Harnessing synergistic SN38/quercetin nanomicelles via nebulized inhalation for enhanced lung cancer treatment.

Lung cancer remains a leading cause of cancer-related mortality worldwide, while the clinical utility of irinotecan-derived therapies is often constrained by poor drug solubility, suboptimal biodistribution, and systemic toxicity. To overcome these limitations, we developed polymeric nanomicelles co-loading 7-Ethyl-10-hydroxycamptothecin (SN38), the active metabolite of irinotecan, and quercetin, a naturally occurring flavonoid with intrinsic antitumor activity, for nebulized inhalation delivery. The dual-drug nanomicelles (SN38/QU-PPM) were prepared by nanoprecipitation and exhibited a uniform particle size distribution, excellent stability, and pH-responsive drug release under acidic conditions. In vitro studies demonstrated that quercetin co-loading enhanced cellular uptake of the nanomicelles and promoted intracellular accumulation of SN38, resulting in significantly greater cytotoxicity against LLC-Luc lung cancer cells compared with SN38-loaded nanomicelles alone. In an orthotopic lung cancer model, nebulized inhalation of SN38/QU-PPM achieved a 3.33-fold higher pulmonary SN38 concentration than intravenous administration at 24 h. Nebulized SN38/QU-PPM also exhibited superior antitumor efficacy, achieving a tumor inhibition rate of 80.7%, accompanied by increased apoptosis, reduced tumor cell proliferation. Histopathological examination and serum biochemical analyses indicated no apparent treatment-related abnormalities following inhalation administration. Collectively, SN38/QU-PPM delivered via nebulized inhalation represents an effective lung-targeted drug delivery strategy that enhances local drug exposure and potentiates the antitumor efficacy of SN38. This dual-drug nanomicelle platform holds considerable promise for the treatment of lung cancer through nebulized inhalation therapy.