Hydrogel microspheres evading alveolar macrophages for sustained pulmonary protein delivery

• Published in: International journal of pharmaceutics 2019-07, Vol.566, p.652-661
• Main Authors: Graf, Moritz, Ziegler, Christian E., Gregoritza, Manuel, Goepferich, Achim M.
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Animals; Aqueous two-phase system; Cell Line; Click chemistry; Controlled release; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - chemistry; Hydrogel; Hydrogels - administration & dosage; Hydrogels - chemistry; Inhalation; Lung - metabolism; Macrophages, Alveolar - drug effects; Macrophages, Alveolar - metabolism; Mice; Microspheres; Muramidase - administration & dosage; Muramidase - chemistry; Phagocytosis; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - chemistry; Propane - administration & dosage; Propane - analogs & derivatives; Propane - chemistry; Propane - radiation effects; Protein delivery; Serum Albumin, Bovine - administration & dosage; Serum Albumin, Bovine - chemistry; Thiol-ene; Ultraviolet Rays
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2019.06.019

[Display omitted] Pulmonary delivery is a highly attractive alternative to injections for biologics such as therapeutic proteins. However, bioavailabilities generally suffer from the presence of phagocytic cells that clear particulate matter entering the lung. In this study, microgel particles were developed using an all-aqueous two-phase system approach and evaluated for their efficacy as an inhalable controlled release system. Norbornene- and thiol-modified four- and eight-armed poly (ethylene glycol) with an average molecular mass of 10,000 Da were prepared as macromonomers for microgel formation. Emulsions of precursor solution droplets containing macromonomers and Irgacure 2959 as photocatalyst were prepared in a dextran solution. Irradiation with UV light was used to covalently crosslink the droplets by triggering the thiol-ene reaction. The resulting microgels were processed to dry powder inhaler formulations, and respirable aerodynamic sizes were assessed in vitro. Microgels were loaded with the model proteins lysozyme and bovine serum albumin, with encapsulation efficiencies of 51.5% and 73.6%, respectively. Depending on the macromonomer type, protein-loaded microgels released their cargo over a 6–14 day period. In an MTT assay, the particles did not show significant cytotoxicity, and their recognition by alveolar macrophages was considerably lower than for polystyrene control particles. This makes the microgels a promising pulmonary delivery system for proteins and other biologics.