Harnessing synergistic SN38/quercetin nanomicelles via inhalation for enhanced lung cancer treatment
Abstract
Abstract Lung cancer continues to be a major contributor to global cancer-related morbidity and mortality, with chemotherapeutic approaches such as irinotecan often limited by poor solubility, systemic toxicity, and multidrug resistance driven by P-glycoprotein (P-gp)-mediated efflux. To address these challenges, this study developed polymeric nanomicelles for the pulmonary co-delivery of SN38—the active metabolite of irinotecan—and quercetin, a natural flavonoid known to reverse P-gp-dependent resistance. The dual-drug-loaded nanomicelles (SN38/QU-PPM), prepared via nanoprecipitation, exhibited uniform morphology, colloidal stability, and pH-responsive drug release under acidic conditions. In vitro evaluations demonstrated enhanced cellular uptake, effective P-gp inhibition, and increased intracellular accumulation of SN38, leading to superior cytotoxicity against lung cancer cells compared to SN38 alone. In an orthotopic lung tumor model, nebulized administration resulted in significantly higher pulmonary SN38 levels and stronger tumor suppression relative to intravenous delivery, alongside evidence of promoted apoptosis and reduced proliferation in tumor tissues, without notable systemic toxicity. These findings indicate that nebulized co-delivery of SN38 and quercetin via polymeric nanomicelles offers a promising lung-targeted strategy that enhances local drug exposure, overcomes efflux-mediated resistance, and reduces off-target effects, supporting its potential…
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