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Biomimetic codelivery overcomes osimertinib-resistant NSCLC and brain metastasis via macrophage-mediated innate immunity.

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.
AuthorsPengfei Zhao, Jiaxin Zhang, Aihua Wu, Meng Zhang, Yuge Zhao, Yisi Tang, Bing Wang, Tianxiang Chen, Feng Li, Qiang Zhao, Yongzhuo Huang
JournalJournal 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
PMID33129919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2020. Published by Elsevier B.V.
Chemical References
  • Acrylamides
  • Aniline Compounds
  • Protein Kinase Inhibitors
  • osimertinib
  • ErbB Receptors
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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