Physicochemical behavior and cellular interactions of novel oral calcitonin delivery systems
Abstract
The attractive properties of peptides and proteins as therapeutic agents and the challenges faced by the oral delivery of such agents have been the primary motivation for the design and development of novel oral delivery systems that could circumvent biological barriers. In this work, salmon calcitonin, a 32 amino acid polypeptide hormone used in the treatment of bone diseases, such as Paget's disease, hypercalcemia and osteoporosis, was employed as the model protein. The main goal of this work was the creation of pH-sensititive hydrogel microspheres composed of Poly(methacrylic acid-grafted-polyethylene glycol)) (PMAA-g-EG), their primary characterization, and the examination of their performance as a transport enhancer for salmon calcitonin. For this purpose, a gastrointestinal cell culture model, the Caco-2 cell line, was employed to investigate the cytotoxic effects of the polymeric carrier, its effects on the cell monolayer integrity, and its ability to enhance the transport of salmon calcitonin. Microsphere carriers composed of P(MAA-g-EG) hydrogels were successfully created by dispersion polymerization utilizing deionize water as the solvent. The characterization of these systems was performed by FTIR revealed that microspheres created by dispersion polymerization possessed similar infrared spectral characteristics to hydrogel films prepared with the same monomer ratio. These hydrogels also possessed narrow particle size distribution and spherical shape as evidenced by PCS and SEM analysis. The examination of the physicochemical interactions of the P(MAA-g-EG) microsphere system with Caco-2 cell monolayers revealed that these systems possessed low cytotoxicity and were capable of opening the tight junctions between epithelial cells by significantly reducing the transepithelial electrical resistance. The presence of P(MAA-g-EG) microspheres significantly increased the transport of paracellularly transported molecules such as 14C-mannitol and fluorescein isothiocyanate dextran when compared to controls. Fluorescein sodium salt solutions were also investigated as an actively transported molecule. The transport of fluorescein was highly affected by PEG chains. Salmon calcitonin transport was significantly enhanced in the presence of the microspheres. The main transport mechanism for salmon calcitonin through epithelial cell monolayers was found to be mainly paracellular.
Degree
Ph.D.
Advisors
Peppas, Purdue University.
Subject Area
Chemical engineering|Biomedical research|Pharmaceuticals
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