A Novel Anti-Diabetic Peptide Nanomedicine Against Pancreatogenic Diabetes

A Novel Anti-Diabetic Peptide Nanomedicine Against Pancreatogenic Diabetes Amrita Banerjee, Ph.D. Department of Biopharmaceutical Sciences University of Illinois at Chicago Chicago, Illinois (2012) Dissertation Chairperson: Hayat Onyuksel, Ph.D. Pancreatogenic diabetes (PD) is a potentially fatal disease that occur secondary to pancreatic disorders such as chronic pancreatitits. The current anti-diabetic therapy for PD is fraught with many adverse effects that can increase morbidity. This research is geared towards the development of a novel peptide nanomedicine: pancreatic polypeptide (PP) in sterically stabilized micelles (SSM) for management of PD. PP is a hormone secreted by the pancreas mostly post-prandially and has well documented anti-diabetic efficacy. The peptide is known to reverse hepatic insulin sensitivity and improve glucose tolerance. However, the short plasma half-life of PP limits its therapeutic application. In order to prolong and improve the activity of PP in vivo, we proposed to deliver the peptide in SSM. The hypothesis of our research was that PP would self-associate with SSM to form a novel peptide nanomedicine and demonstrate effective anti-diabetic activity against pancreatogenic diabetes. We have successfully prepared the formulation of PP in SSM (PP-SSM) and characterized it in terms of its saturation molar ratio of association with phospholipid micelles, particle size distribution, conformation as well as stability of the formulation towards both freeze-drying and against proteolytic degradation. We observed that presence or absence of sodium chloride in aqueous media dictated the association of PP with SSM, the particle size distribution and the stability of the formulation towards lyophilization. PP retained its native conformation in SSM and the micelle associated peptide was more stable to proteolytic degradation than free peptide in buffer. Through in vitro cell studies we found that PP in SSM exhibited similar bioactivity as peptide in buffer. Results from in vivo experiments involving administration of PP-SSM to rodent model of PD indicated that PP-SSM significantly improved glucose tolerance, hepatic insulin sensitivity and increased hepatic glycogen content as compared to PP in buffer. The results of the study established the importance of micellar nanocarriers in protecting enzyme-labile peptides in vivo and delivering them to the target site, thereby enhancing therapeutic efficacy of these biomolecules. In summary, PP-SSM demonstrated promising anti-diabetic efficacy and therefore the nanomedicine should be further developed for effective management of pancreatogenic diabetes in the clinics.