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
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
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.