Optimizing adjuvant inhaled chemotherapy: Synergistic enhancement in paclitaxel cytotoxicity by flubendazole nanocrystals in a cycle model approach.

Lung cancer is the leading cause of cancer-related death. In addition to new innovative approaches, practical strategies that improve the efficacy of already available drugs are urgently needed. In this study, an inhalable dry powder formulation is used to repurpose flubendazole, a poorly soluble anthelmintic drug with potential against a variety of cancer lineages. Flubendazole nanocrystals were obtained through nanoprecipitation, and dry powder was produced by spray drying. Through fractional factorial design, the spray drying parameters were optimized and the impact of formulation on aerolization properties was clarified. The loading limitations were clarified through response surface methodology, and a 15% flubendazole loading was feasible through the addition of 20% L-leucine, leading to a flubendazole particle size of 388.6 nm, median mass aerodynamic diameter of 2.9 µm, 50.3% FPF, emitted dose of 83.2% and triple the initial solubility. Although the cytotoxicity of this formulation in A549 cells was limited, the formulation showed a synergistic effect when associated with paclitaxel, leading to a surprising 1000-fold reduction in the IC50. Compared to 3 cycles of paclitaxel alone, a 3-cycle model combined treatment increased the threshold of cytotoxicity by 25% for the same dose. Our study suggests, for the first time, that orally inhaled flubendazole nanocrystals show high potential as adjuvants to increase cytotoxic agents' potency and reduce adverse effects.