Mitochondria-specific nanocatalysts for chemotherapy-augmented sequential chemoreactive tumor therapy

Hui Huang; Caihong Dong; Meiqi Chang; Li Ding; Liang Chen; Wei Feng; Yu Chen

doi:10.1002/EXP.20210149

Mitochondria-specific nanocatalysts for chemotherapy-augmented sequential chemoreactive tumor therapy

Exploration (Beijing). 2021 Sep 1;1(1):50-60. doi: 10.1002/EXP.20210149. eCollection 2021 Aug.

Authors

Hui Huang^{1

2

3}, Caihong Dong⁴, Meiqi Chang³, Li Ding³, Liang Chen², Wei Feng², Yu Chen^{1

2

3}

Affiliations

¹ School of Environmental and Chemical Engineering Shanghai University Shanghai P. R. China.
² Materdicine Lab, School of Life Sciences Shanghai University Shanghai P. R. China.
³ State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics Chinese Academy of Sciences Shanghai P. R. China.
⁴ Department of Ultrasound, Zhongshan Hospital Fudan University, and Shanghai Institute of Medical Imaging Shanghai P. R. China.

Abstract

Endogenic tumor chemodynamic therapy (CDT) is emerging as a tumor-therapeutic strategy featuring in situ treatments with high efficiency and specificity based on the Fenton reaction principle. Considering the limitation of monotherapy and relatively insufficient intracellular level of endogenous hydrogen peroxide (H₂O₂) in tumor tissues, a mitochondria-specific nanocatalyst composed of cisplatin prodrug and gallic acid-ferrous (GA-Fe(II)) nanocomposites is successfully fabricated to fulfill chemotherapy-augmented sequential chemoreactive tumor therapy. The bioactive cisplatin elevates the level of endogenous H₂O₂ through the activation of nicotinamide adenine dinucleotide phosphate oxidase (NOX)-related cascaded reactions, and the GA-Fe(II) nanocomposites possessing sustainable Fenton catalytic activity subsequently catalyzes H₂O₂ into highly reactive and toxic hydroxyl radicals to substantially inhibit tumor progression. Especially, this mitochondria-specific nanocatalyst amplifies oxidative stress, stimulates mitochondrial dysfunction, downregulates AKT/mTOR signaling and finally induces cell autophagic death. Both in vitro and in vivo measurements verify that the chemotherapy-augmented sequential chemoreactive nanotherapy based on the mitochondria-specific nanocatalyst implements excellent anticancer efficiency and avoids undesired side effects. This work reveals the enormous potential of chemotherapy-augmented CDT for combating tumors.

Keywords: autophagy; chemodynamic therapy; cisplatin prodrug; mitochondria‐specific nanocatalysts.