1The aim of this study was to compare protein-loaded inhalable microparticles 2 manufactured using a range of biocompatible polymers including hydroxypropyl cellulose 3 (HPC), chitosan, hyaluronic acid, alginate, gelatin, ovalbumin and poly (lactide-co-4 glycolide)(PLGA). Spray drying was used to prepare microparticles containing bovine 5 serum albumin labeled with flourescein isothiocyanate (BSA-FITC). Particles of respirable 6 size and high protein loading were obtained. No evidence of BSA degradation was seen 7 from PAGE analysis. The microparticles were mixed with mannitol as a carrier and 8 powder aerosolization was assessed with a multi-dose dry powder inhaler (DPI) using a 9 multi-stage cascade impactor. The mass median aerodynamic diameter (MMAD) ranged 10 between 2.9-4.7m. Potential polymer toxicity in the lungs was compared by impinging 11 the particles on Calu-3 monolayers and assessing the cytotoxicity, induction of cytokine 12 release, changes in transepithelial permeability and electrical resistance. No toxic effects 13were observed with most of the polymers though some evidence of compromised cell 14 monolayer integrity was seen for PLGA and ovalbumin. PLGA and gelatin microparticles 15 caused a significant increase in IL-8 release. Of the polymers studied, PLGA showed the 16 greatest toxicity. Certain polymers showed particular promise for specific protein delivery 17 needs in the lungs, such as HPC to improve flow properties, sodium hyaluronate for 18 controlled release, and chitosan and ovalbumin for systemic delivery. 19

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