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

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.

Latest Advances in the Use of Therapeutic Focused Ultrasound in the Treatment of Pancreatic Cancer

“…It should be noted that in the absence of hyperthermia treatment of the tumours, their non-liposomal doxorubicin concentration was approximately eight times higher than that when liposomal doxorubicin was used (parameters: f = 1.2 MHz, Power = 7 W, d.c = 100%, T = 41.2 ± 1.3 • C) [174]. Additional studies have shown that the delivery of gemcitabine to pancreatic tumours was enhanced by sonoporation in human pancreatic MiaPaCa-2 tumours grown orthotopically in mice [175], while the combination of sonodynamic therapy with various anti-cancer compounds, including 5-aminolevulinic acid [176,177], 5FU [178,179], antibiotic and root extracts [180], gemcitabine [181], nanocomposites able to generate reactive oxygen species or nitric oxide [182][183][184], radiation [185] and epirubicin [186], have provided proof of concept for the intriguing potential that sonodynamic therapy has in pancreatic cancer.…”

Dual-responsive and NIR-driven free radical nanoamplifier with glutathione depletion for enhanced tumor-specific photothermal/thermodynamic/chemodynamic synergistic Therapy

“…27,28 In addition, the upregulated glutathione (GSH) in cancer cells has a potent scavenging effect on the generated free radicals, thereby dramatically diminishing the therapeutic efficiency of TDT. [29][30][31] Thus, designing a tumor-specific nanoreactor with the ability of controlled drug release and GSH depletion is of great importance to realize safe and efficient TDT.…”

Ultrathin‐FeOOH‐Coated MnO2 Sonosensitizers with Boosted Reactive Oxygen Species Yield and Remodeled Tumor Microenvironment for Efficient Cancer Therapy

“…[ 24 , 25 , 26 , 27 ] Thus, TME regulation has also been adopted recently to optimize the SDT performance. [ 11 , 28 , 29 ] For instance, a hydrogenated hollow Pt‐TiO 2 Janus was designed to catalyze the decomposition of endogenous H 2 O 2 to O 2 . The resultant hypoxia alleviation enabled high tumor cell killing efficacy in vitro.…”