Bacterial infection,excessive inflammatory response,and impaired angiogenesis caused by the hyperglycemic microenvironment of diabetic wounds are the primary factors of non-healing wounds.Most contemporary wound repai...Bacterial infection,excessive inflammatory response,and impaired angiogenesis caused by the hyperglycemic microenvironment of diabetic wounds are the primary factors of non-healing wounds.Most contemporary wound repair materials passively release loaded drugs,resulting in poor therapeutic outcomes.In this study,we designed sequentially triggered triple-responsive hydrogels containing alginate(ALG)-phenylboronic acid(PBA),copper polydopamine(Cu-PDA),metformin(MET),and deferoxamine mesylate(DFO)to cover the continuous process of diabetic-infected wound healing and improve the wound microenvironment through warming in the infectious phase and on-demand drug release in the inflammatory and proliferative phase.The hydrogels exhibited good adhesivity,injectability,self-healing ability,and biocompatibility.The hydrogels show remarkable photothermal responsiveness due to the presence of PDA.Studies showed that appropriate high temperatures and the release of Cu2+resulted in the hydrogels displaying excellent bactericidal properties in the infectious phase.Furthermore,the instability of the phenyl borate bond in a hyperglycemic and acidic microenvironment enables the glucose/pH responsiveness of the release of MET and DFO from the hydrogels.Mechanistic studies have shown that the hydrogels could suppress the activity of the NOD-,LRR-,and pyrin structural domain-containing protein 3(NLRP3)/caspase-1/GasderminD(GSDMD)/IL-1βpathway and activate the hypoxia-inducible factor 1 alpha(HIF-1α)/vascular endothelial growth factor(VEGF)pathway.These effects enabled the hydrogels to promote the healing of diabetic-infected wounds.展开更多
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...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.展开更多
基金supported by the National Natural Science Foundation of China(Nos.81974288,82170253,and 82241018).
文摘Bacterial infection,excessive inflammatory response,and impaired angiogenesis caused by the hyperglycemic microenvironment of diabetic wounds are the primary factors of non-healing wounds.Most contemporary wound repair materials passively release loaded drugs,resulting in poor therapeutic outcomes.In this study,we designed sequentially triggered triple-responsive hydrogels containing alginate(ALG)-phenylboronic acid(PBA),copper polydopamine(Cu-PDA),metformin(MET),and deferoxamine mesylate(DFO)to cover the continuous process of diabetic-infected wound healing and improve the wound microenvironment through warming in the infectious phase and on-demand drug release in the inflammatory and proliferative phase.The hydrogels exhibited good adhesivity,injectability,self-healing ability,and biocompatibility.The hydrogels show remarkable photothermal responsiveness due to the presence of PDA.Studies showed that appropriate high temperatures and the release of Cu2+resulted in the hydrogels displaying excellent bactericidal properties in the infectious phase.Furthermore,the instability of the phenyl borate bond in a hyperglycemic and acidic microenvironment enables the glucose/pH responsiveness of the release of MET and DFO from the hydrogels.Mechanistic studies have shown that the hydrogels could suppress the activity of the NOD-,LRR-,and pyrin structural domain-containing protein 3(NLRP3)/caspase-1/GasderminD(GSDMD)/IL-1βpathway and activate the hypoxia-inducible factor 1 alpha(HIF-1α)/vascular endothelial growth factor(VEGF)pathway.These effects enabled the hydrogels to promote the healing of diabetic-infected wounds.
基金supported by the National Natural Science Foundation of China(51773231)the Natural Science Foundation of Guangdong Province(2016A030313315)+1 种基金Shenzhen Science and Technology Project(JCYJ20190807160801664)the Project of Key Laboratory of Sensing Technology and Biomedical Instruments of Guangdong Province(2011A060901013)。
文摘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.
