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Joshua Palacios
BME PhD Proposal Presentation
Date: May 21st, 2019
Time: 3:00PM
Location: Room L1175, Ford ES&T building
Committee Members:
Mark Prausnitz, PhD (Georgia Institute of Technology, School of Chemical and Biomolecular Engineering) (Advisor)
Julie Champion, PhD (Georgia Institute of Technology, School of Chemical and Biomolecular Engineering)
Wilbur Lam, MD, PhD (Georgia Institute of Technology, School of Biomedical Engineering)
Todd Sulchek, PhD (Georgia Institute of Technology, School of Biomedical Engineering)
Andrew Neish, MD (Emory University, School of Medicine)
Title: Ballistic Delivery to the Gastrointestinal Tract
Abstract: Biologic therapies are often the gold standard for managing a variety of chronic diseases and are usually administered through repeated injections, sometimes throughout a patient’s lifetime. These injections, which must be given by healthcare professionals or trained patients, are painful and can increase patient non-compliance, cost of therapy, scar tissue formation at sites of repeated administration, and risk of spreading blood borne diseases. Oral delivery is preferred, but there are physiological barriers within the gastrointestinal tract (GIT) that typically reduce bioavailability of biologics to less than 2%. These barriers include: fluctuating pH levels, secretion of enzymes, a thick mucus barrier (MB), and an epithelial cell layer (ECL). Researchers have shown that nanoparticle (NP) encapsulation can protect biologics from pH denaturation, enzymatic degradation, and facilitate transport into the ECL, but the mucus covering the ECL remains a significant barrier. Generally, oral delivery of NPs relies on diffusion of NPs through mucus. This MB is several hundred microns thick and employs numerous entrapping strategies which dramatically inhibit NP diffusion. Some NPs can be designed to slowly circumvent entrapment, but mucus is constantly being secreted and renewed, causing NP excretion out of the GIT before they can reach the ECL.
Therefore, we propose using a ballistic delivery approach to overcome mucus barriers within the GIT. We hypothesize that an “active” transport of NPs across the MB (propelling NPs through mucus) would lead to greater oral bioavailability of biologics/NPs compared to “passive” transport (diffusion). As such, this proposal aims to engineer an oral delivery system that can propel biologics/NPs through mucosal barriers in the GIT. Preliminary ex vivo porcine intestinal experiments have shown delivery across the MB for various sized polymeric NPs, from a range of velocities, using an external particle shooter device. We have also developed preliminary prototypes of oral delivery systems that can release NPs with high velocity in a safe and controlled/directed manner under simulated in vivo conditions. Therefore, in this proposal we aim to (1) determine the effect of NP parameters and shooting conditions on penetration through the MB in porcine intestinal tissue ex vivo and rat/rabbit intestinal tissue in vivo, (2) develop a delivery system suitable for oral administration that can ballistically deliver payloads at controlled optimal parameters quantified in previous animal studies, and (3) demonstrate that ballistic delivery using our novel oral delivery system leads to higher bioavailability in a rabbit/porcine animal model in vivo. This proposed research will help provide an oral alternative delivery for biologics that is safe, painless, and eliminates the need for repeated biologic injection therapies.
