The high rate of lung cancer and related deaths necessitated new treatment strategies. This study aimed at in vitro, in vivo, and ex vivo evaluation of magnetic field sensitive, ultrasound-mediated, and pemetrexed and pazopanib containing nanobubble (NB) destruction to provide dual drug therapy against non-small cell lung cancer. For this purpose, cytotoxicity analysis (CRL-5807, CRL-5826, A549-Luc-C8), biocompatibility experiments including hemocompatibility, uptake by macrophages, and binding to serum proteins, acute and long-term toxicity analyses, in vivo therapeutic efficacy experiments, pharmacokinetic analyses, histochemistry, and immunohistochemistry experiments were performed on NBs. The IC50 value of NB-400 against A549-Luc-C8 was found to be 31.4 ± 1.6 μg/mL and 34.9 ± 1.2 μg/mL with and without ultrasound application for 72 h, respectively. 30.8% of NB-400 was phagocytosed by macrophage cells and was non-hemolytic. It was determined that NB-800 (prepared for inhaler administration) and NB-400 did not cause acute or long-term toxic effects and reduced tumor size and/or disappeared after treatment, but carrier-free dual drugs did not give a therapeutic response also based on immunohistochemical analyses. It can be said that the emerging intravenous and inhaled delivery systems can be potential therapeutics that can be used in the treatment of non-small cell lung cancer with superior properties such as magnetic targeting and ultrasound sensitivity.
Keywords: Dual therapy; inhaler administration; lung cancer treatment; nanobubble; pazopanib; pemetrexed.