cRGD-targeted gold-based nanoparticles overcome EGFR-TKI resistance of NSCLC via low-temperature photothermal therapy combined with sonodynamic therapy

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is a first-line targeted drug for the treatment of advanced non-small cell lung cancer (NSCLC) in clinical practice, but EGFR-TKI-acquired resistance limits its therapeutic effect. To address this challenge, a novel multifunctional gold-based targeted nanoparticle-based drug delivery system is fabricated. The gold-based nanoparticle is loaded with the EGFR-TKI (gefitinib) and IR780, and the surface-modified gold nanoshell layer has a photothermal effect for thermally triggered drug release. Finally, the unique binding of cyclic arginine-glycine-aspartic acid (cRGD) to the α_vβ₃ receptor ensured that the nanoparticle (cRGD-GIPG) targeted transport into drug-resistant NSCLC cells was functional. Due to the sonodynamic properties of IR780, ultrasound (US) irradiation promoted reactive oxygen species (ROS) generation, while low-temperature photothermal therapy (PTT) not only promoted the release of drug, but also further enhanced the cytotoxic effects of ROS. In turn, it blocked the activation of TGF-β/PDLIM5/SMAD resistance pathway and induced apoptosis of drug-resistant cells through mitochondrial apoptosis, enabling the treatment of EGFR-TKI-resistant NSCLC. The low-temperature PTT combined with sonodynamic therapy (SDT) by cRGD-GIPG thus shows potent anticancer activity against EGFR-TKI-resistant NSCLC cells in vitro and in vivo. The present work provides a valuable strategy for highly targeted and EGFR-TKI-resistant reversal therapy in NSCLC.