill cancer cells and remarkably inhibit tumor growth without obvious side effects. Therefore, we think that the designed nanoparticles may provide a promising paradigm for synergistic cancer therapy and hold a prospect in clinical trials.

Multifunctional siRNA/ferrocene/cyclodextrin nanoparticles for enhanced chemodynamic cancer therapy

“…32,33 DTNB has its characteristic absorption band centered at 312 nm and exhibits a red shift to 412 nm upon reaction with GSH, which is due to the formation of 2-nitro-5-thiobenzoic acid. 34 In order to study GSH depletion by the NPs, GSH (25 μM) was incubated with β-CD + /1 NPs (25 μM), H 2 O 2 (100 μM) and DTNB (10 μM) for 0.5 h, and the absorption spectral changes were then monitored. As a control experiment, the absorption spectrum of the reaction mixture containing GSH and DTNB without β-CD + /1 NPs and H 2 O 2 was recorded.…”

Boosting Reactive Oxygen Species Generation with a Dual-Catalytic Nanomedicine for Enhanced Tumor Nanocatalytic Therapy

“…To confirm the ROS sensitivity of nanoliposome (LIPSe), 200 μg of LIPSe was added into 1 mM H 2 O 2 with dipotassium titanium oxide dioxalate as an indicator. As well reported, TiO bonds could react with H 2 O 2 to yield yellow color, which had a good linear relationship existing between the maximum absorption of H 2 O 2 /Ti­(IV) and H 2 O 2 concentration. − As presented in Figure S5, LIPSe treatment caused significant decrease in H 2 O 2 concentration over time while LIP (nanoliposome without diselenide bonds incorporation) treatment did not reduce H 2 O 2 concentration. This indicated that the incorporated diselenide bonds of the nanoliposome could consume H 2 O 2 .…”

“…As well reported, TiO bonds could react with H 2 O 2 to yield yellow color, which had a good linear relationship existing between the maximum absorption of H 2 O 2 /Ti­(IV) and the H 2 O 2 concentration. − Therefore, in order to confirm the ROS sensitivity of LIPSe, 200 μg of LIPSe was added into 1 mM H 2 O 2 with dipotassium titanium oxide dioxalate as an indicator. After incubation for 1, 2, 4, 6, and 10 h, the absorbance was recorded by UV–vis spectroscopy to calculate the H 2 O 2 depletion and evaluate the ROS sensitivity ability of LIPSe.…”

Advanced porous materials for antimicrobial treatment

“…While several studies have been devoted to MSNs, [147][148][149] PSiNPs, [150][151][152] MOFs, [153][154][155] COFs, [156][157][158] HOFs [159] and carbon porous materials [160,161] in pre-clinical evaluation for cancer therapy, deeper in vivo studies are essential to understand the biodistribution and biosafety of the current advanced porous materials to reach effective infectious disease treatment and, ultimately, be translated to clinical trials.…”