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

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)/Fe_(3)O_(4)-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 Fe^(2+)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/Fe_(3)O_(4)-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.