Astragaloside IV Co-Loaded Osimertinib Liposomes Alleviate EGFR-TKI Resistance in Non-Small Cell Lung Cancer.

INTRODUCTION: Advances in tumor biology have established EGFR-tyrosine kinase inhibitors (EGFR-TKIs) as a key therapy for non-small cell lung cancer (NSCLC). Osimertinib (OSI), a third-generation EGFR-TKI, however, often leads to acquired resistance within about a year. Astragaloside IV (AS-IV), a bioactive saponin from Astragalus membranaceus, exhibits anti-tumor potential and may help reverse resistance-related epithelial-mesenchymal transition (EMT), a process mediated by TGF-β. While combining OSI with AS-IV is a promising strategy, its efficacy is limited by poor solubility and toxicity-challenges that can be addressed through liposomal co-delivery.

METHODS: We prepared OSI and AS-IV co-loaded liposomes (LPs-OSI/AS) and characterized their physicochemical properties and drug release in vitro. Cellular uptake and anti-proliferative effects were evaluated in OSI-sensitive (NCI-H1975) and OSI-resistant (NCI-H1975/AR) NSCLC cells. EMT-related gene expression was analyzed by RT-qPCR. In vivo efficacy was assessed using a subcutaneous xenograft model in BALB/c-nu mice by monitoring tumor growth and body weight.

RESULTS: LPs-OSI/AS liposomes were successfully prepared with uniform particle size (96.92 ± 12.04 nm, PDI 0.28 ± 0.01), high encapsulation efficiency (AS: 89.74 ± 6.53%; OSI: 84.35 ± 8.82%), and sustained release. In vitro, LPs-OSI/AS significantly inhibited proliferation of both NCI-H1975 and OSI-resistant NCI-H1975/OSIR cells, outperforming free drug controls without obvious cytotoxicity, and downregulated EMT-related genes (Vimentin, TGFβ1, TGFβ2). In vivo, LPs-OSI/AS (20 mg/kg OSI + 40 mg/kg AS) reduced tumor volume by approximately 70% compared to OSI monotherapy, with 100% survival and no significant body weight loss. The Ki-67 positive rate was substantially lower in the LPs-OSI/AS group (1.06%) than in the OSI monotherapy group (5.98%), and H&E staining confirmed superior pathological improvement. Safety evaluation demonstrated normal organ structures with no inflammation or necrosis.

CONCLUSION: In summary, LPs-OSI/AS effectively inhibits tumor growth by regulating EMT, exhibits favorable biosafety, and represents a promising therapeutic strategy for NSCLC.