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  2. Hypoxia-Adapted Sono-chemodynamic Treatment of Orthotopic Pancreatic Carcinoma Using Copper Metal-Organic Frameworks Loaded with an Ultrasound-Induced Free Radical Initiator

Hypoxia-Adapted Sono-chemodynamic Treatment of Orthotopic Pancreatic Carcinoma Using Copper Metal-Organic Frameworks Loaded with an Ultrasound-Induced Free Radical Initiator

  • ACS Appl Mater Interfaces. 2021 Aug 18;13(32):38114-38126. doi: 10.1021/acsami.1c11017.
Yu Sun 1 2 Jing Cao 1 2 Xue Wang 1 2 Cong Zhang 1 2 Jiali Luo 1 2 Yiqing Zeng 1 2 Chao Zhang 1 2 Qunying Li 1 2 Ying Zhang 1 2 Wen Xu 1 2 Tao Zhang 1 2 Pintong Huang 1 2
Affiliations

Affiliations

  • 1 Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, No.88 Jiefang Road, Shangcheng District, Hangzhou 310009, P.R. China.
  • 2 Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, P.R. China.
Abstract

The efficacy of sonodynamic therapy (SDT) is largely dependent upon oxygen availability to generate deleterious Reactive Oxygen Species, and as such, hypoxic microenvironments greatly constrain the efficacy of SDT. Development of free radical generators that are not dependent on oxygen and related combination treatment strategies thus have the potential to enhance the antitumor potential of SDT. Combined treatment strategies are expected to improve the efficacy of sonodynamic antitumor therapy. As metal-organic framework (MOF) platforms are highly amenable to integration with other therapeutic approaches, we herein report the development of tumor microenvironment (TME)-responsive nanoparticles constructed by embedding the azo initiator 2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (AIPH) into hypoxia-triggered copper metal-organic framework (Cu-MOF) nanovectors to achieve synergistic sono-chemodynamic therapy in an orthotopic murine pancreatic carcinoma model system. When exposed to hypoxic conditions within the TME, this Cu-MOF structure underwent degradation, leading to the release of Cu2+ and AIPH. Cu2+ was then able to deplete local glutathione stores, resulting in the reduction of Cu2+ to Cu+, which then reacts with endogenous H2O2 in a Fenton-like reaction to yield cytotoxic hydroxyl radicals (OH) for chemodynamic therapy. When exposed to ultrasound irradiation, AIPH further degraded in an oxygen-independent manner to yield nitrogen bubbles and alkyl radicals, the former of which enhanced the ability of these nanoparticles to penetrate deeply into the tumor. The resultant radicals induced substantial DNA damage and apoptotic cell death within target tumors under different levels of oxygen availability. As such, this hypoxic TME-responsive synergistic sono-chemodynamic approach offers an ideal means of achieving oxygen-independent free radical generation and enhanced treatment efficacy.

Keywords

azo initiator; chemodynamic therapy; free radicals; metal−organic framework; sonodynamic therapy; tumor microenvironment-responsive nanoparticles.

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