Carrier-Free CXCR4-Targeted Nanoplexes Designed for Polarizing Macrophages to Suppress Tumor Growth
| Autor: | Maixian Liu, Scott W. Ferguson, Jinli Wang, Tingyi Li, Juliane Nguyen, Jacqueline Gonya, Michael B Deci, Christine J. Lee, Emily E. Bonacquisti |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Chemistry Macrophage polarization Cancer Cell migration 02 engineering and technology 021001 nanoscience & nanotechnology medicine.disease Fusion protein Article General Biochemistry Genetics and Molecular Biology Metastasis 03 medical and health sciences Chemokine receptor 030104 developmental biology Modeling and Simulation Cancer cell Cancer research medicine Macrophage 0210 nano-technology |
| Zdroj: | Cell Mol Bioeng |
| ISSN: | 1865-5033 1865-5025 |
| Popis: | INTRODUCTION: Treatment options for cancer metastases, the primary cause of cancer mortality, are limited. The chemokine receptor CXCR4 is an attractive therapeutic target in cancer because it mediates metastasis by inducing cancer cell and macrophage migration. Here we engineered carrier-free CXCR4-targeting RNA-protein nanoplexes that not only inhibited cellular migration but also polarized macrophages to the M1 phenotype. MATERIALS AND METHODS: A CXCR4-targeting single-chain variable fragment (scFv) antibody was fused to a 3030 Da RNA-binding protamine peptide (RSQSRSRYYRQRQRSRRRRRRS). Self-assembling nanoplexes were formed by mixing the CXCR4-scFv-protamine fusion protein (CXCR4-scFv-RBM) with miR-127-5p, a miRNA shown to mediate M1 macrophage polarization. RNA-protein nanoplexes were characterized with regard to their physicochemical properties and therapeutic efficacy. RESULTS: CXCR4-targeting RNA-protein nanoplexes simultaneously acted as a targeting ligand, a macrophage polarizing drug, and a miRNA delivery vehicle. Our carrier-free, RNA-protein nanoplexes specifically bound to CXCR4-positive macrophages and breast cancer cells, showed high drug loading (~ 90% w/w), and are non-toxic. Further, these RNA-protein nanoplexes significantly inhibited cancer and immune cell migration (75 to 99%), robustly polarized macrophages to the tumor-suppressive M1 phenotype, and inhibited tumor growth in a mouse model of triple-negative breast cancer CONCLUSIONS: We engineered a novel class of non-toxic RNA-protein nanoplexes that modulate the tumor stroma. These nanoplexes are promising candidates for add-ons to clinically approved chemotherapeutics. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12195-019-00589-w) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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