Activated pancreatic stellate cells(PSCs)are the main source of collagen layer deposition and the key target in pancreatic fibrosis.However,no effective treatment specific to pancreatic fibrosis clinically,owing to th...Activated pancreatic stellate cells(PSCs)are the main source of collagen layer deposition and the key target in pancreatic fibrosis.However,no effective treatment specific to pancreatic fibrosis clinically,owing to the drug accumulation blocked by the collagen barrier and thus it is difficult to inhibit activated PSCs precisely.Herein,a PSCs-targeting nano-system based on“nanodrill”strategy(LA-PC)was designed to enhance the accumulation of all-trans retinoic acid(ATRA)in PSCs,relying on the platelet-derived growth factor receptor beta(PDGFRβ)-targeting peptide(p PB:C*SRNLIDC*)and collagenase(Col).After being injected into fibrotic mice via tail vein,the Col modified on LA-PC can remove the excess collagen layer,and the drug delivery efficiency through pPB targeting peptide was more than 5 times higher than that of free ATRA,as well as the degree of fibrosis significantly reduced.Notably,this nano-system effectively inhibited platelet-derived growth factor subunit B(PDGF-BB)/PDGFRβaxis on PSCs via a down-regulated extracellular signal-regulated protein kinase(ERK)pathway,and accordingly reduced the level of PDGFBB.Thus,the smart platform provided a promising strategy for the treatment of pancreatic fibrosis to achieve the precise regulation of PSCs.展开更多
基金financially supported by the National Natural Science Foundation of China(Nos.82020108029,82073398)the National Key Research and Development Program of China(No.2022YFE0198400)supported by Double FirstRate construction plan of China Pharmaceutical University(No.CPU2022QZ18)。
文摘Activated pancreatic stellate cells(PSCs)are the main source of collagen layer deposition and the key target in pancreatic fibrosis.However,no effective treatment specific to pancreatic fibrosis clinically,owing to the drug accumulation blocked by the collagen barrier and thus it is difficult to inhibit activated PSCs precisely.Herein,a PSCs-targeting nano-system based on“nanodrill”strategy(LA-PC)was designed to enhance the accumulation of all-trans retinoic acid(ATRA)in PSCs,relying on the platelet-derived growth factor receptor beta(PDGFRβ)-targeting peptide(p PB:C*SRNLIDC*)and collagenase(Col).After being injected into fibrotic mice via tail vein,the Col modified on LA-PC can remove the excess collagen layer,and the drug delivery efficiency through pPB targeting peptide was more than 5 times higher than that of free ATRA,as well as the degree of fibrosis significantly reduced.Notably,this nano-system effectively inhibited platelet-derived growth factor subunit B(PDGF-BB)/PDGFRβaxis on PSCs via a down-regulated extracellular signal-regulated protein kinase(ERK)pathway,and accordingly reduced the level of PDGFBB.Thus,the smart platform provided a promising strategy for the treatment of pancreatic fibrosis to achieve the precise regulation of PSCs.
