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
There are several limitations to the application of nanoparticles in the treatment of cancer,including their low drug loading,poor colloidal stability,insufficient tumor penetration,and uncontrolled release of the dru...There are several limitations to the application of nanoparticles in the treatment of cancer,including their low drug loading,poor colloidal stability,insufficient tumor penetration,and uncontrolled release of the drug.Herein,gelatin/laponite(LP)/doxorubicin(GLD)nanoparticles are developed by crosslinking LP with gelatin for doxorubicin delivery.GLD shows high doxorubicin encapsulation efficacy(99%)and strong colloidal stability,as seen from the unchanged size over the past 21 days and reduced protein absorption by 48-fold compared with unmodified laponite/doxorubicin nanoparticles.When gelatin from 115 nm GLD reaches the tumor site,matrix metallopeptidase-2(MMP-2)from the tumor environment breaks it down to release smaller 40 nm LP nanoparticles for effective tumor cell endocytosis.As demonstrated by superior penetration in both in vitro three-dimensional(3D)tumor spheroids(138-fold increase compared to the free drug)and in vivo tumor models.The intracellular low pH and MMP-2 further cause doxorubicin release after endocytosis by tumor cells,leading to a higher inhibitory potential against cancer cells.The improved anticancer effectiveness and strong in vivo biocompatibility of GLD have been confirmed using a mouse tumor-bearing model.MMP-2/pH sequentially triggered anticancer drug delivery is made possible by the logical design of tumor-penetrating GLD,offering a useful method for anticancer therapy.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 Basic Research Program of China(973 Program,No.2012CB933600)the National Natural Science Foundation of China(Nos.81771964 and 82072051)+4 种基金the Shanghai Municipal Natural Science Foundation(No.15ZR1408500)funded by the Special Project of Clinical Research of Health Industry of Shanghai Municipal Health Commission(No.201940178)the Scientific Research Project of Hongkou District Health Committee of Shanghai(No.2002-17)the Clinical Research Project of Wu Jieping Medical Foundation(No.320.6750.2020-18-2)the Research Project of Shanghai Fourth People’s Hospital(No.sykyqd 00701&00702).
文摘There are several limitations to the application of nanoparticles in the treatment of cancer,including their low drug loading,poor colloidal stability,insufficient tumor penetration,and uncontrolled release of the drug.Herein,gelatin/laponite(LP)/doxorubicin(GLD)nanoparticles are developed by crosslinking LP with gelatin for doxorubicin delivery.GLD shows high doxorubicin encapsulation efficacy(99%)and strong colloidal stability,as seen from the unchanged size over the past 21 days and reduced protein absorption by 48-fold compared with unmodified laponite/doxorubicin nanoparticles.When gelatin from 115 nm GLD reaches the tumor site,matrix metallopeptidase-2(MMP-2)from the tumor environment breaks it down to release smaller 40 nm LP nanoparticles for effective tumor cell endocytosis.As demonstrated by superior penetration in both in vitro three-dimensional(3D)tumor spheroids(138-fold increase compared to the free drug)and in vivo tumor models.The intracellular low pH and MMP-2 further cause doxorubicin release after endocytosis by tumor cells,leading to a higher inhibitory potential against cancer cells.The improved anticancer effectiveness and strong in vivo biocompatibility of GLD have been confirmed using a mouse tumor-bearing model.MMP-2/pH sequentially triggered anticancer drug delivery is made possible by the logical design of tumor-penetrating GLD,offering a useful method for anticancer therapy.
