There remain several intractable challenges for chemotherapy in glioma treatment,including the blood-brain barrier(BBB),blood-brain tumor barrier(BBTB),and tumor heterogeneity caused by cancer stem cells(CSCs),which a...There remain several intractable challenges for chemotherapy in glioma treatment,including the blood-brain barrier(BBB),blood-brain tumor barrier(BBTB),and tumor heterogeneity caused by cancer stem cells(CSCs),which are resistant to conventional chemotherapy.Here,we established a nano strategy to kill glioma cells and CSCs,combining carfilzomib and bis(diethyldithiocarbamate)copper.The synergistic drug combination disturbed cell protein metabolism at different stages and induced apoptosis and cuproptosis.The Y-shaped targeting ligand pHA-VAP-modified nanodiscs were designed to help the chemotherapeutic agents cross the BBB/BBTB and finally accumulate in tumor site.This all-stage targeting and all-stage treatment nanomedicine significantly prolonged the survival in glioma-bearing mice and might inspire the rational design of advanced drug delivery platforms.展开更多
Lipid nanoparticles(LNPs)formulated with ionizable lipids,such as ALC-0315 and SM-102,suffer from significant hepatic off-target expression following intramuscular administration,which could potentially impair hepatic...Lipid nanoparticles(LNPs)formulated with ionizable lipids,such as ALC-0315 and SM-102,suffer from significant hepatic off-target expression following intramuscular administration,which could potentially impair hepatic function and reduce therapeutic efficacy.Currently,novel ionizable lipid discovery predominantly relies on stochastic high-throughput screening.Here,we designed a 2-aminoimidazole(AM)-based ionizable lipid library and established a molecular dynamics-guided strategy for quantitatively analyzing the lipid-mRNA interaction strength,which might offer a rational screening alternative.A33-D268 emerged as the top-performing candidate through molecular dynamics simulations.Following formulation optimization via definitive screening design experiments,the AM-LNP/mRNA formulated with A33-D268 demonstrated an intramuscular transfection efficiency similar to that of ALC-0315-based LNPs,with markedly reduced hepatic off-target expression.展开更多
Thrombolytic agents have thus far yielded limited therapeutic benefits in the treatment of thrombotic disease due to their short half-life,low targeting ability,and association with serious adverse reactions,such as b...Thrombolytic agents have thus far yielded limited therapeutic benefits in the treatment of thrombotic disease due to their short half-life,low targeting ability,and association with serious adverse reactions,such as bleeding complications.Inspired by the natural roles of platelets during thrombus formation,we fabricated a platelet-based delivery system(NO@uPA/PLTs)comprising urokinase(uPA)and arginine(Arg)for targeted thrombolysis and inhibition of re-embolism.The anchoring of uPA to the platelet surface by lipid insertion increased the thrombotic targeting and in vivo circulation duration of uPA without disturbing platelet functions.Nitric oxide(NO)generated by the loaded Arg inhibited platelet aggregation and activation at the damaged blood vessel,thereby inhibiting re-embolism.NO@uPA/PLTs effectively accumulated at the thrombi in pulmonary embolism and carotid artery thrombosis model mice and exerted superior thrombolytic efficacy.In addition,the platelet delivery system showed excellent thrombus recurrence prevention ability in a mouse model of secondary carotid artery injury.The coagulation indicators in vivo showed that the platelet-based uPA and NO co-delivery system possessed a low hemorrhagic risk,providing a promising tool for rapid thrombolysis and efficient inhibition of posttreatment re-embolism.展开更多
Brain metastasis is a common and serious complication of breast cancer,which is commonly associated with poor survival and prognosis.In particular,the treatment of brain metastasis from triplenegative breast cancer(BM...Brain metastasis is a common and serious complication of breast cancer,which is commonly associated with poor survival and prognosis.In particular,the treatment of brain metastasis from triplenegative breast cancer(BM-TNBC)has to face the distinct therapeutic challenges from tumor heterogeneity,circulating tumor cells(CTCs),blood-brain barrier(BBB)and blood-tumor barrier(BTB),which is in unmet clinical needs.Herein,combining with the advantages of synthetic and natural targeting moieties,we develop a“Y-shaped”peptide pVAP-decorated platelet-hybrid liposome drug delivery system to address the all-stage targeted drug delivery for the whole progression of BM-TNBC.Inherited from the activated platelet,the hybrid liposomes still retain the native affinity toward CTCs.Further,the peptide-mediated targeting to breast cancer cells and transport across BBB/BTB are demonstrated in vitro and in vivo.The resultant delivery platform significantly improves the drug accumulation both in orthotopic breast tumors and brain metastatic lesions,and eventually exhibits an outperformance in the inhibition of BM-TNBC compared with the free drug.Overall,this work provides a promising prospect for the comprehensive treatment of BMTNBC,which could be generalized to other cell types or used in imaging platforms in the future.展开更多
AL3810,a molecular dual inhibitor of the vascular endothelial growth factor receptor(VEGFR)and fibroblast growth factor receptor(FGFR),has earned the permission of phase II clinical trial for tumor treatment by China ...AL3810,a molecular dual inhibitor of the vascular endothelial growth factor receptor(VEGFR)and fibroblast growth factor receptor(FGFR),has earned the permission of phase II clinical trial for tumor treatment by China FDA.As a reversible ATP-competitive inhibitor,AL3810 targets ATP-binding site on intracellular region of VEGFR and FGFR,whereas,AL3810 lacking interplay with extracellular region of receptors rendered deficient bloodebrain tumor barrier(BBTB)recognition,poor brain penetration and unsatisfactory anti-glioma efficacy.Integrin avb3 overexpressed on capillary endothelial cells of BBTB as well as glioma cells illuminated ligand-modified liposomes for pinpoint spatial delivery into glioma.The widely accepted peptide c(RGDyK)-modified liposome loading AL3810 of multiple dosing caused hypothermia,activated anti-c(RGDyK)-liposome IgG and IgM antibody and pertinent complements C3 b and C5 b-9,and experienced complement-dependent opsonization.We newly proposed a pentapeptide mn with superb avb3-binding affinity and tailored AL3810-loaded mn-modified liposome that afforded impervious blood circulation,targeting ability,and glioma therapeutic expertise as vastly alleviated immune opsonization on the underpinning of the finite antibodies and complements assembly.Stemming from attenuated immunogenicity,peptide mn strengthened liposome functions as a promising nanocarrier platform for molecular targeting agents.展开更多
基金sponsored by Shanghai Education Commission Major Project(2017-01-07-00-07-E00052)National Natural Science Foundation of China(No.81773657)+1 种基金Shanghai Sailing Program(No.20YF1404500)Scientific Research Foundation of Huashan Hospital,Fudan University(No.2019QD012).
文摘There remain several intractable challenges for chemotherapy in glioma treatment,including the blood-brain barrier(BBB),blood-brain tumor barrier(BBTB),and tumor heterogeneity caused by cancer stem cells(CSCs),which are resistant to conventional chemotherapy.Here,we established a nano strategy to kill glioma cells and CSCs,combining carfilzomib and bis(diethyldithiocarbamate)copper.The synergistic drug combination disturbed cell protein metabolism at different stages and induced apoptosis and cuproptosis.The Y-shaped targeting ligand pHA-VAP-modified nanodiscs were designed to help the chemotherapeutic agents cross the BBB/BBTB and finally accumulate in tumor site.This all-stage targeting and all-stage treatment nanomedicine significantly prolonged the survival in glioma-bearing mice and might inspire the rational design of advanced drug delivery platforms.
基金supported by the National Science Foundation of China(No.81973249)the Shanghai Commission of Science and Technology(No.20S11905500)。
文摘Lipid nanoparticles(LNPs)formulated with ionizable lipids,such as ALC-0315 and SM-102,suffer from significant hepatic off-target expression following intramuscular administration,which could potentially impair hepatic function and reduce therapeutic efficacy.Currently,novel ionizable lipid discovery predominantly relies on stochastic high-throughput screening.Here,we designed a 2-aminoimidazole(AM)-based ionizable lipid library and established a molecular dynamics-guided strategy for quantitatively analyzing the lipid-mRNA interaction strength,which might offer a rational screening alternative.A33-D268 emerged as the top-performing candidate through molecular dynamics simulations.Following formulation optimization via definitive screening design experiments,the AM-LNP/mRNA formulated with A33-D268 demonstrated an intramuscular transfection efficiency similar to that of ALC-0315-based LNPs,with markedly reduced hepatic off-target expression.
基金This work was supported by the National Natural Science Foundation of China(No.81690263).
文摘Thrombolytic agents have thus far yielded limited therapeutic benefits in the treatment of thrombotic disease due to their short half-life,low targeting ability,and association with serious adverse reactions,such as bleeding complications.Inspired by the natural roles of platelets during thrombus formation,we fabricated a platelet-based delivery system(NO@uPA/PLTs)comprising urokinase(uPA)and arginine(Arg)for targeted thrombolysis and inhibition of re-embolism.The anchoring of uPA to the platelet surface by lipid insertion increased the thrombotic targeting and in vivo circulation duration of uPA without disturbing platelet functions.Nitric oxide(NO)generated by the loaded Arg inhibited platelet aggregation and activation at the damaged blood vessel,thereby inhibiting re-embolism.NO@uPA/PLTs effectively accumulated at the thrombi in pulmonary embolism and carotid artery thrombosis model mice and exerted superior thrombolytic efficacy.In addition,the platelet delivery system showed excellent thrombus recurrence prevention ability in a mouse model of secondary carotid artery injury.The coagulation indicators in vivo showed that the platelet-based uPA and NO co-delivery system possessed a low hemorrhagic risk,providing a promising tool for rapid thrombolysis and efficient inhibition of posttreatment re-embolism.
基金supported by Shanghai Education Commission Major Project(No.2017-01-07-00-07-E00052,China)National Natural Science Foundation of China(Nos.81773657,81690263,and 81903547,China)Shanghai Sailing Program(No.20YF1404500,China)。
文摘Brain metastasis is a common and serious complication of breast cancer,which is commonly associated with poor survival and prognosis.In particular,the treatment of brain metastasis from triplenegative breast cancer(BM-TNBC)has to face the distinct therapeutic challenges from tumor heterogeneity,circulating tumor cells(CTCs),blood-brain barrier(BBB)and blood-tumor barrier(BTB),which is in unmet clinical needs.Herein,combining with the advantages of synthetic and natural targeting moieties,we develop a“Y-shaped”peptide pVAP-decorated platelet-hybrid liposome drug delivery system to address the all-stage targeted drug delivery for the whole progression of BM-TNBC.Inherited from the activated platelet,the hybrid liposomes still retain the native affinity toward CTCs.Further,the peptide-mediated targeting to breast cancer cells and transport across BBB/BTB are demonstrated in vitro and in vivo.The resultant delivery platform significantly improves the drug accumulation both in orthotopic breast tumors and brain metastatic lesions,and eventually exhibits an outperformance in the inhibition of BM-TNBC compared with the free drug.Overall,this work provides a promising prospect for the comprehensive treatment of BMTNBC,which could be generalized to other cell types or used in imaging platforms in the future.
基金supported by the National Natural Science Foundation of China(Nos.81773657,and 81690263)Innovation Program of Shanghai Municipal Education Commission(2017-0107-00-07E00052,China)National Basic Research Program of China(973 Program,No.2013CB932500,China)
文摘AL3810,a molecular dual inhibitor of the vascular endothelial growth factor receptor(VEGFR)and fibroblast growth factor receptor(FGFR),has earned the permission of phase II clinical trial for tumor treatment by China FDA.As a reversible ATP-competitive inhibitor,AL3810 targets ATP-binding site on intracellular region of VEGFR and FGFR,whereas,AL3810 lacking interplay with extracellular region of receptors rendered deficient bloodebrain tumor barrier(BBTB)recognition,poor brain penetration and unsatisfactory anti-glioma efficacy.Integrin avb3 overexpressed on capillary endothelial cells of BBTB as well as glioma cells illuminated ligand-modified liposomes for pinpoint spatial delivery into glioma.The widely accepted peptide c(RGDyK)-modified liposome loading AL3810 of multiple dosing caused hypothermia,activated anti-c(RGDyK)-liposome IgG and IgM antibody and pertinent complements C3 b and C5 b-9,and experienced complement-dependent opsonization.We newly proposed a pentapeptide mn with superb avb3-binding affinity and tailored AL3810-loaded mn-modified liposome that afforded impervious blood circulation,targeting ability,and glioma therapeutic expertise as vastly alleviated immune opsonization on the underpinning of the finite antibodies and complements assembly.Stemming from attenuated immunogenicity,peptide mn strengthened liposome functions as a promising nanocarrier platform for molecular targeting agents.
