Background:Hepatocellular carcinoma(HCC)is a health problem due to multi-drug resistance(MDR).Codelivery of multiple oncotherapy in one cargo as chimeric cancer therapy(CCT)is suggested as a solution for MDR.This stud...Background:Hepatocellular carcinoma(HCC)is a health problem due to multi-drug resistance(MDR).Codelivery of multiple oncotherapy in one cargo as chimeric cancer therapy(CCT)is suggested as a solution for MDR.This study aims to engineer chitosan-coated nanostructure lipid carriers(NLCs)loaded with gefitinib(GF)and simvastatin(SV)as CCT for HCC.Methods:Both GF and SV-loaded nanostructure lipids carriers(GFSVNLC)and chitosan-capped GF and SV-loaded nanostructure lipids carriers(CGFSVNLC)formulations were assembled by topdown techniques.Moreover,particle size(PS),zeta potential(ZP),and polydispersity index(PDI)were measured by Zetasizer.The biosafety of GFSVNLC preparations was investigated by using erythrocytes as a biological model.The cytotoxic,and apoptotic effects of the prepared GFSVNLCs were investigated using HepG2 cell lines as a substitute model for HCC.The effect of GF,SV,and NLC composition on JNK3,HDAC6,and telomerase was studied using molecular docking simulation(MDS).Results:The present results revealed that the obtained GFSVNLC and CGFSVNLC have nanosized and consistent,CS coating shifts anionic ZP of GFSVNLC into CGFSVNLC with cationic ZP.Moreover,both formulations are biocompatible as indicated by their gentle effect on erythrocyte hemolysis.The treatment of HepG2 cells with GFSVNLC,and CGFSVNLC induced marked cell death compared to other groups with a decrease of IC50.Equally,the percentage of the apoptotic HepG2 cells was increased upon treatment of the cells with GFSV,GFSVNLC,and CGFSVNLC compared to the control group.Additionally,GF,SV,stearic acid(SA),and oleic acid(OA)modulate the activity of JNK3,HDAC6,and telomerase.Conclusions:This study suggests CGFSVNLC achieves codelivery,selective targeting,and enhancing the synergistic effect of GF and SV for inducing HepG2 cell death.Mechanistically,CGFSVNLC inhibits key cascades implicated in MDR and HepG2 cell survival.CGFSVNLC is promising for overcoming drug resistance mechanisms and improving therapeutic outcomes against HepG2 cells.展开更多
Objective:Prostate cancer(PCA)is the second most widespread cancer among men globally,with a rising mortality rate.Enzyme-responsive lipid nanoparticles(ERLNs)are promising vectors for the selective delivery of antica...Objective:Prostate cancer(PCA)is the second most widespread cancer among men globally,with a rising mortality rate.Enzyme-responsive lipid nanoparticles(ERLNs)are promising vectors for the selective delivery of anticancer agents to tumor cells.The goal of this study is to fabricate ERLNs for dual delivery of gefitinib(GF)and simvastatin(SV)to PCA cells.Methods:ERLNs loaded with GF and SV(ERLNGFSV)were assembled using bottomup and top-down techniques.Subsequently,these ERLN cargoes were coated with triacylglycerol,and phospholipids and capped with chitosan(CS).The ERLNGFSV,and CS engineered ERLNGFSV(CERLNGFSV)formulations were characterized for particle size(PS),zeta potential(ZP),and polydispersity index(PDI).The biocompatibility,and cytotoxicity of the plain and GF plus SV-loaded ERLN cargoes were assessed using erythrocytes and PC-3 cell line.Additionally,molecular docking simulations(MDS)were conducted to examine the influence of GF and SV on succinate dehydrogenase(SDH),glutathione peroxidase-4(GPX-4),and 5α-reductase(5α-RD).Results:These results showed that plain,ERLNGFSV,and CERLNGFSV cargoes have a nanoscale size and homogeneous appearance.Moreover,ERLNGFSV and CERLNGFSV were biocompatible,with no detrimental effects on erythrocytes.Treatment with GF,SV,GF plus SV,ERLNGFSV,and CERLNGFSV significantly reduced the viability of PC-3 cells compared to control cells.Particularly,the blend of GF and SV,as well as ERLNGFSV and CERLNGFSV augmented PC-3 cell death.Also,treating PC-3 cells with free drugs,their combination,ERLNGFSV,and CERLNGFSV formulations elevated the percentage of apoptotic cells.MDS studies demonstrated that GF and SV interact with the active sites of SDH,GPX-4,and 5α-reductase.Conclusions:This study concludes that SVGF combination and ERLNs loading induce particular delivery,and synergism on PC-3 death through action on multiple pathways involved in cell proliferation,and apoptosis,besides the interaction with SDH,GPX-4,and 5α-RD.Therefore,GFSV-loaded ERLN cargoes are a promising strategy for PCA treatment.In vivo studies are necessary to confirm these findings for clinical applications.展开更多
基金Support Project(RSPD2024R1037),King Saud University,Riyadh,Saudi Arabia.
文摘Background:Hepatocellular carcinoma(HCC)is a health problem due to multi-drug resistance(MDR).Codelivery of multiple oncotherapy in one cargo as chimeric cancer therapy(CCT)is suggested as a solution for MDR.This study aims to engineer chitosan-coated nanostructure lipid carriers(NLCs)loaded with gefitinib(GF)and simvastatin(SV)as CCT for HCC.Methods:Both GF and SV-loaded nanostructure lipids carriers(GFSVNLC)and chitosan-capped GF and SV-loaded nanostructure lipids carriers(CGFSVNLC)formulations were assembled by topdown techniques.Moreover,particle size(PS),zeta potential(ZP),and polydispersity index(PDI)were measured by Zetasizer.The biosafety of GFSVNLC preparations was investigated by using erythrocytes as a biological model.The cytotoxic,and apoptotic effects of the prepared GFSVNLCs were investigated using HepG2 cell lines as a substitute model for HCC.The effect of GF,SV,and NLC composition on JNK3,HDAC6,and telomerase was studied using molecular docking simulation(MDS).Results:The present results revealed that the obtained GFSVNLC and CGFSVNLC have nanosized and consistent,CS coating shifts anionic ZP of GFSVNLC into CGFSVNLC with cationic ZP.Moreover,both formulations are biocompatible as indicated by their gentle effect on erythrocyte hemolysis.The treatment of HepG2 cells with GFSVNLC,and CGFSVNLC induced marked cell death compared to other groups with a decrease of IC50.Equally,the percentage of the apoptotic HepG2 cells was increased upon treatment of the cells with GFSV,GFSVNLC,and CGFSVNLC compared to the control group.Additionally,GF,SV,stearic acid(SA),and oleic acid(OA)modulate the activity of JNK3,HDAC6,and telomerase.Conclusions:This study suggests CGFSVNLC achieves codelivery,selective targeting,and enhancing the synergistic effect of GF and SV for inducing HepG2 cell death.Mechanistically,CGFSVNLC inhibits key cascades implicated in MDR and HepG2 cell survival.CGFSVNLC is promising for overcoming drug resistance mechanisms and improving therapeutic outcomes against HepG2 cells.
文摘Objective:Prostate cancer(PCA)is the second most widespread cancer among men globally,with a rising mortality rate.Enzyme-responsive lipid nanoparticles(ERLNs)are promising vectors for the selective delivery of anticancer agents to tumor cells.The goal of this study is to fabricate ERLNs for dual delivery of gefitinib(GF)and simvastatin(SV)to PCA cells.Methods:ERLNs loaded with GF and SV(ERLNGFSV)were assembled using bottomup and top-down techniques.Subsequently,these ERLN cargoes were coated with triacylglycerol,and phospholipids and capped with chitosan(CS).The ERLNGFSV,and CS engineered ERLNGFSV(CERLNGFSV)formulations were characterized for particle size(PS),zeta potential(ZP),and polydispersity index(PDI).The biocompatibility,and cytotoxicity of the plain and GF plus SV-loaded ERLN cargoes were assessed using erythrocytes and PC-3 cell line.Additionally,molecular docking simulations(MDS)were conducted to examine the influence of GF and SV on succinate dehydrogenase(SDH),glutathione peroxidase-4(GPX-4),and 5α-reductase(5α-RD).Results:These results showed that plain,ERLNGFSV,and CERLNGFSV cargoes have a nanoscale size and homogeneous appearance.Moreover,ERLNGFSV and CERLNGFSV were biocompatible,with no detrimental effects on erythrocytes.Treatment with GF,SV,GF plus SV,ERLNGFSV,and CERLNGFSV significantly reduced the viability of PC-3 cells compared to control cells.Particularly,the blend of GF and SV,as well as ERLNGFSV and CERLNGFSV augmented PC-3 cell death.Also,treating PC-3 cells with free drugs,their combination,ERLNGFSV,and CERLNGFSV formulations elevated the percentage of apoptotic cells.MDS studies demonstrated that GF and SV interact with the active sites of SDH,GPX-4,and 5α-reductase.Conclusions:This study concludes that SVGF combination and ERLNs loading induce particular delivery,and synergism on PC-3 death through action on multiple pathways involved in cell proliferation,and apoptosis,besides the interaction with SDH,GPX-4,and 5α-RD.Therefore,GFSV-loaded ERLN cargoes are a promising strategy for PCA treatment.In vivo studies are necessary to confirm these findings for clinical applications.
