Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy.Herein,a kind of tumor cascade-targeted responsive liposome(NLG919@Lip-pep1)is develope...Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy.Herein,a kind of tumor cascade-targeted responsive liposome(NLG919@Lip-pep1)is developed by conjugating polypeptide inhibitor of PD-1 signal pathway(AUNP-12),which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2(MMP-2)cleavable peptide(GPLGVRGD).This targeted liposome is prepared through a mature preparation process,and indoleamine-2,3-dioxygenase(IDO)inhibitor NLG919 was encapsulated into it.Moreover,mediated by the enhanced permeability and retention effect(EPR effect)and AUNP-12,NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues.At the same time,the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12,thus realizing the precise block of PD-1 signal pathway,and restoring the activity of T cells.The exposure of secondary targeting moduleⅡVRGDC-NLG919@Lip mediated tumor cells targeting,and further relieved the immunosuppressive microenvironment.Overall,this study offers a potentially appealing paradigm of a high efficiency,low toxicity,and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer,which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.展开更多
The clinical outcomes of cancer nanovaccine have been largely impeded owing to the low antigen-specific T cell response rate and acquired resistance caused by the immunosuppressive tumor microenvironment(TME).Here,we ...The clinical outcomes of cancer nanovaccine have been largely impeded owing to the low antigen-specific T cell response rate and acquired resistance caused by the immunosuppressive tumor microenvironment(TME).Here,we reported a tumor acidity-responsive nanovaccine to remodel the immunosuppressive TME and expand the recruitment of tumor infiltrating lymphocytes(TILs)using hybrid micelles(HM),which encapsulated colony stimulating factor 1 receptor(CSF1-R)inhibitor BLZ-945 and indoleamine 2,3-dioxygenase(IDO)inhibitor NLG-919 in its core and displayed a model antigen ovalbumin(OVA)on its surface(denoted as BN@HM-OVA).The bioactive nanovaccine is coated with a polyethylene glycol(PEG)shell for extending nanoparticle circulation.The shell can be shed in response to the weakly acidic tumor microenvironment.The decrease in size and the increase in positive charge may cause the deep tumor penetration of drugs.We demonstrated that the bioactive nanovaccine dramatically enhance antigen presentation by dendritic cells(DCs)and drugs transportation into M1-like tumor-associated macrophages(TAMs)and tumor cells via size reduction and increasing positive charge caused by the weakly acidic TME.Such bioactive nanovaccine could remodel the immunosuppressive TME into an effector T cells favorable environment,leading to tumor growth inhibition in prophylactic and therapeutic E.G7-OVA tumor models.Furthermore,combining the bioactive nanovaccine with simultaneous anti-PD-1 antibody treatment leads to a long-term tumor inhibition,based on the optimal timing and sequence of PD-1 blockade against T cell receptor.This research provides a new strategy for the development of efficient cancer immunotherapy.展开更多
基金the National Natural Science Foundation of China(82173762,China)111 Project(B18035,China)+2 种基金the Fundamental of Research Funds for the Central Universities(China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2022JDJQ0050,China)Project of Chengdu Science and Technology Bureau(2020-GH03-00003-HZ)。
文摘Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy.Herein,a kind of tumor cascade-targeted responsive liposome(NLG919@Lip-pep1)is developed by conjugating polypeptide inhibitor of PD-1 signal pathway(AUNP-12),which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2(MMP-2)cleavable peptide(GPLGVRGD).This targeted liposome is prepared through a mature preparation process,and indoleamine-2,3-dioxygenase(IDO)inhibitor NLG919 was encapsulated into it.Moreover,mediated by the enhanced permeability and retention effect(EPR effect)and AUNP-12,NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues.At the same time,the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12,thus realizing the precise block of PD-1 signal pathway,and restoring the activity of T cells.The exposure of secondary targeting moduleⅡVRGDC-NLG919@Lip mediated tumor cells targeting,and further relieved the immunosuppressive microenvironment.Overall,this study offers a potentially appealing paradigm of a high efficiency,low toxicity,and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer,which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.
基金by the National Natural Science Foundation of China(U19A2006,12132004,12032007,11972111,31900940,32071304,32171309,32171395)the Sichuan Science and Technology Program(21YJ0130)+1 种基金the Joint Funds of Center for Engineering Medicine(ZYGX2021YGLH010,ZYGX2021YGLH017,ZYGX2021YGLH023)the technical support from the Public Experiment Centre of State Bioindustrial Base(Chongqing).
文摘The clinical outcomes of cancer nanovaccine have been largely impeded owing to the low antigen-specific T cell response rate and acquired resistance caused by the immunosuppressive tumor microenvironment(TME).Here,we reported a tumor acidity-responsive nanovaccine to remodel the immunosuppressive TME and expand the recruitment of tumor infiltrating lymphocytes(TILs)using hybrid micelles(HM),which encapsulated colony stimulating factor 1 receptor(CSF1-R)inhibitor BLZ-945 and indoleamine 2,3-dioxygenase(IDO)inhibitor NLG-919 in its core and displayed a model antigen ovalbumin(OVA)on its surface(denoted as BN@HM-OVA).The bioactive nanovaccine is coated with a polyethylene glycol(PEG)shell for extending nanoparticle circulation.The shell can be shed in response to the weakly acidic tumor microenvironment.The decrease in size and the increase in positive charge may cause the deep tumor penetration of drugs.We demonstrated that the bioactive nanovaccine dramatically enhance antigen presentation by dendritic cells(DCs)and drugs transportation into M1-like tumor-associated macrophages(TAMs)and tumor cells via size reduction and increasing positive charge caused by the weakly acidic TME.Such bioactive nanovaccine could remodel the immunosuppressive TME into an effector T cells favorable environment,leading to tumor growth inhibition in prophylactic and therapeutic E.G7-OVA tumor models.Furthermore,combining the bioactive nanovaccine with simultaneous anti-PD-1 antibody treatment leads to a long-term tumor inhibition,based on the optimal timing and sequence of PD-1 blockade against T cell receptor.This research provides a new strategy for the development of efficient cancer immunotherapy.