Jesús E. Campos Pacheco1,2, Aura Rocío Hernández1,2, Ekaterina Bogdanova1,2, Tetiana Yalovenko1,2, Camilla Davids3, Aurélie Marchès1,2, Lauryna Startaitė 1,2, Peter Falkman1,2, Mikael Ekström4, Gabriela Godaly3, Georgia A. Pilkington5 and Sabrina Valetti1,2
1 Department of Biomedical Sciences, Faculty of Health and Society, Malmö University, 205 06 Malmö, Sweden
2Biofilms – Research Center for Biointerfaces (BRCB), Malmö University, 205 06 Malmö, Sweden
3Department of Microbiology, Immunology and Glycobiology, Institution of Laboratory Medicine, Lund University, 223 70 Lund, Sweden
4Iconovo AB, Ideongatan 3A-B, 223 70 Lund, Sweden
5Department of Chemistry, KTH Royal Institute of Technology, SE-100 44 Stockholm, Sweden
Summary
Dry powder inhalation formulations (DPI) provide formulation stability, compactness and simplified logistic. However, conventional excipients in DPI often underperform in delivering poorly soluble drugs or active proteins to the lungs. Mesoporous silica particles (MSPs) have garnered significant interest as solid micronized drug carriers, enhancing drug dissolution, protein stability, and aerodynamic properties. This extensive work bridges formulation with biological activity and safety, showcasing the use of MSPs as sole excipient in DPI formulations for poorly soluble drugs (i.e., clofazimine) and proteins (i.e., lysozyme and DNase I). Drug formulations with MSP as sole carrier had excellent aerodynamic properties (FPF between 40-70%) drastically increasing (i.e., 16-fold) clofazimine and releasing active protein (i.e., 100% retained DNase I activity) in simulated lung fluid. A bioinspired coating with the abundant lung phospholipid (i.e., DPPC) promoted interaction with endogenous surfactant, significantly enhancing mucoadhesion and antimicrobial activity. MSP carriers dissolved in simulated lung fluid, transitioning through intermediate nanoparticles that actively target bacteria residing within macrophages (i.e., dual micro-nano strategy) reaching effective antimicrobial concentrations against M. tuberculosis. The in vitro lowest observed adverse effect level was found to be 0.06 mg/mL, based on assessments of cytotoxicity and immunological responses in both human bronchial epithelium and primary macrophages. Overall, these findings highlight the potential of bioinspired MSPs as a novel drug carrier, capable of delivering effective antimicrobial and protein concentrations to the lungs. This approach could significantly reduce the required doses compared to current oral treatments, with an estimated 600-fold dose reduction for clofazimine.