TUBB3/DTX LNPs Dry Powder Inhaler and an Efficient Delivery Device for Targeted Therapy of Lung Cancer

Lung cancer is the most prevalent and deadly tumor globally, marked by drug resistance and a poor prognosis. Specialized formulations with strong lung targeting are currently lacking. Docetaxel (DTX) and TUBB3-siRNA represent chemotherapy and RNA interference (RNAi), two strategies for lung cancer treatment. Lipid nanoparticles (LNPs) are nanocarriers suitable for nucleic acid delivery. In this study, spray freeze-drying (SFD) converted LNP colloidal solutions into inhalable dry powders. Fresh and rehydrated LNP (SFD) showed sizes below 200 nm, ζ potentials near 0 mV, and uniform roundness by transmission electron microscopy. The geometric particle size distribution (D50) of TUBB3-LNPs, DTX-LNPs, and TUBB3/DTX-LNPs inhalable powders did not differ significantly (1.99-5.90 μm). The median mass aerodynamic diameter (MMAD) was 2.61 ± 0.32 μm, suitable for pulmonary deposition. Experiments with BEAS-2B and H460 cells showed that TUBB3/DTX-LNPs had low cytotoxicity and good biocompatibility with BEAS-2B but strongly inhibited H460 cells. Differences in apoptosis induced by fresh LNPs and rehydrated LNP (SFD) indicate that the SFD process preserves normal cell viability while maintaining tumor inhibition. Because dry powder inhalers combine the drug formulation with the delivery device, a specialized single-dose prefilled device was developed that featured four symmetrically configured orifices (vents) located in the middle of the tube body; it achieved a high dry powder emptying rate of 95-100%. Furthermore, this study demonstrated the lung-targeting efficacy and sustained-release properties of the formulation.