Sequential Treatment of Bioresponsive Nanoparticles Elicits Antiangiogenesis and Apoptosis and Synergizes with a CD40 Agonist for Antitumor Immunity.
Xiang LingXiaomin JiangYouyou LiWenbo HanMegan RodriguezZiwan XuWenbin LinPublished in: ACS nano (2020)
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.
Keyphrases
- vascular endothelial growth factor
- endothelial cells
- cell cycle arrest
- mouse model
- cell death
- stem cells
- dendritic cells
- randomized controlled trial
- clinical trial
- regulatory t cells
- combination therapy
- radiation therapy
- signaling pathway
- single cell
- replacement therapy
- risk assessment
- mesenchymal stem cells
- drug delivery
- study protocol
- recombinant human