A novel peptide nanomedicine for treatment of pancreatogenic diabetes

Abstract

Pancreatogenic diabetes (PD) is a potentially fatal disease that occurs secondary to pancreatic disorders. The current anti-diabetic therapy for PD is fraught with adverse effects that can increase morbidity. Here we investigated the efficacy of novel peptide nanomedicine: pancreatic polypeptide (PP) in sterically stabilized micelles (SSM) for management of PD. PP exhibits significant anti-diabetic efficacy but its short plasma half-life curtails its therapeutic application. To prolong and improve activity of PP in vivo, we evaluated the delivery of PP in SSM. PP-SSM administered to rats with PD, significantly improved glucose tolerance, insulin sensitivity and hepatic glycogen content compared to peptide in buffer. The studies established the importance of micellar nanocarriers in protecting enzyme-labile peptides in vivo and delivering them to target site, thereby enhancing their therapeutic efficacy. In summary, this study demonstrated that PP-SSM is a promising novel anti-diabetic nanomedicine and therefore should be further developed for management of PD.

From the clinical editor: Pancreatic peptide was earlier demonstrated to address pancreatogenic diabetes, but its short half-life represented major difficulties in further development for therapeutic use. PP-SSM (pancreatic polypeptide in sterically stabilized micelles) is a promising novel anti-diabetic nanomedicine that enables prolonged half-life and increased bioactivity of PP, as shown in this novel study, paving the way toward clinical studies in the near future.

Keywords: 1,2-Distearoyl-sn-glycero-3-phosphatidylethanolamine-N-[methoxy (polyethyleneglycol)-2000]; CP; Chronic pancreatitis; DPSPE-PEG(2000); EPR; Enhanced permeation and retention; GLP-1; GLUT4; GTT; Glucagon-like peptide -1; Glucose tolerance test; Glucose transporter 4; IST; Insulin sensitivity test; PBS; PD; PP; Pancreatic polypeptide; Pancreatogenic diabetes; Phosphate buffered saline; SEM; SSM; Standard error of mean; Sterically stabilized micelles; T3cDM; Type 3c diabetes mellitus; VIP; Vasoactive intestinal peptide.

Figure 1

Schema for anti-diabetic efficacy studies in rats. Not according to scale. GTT: glucose tolerance test; IST: Insulin sensitivity test

Figure 2. Glucose tolerance in normal, diseased and drug treated animals

Blood glucose levels at 60 minutes after glucose injection in normal, diseased and drug treated animals. † indicates statistically significant difference between normal and diseased animals (p < 0.05; n=5/group) while * represents statistically significant improvement in disposal of glucose from blood, in drug treated animals as compared to diseased animals. (p < 0.05; n=5/group).

Figure 3. Insulin sensitivity in normal, diseased and drug treated animals

Insulin sensitivity represented as percent change in blood glucose level between 0 and 30 minutes after insulin injection for normal, diseased and treated animals. † represents statistically significant difference between normal and diseased animals; * indicates significant improvement in insulin sensitivity in treated animals compared to diseased animals (p<0.05, n=5/group) while # represents statistically significant enhancement of activity in PP-SSM treated group compared to PP treated group (p<0.05; n=5/group).

Figure 4. Glycogen content in livers of animals subjected to different treatments

Hepatic glycogen content represented in mg/dl from animals treated with PP/PP-SSM and controls obtained at the end of efficacy study. * indicates statistically significant higher hepatic glycogen content in PP-SSM treated group compared to PP treated group (p<0.05 n=5/group).