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      Sequential Treatment of Bioresponsive Nanoparticles Elicits Antiangiogenesis and Apoptosis and Synergizes with a CD40 Agonist for Antitumor Immunity.

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          Abstract

          The combination of antiangiogenesis and chemotherapy regimens with cancer immunotherapy has the potential to synergistically boost antitumor immunity. Herein, we report the construction of two bioresponsive nanoparticles, namely, Podo-NP and CbP-NP, comprising prodrugs of podophyllotoxin (Podo) and carboplatin, respectively. Sequential treatment with esterase-responsive Podo-NP, redox-sensitive CbP-NP, and a CD40 agonist promotes antitumor T cell response. Podo-NP suppresses angiogenesis by preventing proliferation and migration of endothelial cells, sprouting of neovessels, formation of tubules, and stabilization of newly formed vessels. Vascular endothelial growth factor blockade and endostatin stimulation normalize tortuous tumor vasculatures to allow efficient infiltration of effector immune cells. Subsequent treatment with CbP-NP arrests the cell-division cycle and elicits the apoptosis of tumor cells. CD40 agonist activates antigen-presenting cells to process the released tumor-associated antigens from dying tumor cells, thus reversing immunosuppressive tumor microenvironments. Sequential delivery of antiangiogenic and chemotherapeutic agents with bioresponsive NPs activates tumor microenvironments and synergizes with CD40 agonist to regress transplanted tumors and inhibit disseminated tumors in a lung cancer mouse model.

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          Author and article information

          Journal
          ACS Nano
          ACS nano
          American Chemical Society (ACS)
          1936-086X
          1936-0851
          January 26 2021
          : 15
          : 1
          Affiliations
          [1 ] Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States.
          [2 ] Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois 60637, United States.
          Article
          10.1021/acsnano.0c07132
          33347262
          b1a7366b-4f44-4480-a309-5dcce3a365f1
          History

          chemotherapy,tumor,sequential strategy,bioresponsive nanoparticle,antiangiogenesis,CD40

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