Binary Cooperative Prodrug Nanoparticles Improve Immunotherapy by Synergistically Modulating Immune Tumor Microenvironment

Checkpoint blockade immunotherapy is promising for clinical treatment of various malignant tumors. However, checkpoint blockade immunotherapy suffers from a low response rate due to insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (ITM). In this study, a tumor‐micro...

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Bibliographic Details
Published in:Advanced materials (Weinheim) 2018-09, Vol.30 (38), p.e1803001-n/a
Main Authors: Feng, Bing, Zhou, Fangyuan, Hou, Bo, Wang, Dangge, Wang, Tingting, Fu, Yuanlei, Ma, Yuting, Yu, Haijun, Li, Yaping
Format: Article
Language:English
Subjects:
Accumulation
Animals
Cancer
Cell death
Glutathione
immune tumor microenvironment
Immunity
immunogenic cell death
Immunosuppression
Immunotherapy
Lymphocytes
Materials science
Mice
Nanoparticles
Neoplasms
Polyethylene glycol
prodrug nanoparticles
Prodrugs
Reduction
stimuli‐activation
Tumor Microenvironment
Tumors
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Summary:Checkpoint blockade immunotherapy is promising for clinical treatment of various malignant tumors. However, checkpoint blockade immunotherapy suffers from a low response rate due to insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (ITM). In this study, a tumor‐microenvironment‐activatable binary cooperative prodrug nanoparticle (BCPN) is rationally designed to improve immunotherapy by synergistically modulating the immune tumor microenvironment. BCPN is purely constructed from a tumor acidity and reduction dual‐responsive oxaliplatin (OXA) prodrug for triggering immunogenic cell death (ICD) and eliciting antitumor immunity, and a reduction‐activatable homodimer of NLG919 for inactivating indoleamine 2,3‐dioxygenase 1, which is a key regulator for ITM. Upon tumor‐acidity‐triggered cleavage of the poly(ethylene glycol) shell, PN shows negative to positive charge switch for enhanced tumor accumulation and deep penetration. OXA and NLG919 are then activated in the tumor cells via glutathione‐mediated reduction. It is demonstrate that activated OXA promotes intratumoral accumulation of cytotoxic T lymphocytes by triggering ICD of cancer cells. Meanwhile, NLG919 downregulates IDO‐1‐mediated immunosuppression and suppresses regulatory T cells. Most importantly, PN shows much higher efficiency than free OXA or the combination of free OXA and NLG919 to regress tumor growth and prevent metastasis of mouse models of both breast and colorectal cancer. A binary cooperative prodrug nanoparticle (BCPN) is presented for immunotherapy. BCPN is composed of a stimuli‐activatable dimer of NLG919 and prodrug of oxaliplatin. NLG919 reverses the immunosuppressive tumor microenvironment by inhibiting the activity of IDO‐1 and suppressing the tumor infiltration of regulatory T cells. Meanwhile, oxaliplatin promotes intratumoral accumulation of cytotoxic T lymphocytes by triggering immunogenetic cell death.
ISSN:0935-9648
1521-4095
DOI:10.1002/adma.201803001