Cell-engineered synthetic chylomicrons for oral drug delivery applications

The delivery of biological drugs such as therapeutic peptides and proteins via the oral route is an important area of research. However, successful peptide delivery via any administration route is currently highly challenging. The oral delivery of peptides is hampered due to their low bioavailability, which results from low absorption and high rates of first-pass extraction, due to enzymatic and pH mediated hydrolysis in the gastrointestinal (GI) tract and liver. Given the successful generation of antidiabetic peptides and insulin-like peptides (such as glucagon-like peptide-1 (GLP-1), there is great interest in developing oral peptide delivery methodologies due to high patient compliance and market potential.
Chylomicrons are lipoproteins (a group of soluble proteins that combine with and transport fat or other lipids in the blood plasma) formed in enterocytes via the packaging of nascent triacylglycerols, cholesterol, cholesterol esters, at least one fat soluble vitamin, and apolipoprotein B48 (ApoB48). Chylomicrons are secreted from the enterocyte into the mesenteric lymph. Incorporation of hydrophobic molecules and drugs into chylomicrons can exploit this pathway for drug delivery to the lymphatics. In this project, we aim to create a new paradigm for lipophilic peptide delivery across the gut by hijacking and exploiting chylomicron cellular machinery in enterocytes with the chylomicrons in effect acting as stealth shields for the peptide of interest. By combining droplet-based microfluidics with robotics we will able to manufacture synthetic chylomicrons for the first time (termed chylosomes) enabling us to systematically vary their composition and study the molecular interactions that underpin their stability. Using the resulting molecular engineering rules that will emerge from these studies we will design de-novo chylomicrons that can onboard user-defined peptides. Using organon-a-chip technologies coupled with super-resolution microscopy (nanoscopy) we will then study the mechanism of interaction between the chylomicrons and the gut lining.

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