Anti-inflammatory chromogranin A-derived peptides -loaded biodegradable nanoparticles : Application to inflammatory bowel diseases – CHROBIOPAR

Patients with inflammatory bowel disease (IBD) show defects in intestinal epithelial barrier function, thus allowing bacteria to colonize colonic lamina propria. Bacterial antigens are presented by dendritic cells and macrophages, which secrete pro-inflammatory cytokines in the lamina propria, triggering recruitment of circulating immune cells via expression of adhesion molecules on endothelial cells. These pathogenic processes are the targets of modern IBD therapeutic approaches. Traditionally, drugs mediating these desired effects are usually administered in high doses, leading to significant adverse events. A major challenge in the therapeutic strategy for diseases such as IBD is the ability to target drugs in sufficient quantities to a site of inflammation, allowing maximization of local drug concentration with minimal systemic side-effects. Another challenge is that the gastrointestinal tract, particularly the colon, differs in drug absorption properties, and it is difficult to deliver the drug to the colon with minimal digestive enzyme degradation and/or systemic absorption. Recently, we described an original technique targeting the colon with anti-inflammatory drug-loaded nanoparticles (NPs) encapsulated in an alginate-chitosan hydrogel that outcomes these challenges. My results showed that gavage of anti-inflammatory drug-loaded encapsulated NPs offered a versatile drug delivery system with the ability to overcome physiological barriers and to target the anti-inflammatory drug to inflamed colonic regions. Our optimized NP synthesis process allows encapsulation of many types of water-soluble molecules.
The present research program concerns the encapsulation of chromogranins-derived peptides. Chromogranins are stress proteins released after exocytosis by nervous, endocrine and immune cells. They are naturally processed to generate numerous peptides with various biological functions. These peptides act to allow that the organisms recover homeostasis after the stress situations. Among these activities the laboratory Inserm-UMR977 has isolated and characterized new natural antimicrobial chromogranins-derived peptides non toxic for host cells and able to modulate inflammation. Recent data indicate antimicrobial activities at the micromolar range against Klebsiella, Shigella, Salmonella and Vibrio. Furthermore, some peptides display synergistic effects with minocyclin allowing to decrease the minimal inhibitory concentration of the drug by a factor 3.
Chromogranins-derived peptides are great candidates and potential effective drugs during IBD but need to be protected to reach the colon in a effective and quantitative form. In the present proposal, I will design and test the effects of gavage of encapsulated targeted chromogranins-loaded NPs on recovery following murine model of colitis. This research program will use the expertise acquired during my post-doc position, the new active molecules studies in the Inserm-UMR-977 and the complementary technical expertises.