Combination of passive targeting with active targeting is a promising approach to improve the therapeutic efficacy of nanotherapy.However,most reported polymeric systems have sizes above100 nm,which limits effective e...Combination of passive targeting with active targeting is a promising approach to improve the therapeutic efficacy of nanotherapy.However,most reported polymeric systems have sizes above100 nm,which limits effective extravasation into tumors that are poorly vascularized and have dense stroma.This will,in turn,limit the overall effectiveness of the subsequent uptake by tumor cells via active targeting.In this study,we combined the passive targeting via ultra-small-sized gemcitabine(GEM)-based nanoparticles(NPs)with the active targeting provided by folic acid(FA)conjugation for enhanced dual targeted delivery to tumor cells and tumor-associated macrophages(TAMs).We developed an FAmodified prodrug carrier based on GEM(PGEM)to load doxorubicin(DOX),for co-delivery of GEM and DOX to tumors.The co-delivery system showed small particle size of~10 nm in diameter.The ligand-free and FA-targeted micelles showed comparable drug loading efficiency and a sustained DOX release profile.The FA-conjugated micelles effectively increased DOX uptake in cultured KB cancer cells that express a high level of folate receptor(FR),but no obvious increase was observed in 4T1.2 breast cancer cells that have a low-level expression of FR.Interestingly,in vivo,systemic delivery of FAPGEM/DOX led to enhanced accumulation of the NPs in tumor and drastic reduction of tumor growth in a murine 4T1.2 breast cancer model.Mechanistic study showed that 4T1.2 tumor grown in mice expressed a significantly higher level of FOLR2,which was selectively expressed on TAMs.Thus,targeting of TAM may also contribute to the improved in vivo targeted delivery and therapeutic efficacy.展开更多
PEGylated-L-asparaginase(PEG-ASNase)is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia(ALL).Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis,w...PEGylated-L-asparaginase(PEG-ASNase)is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia(ALL).Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis,with obesity and older age considered risk factors of the injury.Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury.Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1,3,5,and 7 days after drug administration.Liver triglycerides were quantified,and plasma bilirubin,ALT,AST,and non-esterified fatty acids(NEFA)were measured.The mRNA and protein levels of genes involved in hepatic fatty acid synthesis,β-oxidation,very low-density lipoprotein(VLDL)secretion,and white adipose tissue(WAT)lipolysis were determined.Mice developed hepatic steatosis after PEG-ASNase,which associated with increases in bilirubin,ALT,and AST.The hepatic genes Ppara,Lcad/Mcad,Hadhb,Apob100,and Mttp were upregulated,and Srebp-1 c and Fas were downregulated after PEG-ASNase.Increased plasma NEFA,WAT loss,and adipose tissue lipolysis were also observed after PEG-ASNase.Furthermore,we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice,consistent with clinical studies of ASNase-induced liver injury.Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.展开更多
基金supported by National Institute of Health grants R01CA174305,R01CA219399,R01CA223788(Song Li,USA),R21CA249649(Jingjing Sun,USA)a grant from Shear Family Foundation(Song Li,USA)。
文摘Combination of passive targeting with active targeting is a promising approach to improve the therapeutic efficacy of nanotherapy.However,most reported polymeric systems have sizes above100 nm,which limits effective extravasation into tumors that are poorly vascularized and have dense stroma.This will,in turn,limit the overall effectiveness of the subsequent uptake by tumor cells via active targeting.In this study,we combined the passive targeting via ultra-small-sized gemcitabine(GEM)-based nanoparticles(NPs)with the active targeting provided by folic acid(FA)conjugation for enhanced dual targeted delivery to tumor cells and tumor-associated macrophages(TAMs).We developed an FAmodified prodrug carrier based on GEM(PGEM)to load doxorubicin(DOX),for co-delivery of GEM and DOX to tumors.The co-delivery system showed small particle size of~10 nm in diameter.The ligand-free and FA-targeted micelles showed comparable drug loading efficiency and a sustained DOX release profile.The FA-conjugated micelles effectively increased DOX uptake in cultured KB cancer cells that express a high level of folate receptor(FR),but no obvious increase was observed in 4T1.2 breast cancer cells that have a low-level expression of FR.Interestingly,in vivo,systemic delivery of FAPGEM/DOX led to enhanced accumulation of the NPs in tumor and drastic reduction of tumor growth in a murine 4T1.2 breast cancer model.Mechanistic study showed that 4T1.2 tumor grown in mice expressed a significantly higher level of FOLR2,which was selectively expressed on TAMs.Thus,targeting of TAM may also contribute to the improved in vivo targeted delivery and therapeutic efficacy.
基金supported by the National Institutes of Health grants CA216815 and TL1TR001858(USA)the Pittsburgh Liver Research Center,Rho Chi Society+1 种基金American Foundation for Pharmaceutical Education(USA)the University of Pittsburgh School of Pharmacy(USA)。
文摘PEGylated-L-asparaginase(PEG-ASNase)is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia(ALL).Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis,with obesity and older age considered risk factors of the injury.Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury.Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1,3,5,and 7 days after drug administration.Liver triglycerides were quantified,and plasma bilirubin,ALT,AST,and non-esterified fatty acids(NEFA)were measured.The mRNA and protein levels of genes involved in hepatic fatty acid synthesis,β-oxidation,very low-density lipoprotein(VLDL)secretion,and white adipose tissue(WAT)lipolysis were determined.Mice developed hepatic steatosis after PEG-ASNase,which associated with increases in bilirubin,ALT,and AST.The hepatic genes Ppara,Lcad/Mcad,Hadhb,Apob100,and Mttp were upregulated,and Srebp-1 c and Fas were downregulated after PEG-ASNase.Increased plasma NEFA,WAT loss,and adipose tissue lipolysis were also observed after PEG-ASNase.Furthermore,we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice,consistent with clinical studies of ASNase-induced liver injury.Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.
