Multiple stimuli-responsive nanosystem for potent, ROS-amplifying, chemo-sonodynamic antitumor therapy

JunJie Tang; Xiaoge Zhang; Lili Cheng; Yadong Liu; You Chen; Zhaozhong Jiang; Jie Liu

doi:10.1016/j.bioactmat.2021.12.002

Multiple stimuli-responsive nanosystem for potent, ROS-amplifying, chemo-sonodynamic antitumor therapy

Bioact Mater. 2021 Dec 20:15:355-371. doi: 10.1016/j.bioactmat.2021.12.002. eCollection 2022 Sep.

Authors

JunJie Tang¹, Xiaoge Zhang¹, Lili Cheng¹, Yadong Liu¹, You Chen¹, Zhaozhong Jiang², Jie Liu¹

Affiliations

¹ School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.
² Faculty of Arts and Sciences, Department of Biomedical Engineering, Integrated Science and Technology Center, Yale University, 600 West Campus Drive, West Haven, CT, 06516, United States.

Abstract

Although sonodynamic therapy (SDT) is a promising non-invasive tumor treatment strategy due to its safety, tissue penetration depth and low cost, the hypoxic tumor microenvironment limits its therapeutic effects. Herein, we have designed and developed an oxygen-independent, ROS-amplifying chemo-sonodynamic antitumor therapy based on novel pH/GSH/ROS triple-responsive PEG-PPMDT nanoparticles. The formulated artemether (ART)/Fe₃O₄-loaded PEG-PPMDT NPs can rapidly release drug under the synergistic effect of acidic endoplasmic pH and high intracellular GSH/ROS levels to inhibit cancer cell growth. Besides, the ROS level in the NPs-treated tumor cells is magnified by ART via interactions with both Fe²⁺ ions formed in situ at acidic pH and external ultrasound irradiation, which is not affected by hypoxia tumor microenvironment. Consequently, the enriched intracellular ROS level can cause direct necrosis of ROS-stressed tumor cells and further accelerate the drug release from the ROS-responsive PEG-PPMDT NPs, achieving an incredible antitumor potency. Specifically, upon the chemo-sonodynamic therapy by ART/Fe₃O₄-loaded PEG-PPMDT NPs, all xenotransplants of human hepatocellular carcinoma (HepG2) in nude mice shrank significantly, and 40% of the tumors were completely eliminated. Importantly, the Fe₃O₄ encapsulated in the NPs is an efficient MRI contrast agent and can be used to guide the therapeutic procedures. Further, biosafety analyses show that the PEG-PPMDT NPs possess minimal toxicity to main organs. Thus, our combined chemo-sonodynamic therapeutic method is promising for potent antitumor treatment by controlled release of drug and facile exogenous generation of abundant ROS at target tumor sites.

Keywords: Chemodynamic therapy; MRI imaging; Nanoparticle; Sonodynamic therapy; pH/GSH/ROS triple-Responsive.