Near-infrared/pH dual-responsive nanocomplexes for targeted imaging and chemo/gene/photothermal tri-therapies of non-small cell lung cancer

Combination therapy offers promising opportunities for treating advanced non-small cell lung cancer (NSCLC). Here, we established a chitosan-based nanocomplex CE7Q/CQ/S to deliver molecular-targeted drug erlotinib (Er), Survivin shRNA-expressing plasmid (SV), and photothermal agent heptamethine cyanine dye (Cy7) in one platform for simultaneous near-infrared (NIR) fluorescence imaging and triple-combination therapy of NSCLC bearing epidermal growth factor receptor (EGFR) mutations. The obtained CE7Q/CQ/S exhibited favorable photothermal effects, good DNA binding ability, and pH/NIR dual-responsive release behaviors. The conjugated Er could mediate specific delivery of Cy7 to EGFR-mutated NSCLC cells to enable targeted NIR fluorescence imaging and photothermal therapy (PTT). The in vitro and in vivo results showed that downregulation of Survivin expression and the photothermal effects could act synergistically with Er to induce satisfactory anticancer effects in either Er-sensitive or Er-resistant EGFR-mutated NSCLC cells. By integrating chemo/gene/photothermal therapies into one theranostic nanoplatform, CE7Q/CQ/S could significantly suppress EGFR-mutated NSCLC, indicating its potential use in treating NSCLC. STATEMENT OF SIGNIFICANCE: The development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has improved overall survival in patients with NSCLC driven by EGFR mutations. Unfortunately, the emergence of acquired resistance of EGFR-TKIs is almost inevitable after treatment. Here, we constructed a NIR/pH dual-responsive nanocomplex CE7Q/CQ/S based on chitosan which could integrate targeted near-infrared fluorescence imaging and chemo/gene/phototheramal tri-therapies together. We found that CE7Q/CQ/S possessed a promising outcome in fighting against EGFR-mutated NSCLC. The inhibition of Survivin expression and the application of photothermal therapy could act synergistically with erlotinib and reverse erlotinib resistance. The results of this work suggested that this chitosan-based combination therapeutic nanoplatform could be a promising candidate for NSCLC treatment.