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

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.