Nanoagglomerate-enabled inhaled paclitaxel nanoparticle delivery for lung cancer chemotherapy: Proof-of-concept biodistribution and efficacy studies in biorelevant in vitro and in vivo models.

Integrating pulmonary drug delivery and nanotechnology presents a promising strategy to enhance the efficacy and safety profile of lung cancer chemotherapy. This study aimed to (1) develop an in vitro air-liquid interface (ALI) lung cancer organoid (LCO) culture model for biorelevant antitumor efficacy screening of inhalable chemotherapy formulations and (2) evaluate the therapeutic potential of paclitaxel nanoagglomerate powder (PTX-NADP)-enabled inhaled PTX nanoparticle delivery in lung cancer. Aerosolized PTX-NADP exhibited dose-dependent efficacy and outperformed raw PTX powder in in vitro ALI FA34-O LCO cultures. Intratracheal (IT) instillation of PTX nanosuspensions reconstituted from PTX-NADP resulted in enhanced pulmonary PTX concentrations and reduced off-target tissue distribution compared to intravenous (IV) injection in vivo. In an orthotopic lung adenocarcinoma mouse model, administration of reconstituted PTX nanosuspensions via IT instillation was well tolerated and achieved numerically similar tumor growth suppression (∼67%) relative to IV injection at lower cumulative doses. Notably, a higher proportion of mice receiving combined IT and IV treatment exhibited reduced tumor burden, suggesting that combining inhaled with systemic chemotherapy could facilitate therapeutic intensification. These findings support the therapeutic potential of PTX-NADP-enabled inhaled PTX nanoparticle delivery for lung cancer treatment and offer new insights into the development of inhaled nanoparticle-based chemotherapy as a convenient treatment option to improve lung cancer outcomes. Furthermore, the results demonstrate the promise of the in vitro ALI LCO culture model, which recapitulates key features of lung tumors in vivo, as a novel new approach methodology (NAM) platform for biorelevant screening of inhalable chemotherapy formulations.