CSF1R- and SHP2-Inhibitor-Loaded Nanoparticles Enhance Cytotoxic Activity and Phagocytosis in Tumor-Associated Macrophages
© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
| Publié dans: | Advanced materials (Deerfield Beach, Fla.). - 1998. - 31(2019), 51 vom: 15. Dez., Seite e1904364 |
|---|---|
| Auteur principal: | |
| Autres auteurs: | , , |
| Format: | Article en ligne |
| Langue: | English |
| Publié: |
2019
|
| Accès à la collection: | Advanced materials (Deerfield Beach, Fla.) |
| Sujets: | Journal Article cancer immunotherapy macrophages phagocytosis repolarization Antineoplastic Agents CSF1R protein, human Drug Carriers Receptors, Granulocyte-Macrophage Colony-Stimulating Factor plus... |
| Résumé: | © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Immune modulation of macrophages has emerged as an attractive approach for anti-cancer therapy. However, there are two main challenges in successfully utilizing macrophages for immunotherapy. First, macrophage colony stimulating factor (MCSF) secreted by cancer cells binds to colony stimulating factor 1 receptor (CSF1-R) on macrophages and in turn activates the downstream signaling pathway responsible for polarization of tumor-associated macrophages (TAMs) to immunosuppressive M2 phenotype. Second, ligation of signal regulatory protein α (SIRPα) expressed on myeloid cells to CD47, a transmembrane protein overexpressed on cancer cells, activates the Src homology region 2 (SH2) domain -phosphatases SHP-1 and SHP-2 in macrophages. This results in activation of "eat-me-not" signaling pathway and inhibition of phagocytosis. Here, it is reported that self-assembled dual-inhibitor-loaded nanoparticles (DNTs) target M2 macrophages and simultaneously inhibit CSF1R and SHP2 pathways. This results in efficient repolarization of M2 macrophages to an active M1 phenotype, and superior phagocytic capabilities as compared to individual drug treatments. Furthermore, suboptimal dose administration of DNTs in highly aggressive breast cancer and melanoma mouse models show enhanced anti-tumor efficacy without any toxicity. These studies demonstrate that the concurrent inhibition of CSF1-R and SHP2 signaling pathways for macrophage activation and phagocytosis enhancement could be an effective strategy for macrophage-based immunotherapy |
|---|---|
| Description: | Date Completed 30.04.2020 Date Revised 30.09.2020 published: Print-Electronic Citation Status MEDLINE |
| ISSN: | 1521-4095 |
| DOI: | 10.1002/adma.201904364 |