Abstract |
The third-generation of EGFR-TKI osimertinib has been approved as a first-line therapy in NSCLC, representing the most successful advance in molecularly targeted therapy. However, the rapid development of osimertinib resistance renders the unsustainable treatment benefit. Plus, brain metastasis (BMs) is a major mortality cause for NSCLC; there is no drug specifically approved for the osimertinib-resistant BMs of NSCLC yet. To tackle these critical issues, a BBB-permeable biomimetic codelivery system was designed for specifically treating osimertinib-resistant BMs. The T12 peptide-modified albumin nanoparticles coloaded with regorafenib and disulfiram/copper ion chelate repolarized the tumor-promoting CD206hi TGF-β1+ MΦ via inhibition of FROUNT and thus remodeled tumor immune microenvironment. The treatment efficacy in both the subcutaneous H1975/AZDR model and the brain metastasized model demonstrated the effectiveness of the BBB-penetrating combination therapy and the macrophage-mediated innate immunity. This nanotherapeutic combination strategy provides a translational solution to the formidable challenges of overcoming TKI resistance and treating the TKI-resistant BMs.
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Authors | Pengfei Zhao, Jiaxin Zhang, Aihua Wu, Meng Zhang, Yuge Zhao, Yisi Tang, Bing Wang, Tianxiang Chen, Feng Li, Qiang Zhao, Yongzhuo Huang |
Journal | Journal of controlled release : official journal of the Controlled Release Society
(J Control Release)
Vol. 329
Pg. 1249-1261
(01 10 2021)
ISSN: 1873-4995 [Electronic] Netherlands |
PMID | 33129919
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2020. Published by Elsevier B.V. |
Chemical References |
- Acrylamides
- Aniline Compounds
- Protein Kinase Inhibitors
- osimertinib
- ErbB Receptors
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Topics |
- Acrylamides
- Aniline Compounds
- Biomimetics
- Brain Neoplasms
(drug therapy)
- Cell Line, Tumor
- Drug Resistance, Neoplasm
- ErbB Receptors
(genetics)
- Humans
- Immunity, Innate
- Lung Neoplasms
(drug therapy)
- Macrophages
- Mutation
- Protein Kinase Inhibitors
(pharmacology)
- Tumor Microenvironment
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