Journal
THERANOSTICS
Volume 10, Issue 14, Pages 6122-6135Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.42234
Keywords
brain targeting delivery; tumor-associated macrophage; non-small cell lung cancer (NSCLC); drug resistance; tyrosine kinase inhibitors (TKI); EGFR T790M mutation
Categories
Funding
- NFSC [81925035, 81673382, 81521005]
- Strategic Priority Research Program of CAS [XDA12050307]
- National Special Project for Significant New Drugs Development [2018ZX09711002-010-002]
- CAS Scientific Research and Equipment Development Project [YZ201437]
- Fudan-SIMM Joint Research Fund [FU-SIMM20174009]
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EGFR TKI therapy has become a first-line regimen for non-small cell lung cancer (NSCLC) patients with EGRF mutations. However, there are two big challenges against effective therapy-the secondary EGFR mutation-associated TKI resistance and brain metastasis (BMs) of lung cancer. The BMs is a major cause of death for advanced NSCLC patients, and the treatment of BMs with TKI resistance remains difficult. Methods: Tumor-associated macrophages (TAM) is a promising drug target for inhibiting tumor growth, overcoming drug resistance, and anti-metastasis. TAM also plays an essential role in regulating tumor microenvironment. We developed a dual-targeting liposomal system with modification of anti-PD-L1 nanobody and transferrin receptor (TfR)-binding peptide T12 for codelivery of simvastatin/gefitinib to treat BMs of NSCLC. Results: The dual-targeting liposomes could efficiently penetrate the blood-brain barrier (BBB) and enter the BMs, acting on TAM repolarization and reversal of EGFR(T790M)-associated drug resistance. The treatment mechanisms were related to the elevating ROS and the suppression of the EGFR/Akt/Erk signaling pathway. Conclusion: The dual-targeting liposomal codelivery system offers a promising strategy for treating the advanced EGFR(T790M) NSCLC patients with BMs.
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