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IDO-inhibitor potentiated immunogenic chemotherapy abolishes primary tumor growth and eradicates metastatic lesions by targeting distinct compartments within tumor microenvironment.

Authors :
Li, Qilin
Liu, Jia
Fan, Huiling
Shi, Lin
Deng, Yan
Zhao, Lei
Xiang, Mengxi
Xu, Yunruo
Jiang, Xulin
Wang, Guobin
Wang, Lin
Wang, Zheng
Source :
Biomaterials. Feb2021, Vol. 269, pN.PAG-N.PAG. 1p.
Publication Year :
2021

Abstract

Immunogenic chemotherapy (IC) is a type of chemotherapy where certain chemodrugs induce immunogenic cancer cell death (ICD), which in turn arouses T cell antitumor immunity. However, IC concurrently upregulates a key immune suppressor, indoleamine-2,3-dioxygenase (IDO), in both cancer cells and immune cells. IDO-mediated immunosuppression significantly offsets IC's therapeutic benefits in cancer patients, suggesting a necessity of combination with IDO inhibitors. Here, we report an enzyme-, pH-, and redox-triple-sensitive nanosystem using mesoporous silica nanoparticles (MSNs) as a core encapsulating doxorubicin (DOX, an immunogenic chemodrug); the core is coated with a shell (β -CD-PEI/Ge1MT) for co-delivering 1-methyl-D-tryptophan (1 MT, an IDO inhibitor). By using these responsivenesses sequentially triggering the release of 1 MT into tumor extracellular compartment and DOX into intracellular endo/lysosomal compartment, this nanosystem (DOX@GMTMSNs) precisely delivers the drugs to their target cells residing in different compartments. Released 1 MT uptake by IDO-expressing dendritic cells (DCs) and cancer cells suppresses IDO activity, reducing immunosuppressive Tregs' presence; DOX unloaded within cancer cells induces ICD, promoting effector T-cell infiltration. In two preclinical cancer models, DOX@GMTMSNs potentiate both tumor local and systemic antitumor immunity, suppressing primary tumor growth by 78% with an 83% reduction in metastatic foci, as well as extending animal survival, thus strongly demonstrating DOX@ GMTMSNs' clinical translational potential. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
01429612
Volume :
269
Database :
Academic Search Index
Journal :
Biomaterials
Publication Type :
Academic Journal
Accession number :
148478523
Full Text :
https://doi.org/10.1016/j.biomaterials.2020.120388