Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during c...Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during cancer treatment.Herein,we develop a concise strategy to prepare pH-responsive nanoparticles via the CaCO3-assisted double emulsion method,thereby enabling effective co-encapsulation of both doxorubicin(DOX),an immunogenic cell death(ICD)inducer,and alkylated NLG919(aNLG919),an inhibitor of indoleamine 2,3-dioxygenase 1(IDO1).The obtained DOX/aNLG919-loaded CaCO3 nanoparticles(DNCaNPs)are able to cause effective ICD of cancer cells and at the same time restrict the production of immunosuppressive kynurenine by inhibiting IDO1.Upon intravenous injection,such DNCaNPs show efficient tumor accumulation,improved tumor penetration of therapeutics and neutralization of acidic TME.As a result,those DNCaNPs can elicit effective anti-tumor immune responses featured in increased density of tumor-infiltrating CD8+cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells(Tregs),thus effectively suppressing the growth of subcutaneous CT26 and orthotopic 4T1 tumors on the Balb/c mice through combined chemotherapy&immunotherapy.This study presents a compendious strategy for construction of pH-responsive nanoparticles,endowing significantly enhanced chemo-immunotherapy of cancer by overcoming the immunosuppressive TME.展开更多
基金partially supported by the National Natural Science Foundation of China(51802209,22077093,51761145041,51525203)the National Research Programs from Ministry of Science and Technology(MOST)of China(2016YFA0201200)+3 种基金the Natural Science Foundation of Jiangsu Province(BK20180848)the Jiangsu Social Development Project(BE2019658)Collaborative Innovation Center of Suzhou Nano Science and Technologythe 111 Program from the Ministry of Education of China.
文摘Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during cancer treatment.Herein,we develop a concise strategy to prepare pH-responsive nanoparticles via the CaCO3-assisted double emulsion method,thereby enabling effective co-encapsulation of both doxorubicin(DOX),an immunogenic cell death(ICD)inducer,and alkylated NLG919(aNLG919),an inhibitor of indoleamine 2,3-dioxygenase 1(IDO1).The obtained DOX/aNLG919-loaded CaCO3 nanoparticles(DNCaNPs)are able to cause effective ICD of cancer cells and at the same time restrict the production of immunosuppressive kynurenine by inhibiting IDO1.Upon intravenous injection,such DNCaNPs show efficient tumor accumulation,improved tumor penetration of therapeutics and neutralization of acidic TME.As a result,those DNCaNPs can elicit effective anti-tumor immune responses featured in increased density of tumor-infiltrating CD8+cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells(Tregs),thus effectively suppressing the growth of subcutaneous CT26 and orthotopic 4T1 tumors on the Balb/c mice through combined chemotherapy&immunotherapy.This study presents a compendious strategy for construction of pH-responsive nanoparticles,endowing significantly enhanced chemo-immunotherapy of cancer by overcoming the immunosuppressive TME.
