Improved Oral Delivery of High Isoelectric Point Therapeutic Proteins using P(IA-co-NVP) Hydrogels Michael C. Koetting, M.S.1, Joseph F. Guido1, Annie D. Zhang1, Nicholas A. Peppas, Sc.D.1,2,3,4 1McKetta Department of Chemical Engineering, 2Department of Biomedical Engineering, 3College of Pharmacy, and 4Institute for Biomaterials, Drug Delivery and Regenerative Medicine The University of Texas at Austin, Austin, TX 78712 Although therapeutic proteins are a fundamental feature of modern medicine, accounting for well over $100 billion in drug sales annually, they are not easily delivered orally due to degradative enzymes and harsh conditions in the gastrointestinal tract. As a result, these drugs are currently available almost exclusively in injection form, leading to reduced patient compliance from associated fear, pain, and inconvenience. pH-Sensitive hydrogels have shown promise as vehicles to enable the preferred oral delivery pathway, but early systems have displayed limited release of proteins featuring a high isoelectric point (pI) due to coulombic interactions. Here we present delivery systems comprised of poly(itaconic acid-co-Nvinylpyrrolidone) that demonstrate improved delivery capability for high pI proteins. In vitro tests show up to 170% improvement in delivery capability of the high pI protein salmon calcitonin (sCT) resulting from use of itaconic acid as the pH-responsive moiety instead of methacrylic acid as previous systems have used. We further show that a formulation with 5 mol% crosslinker results in optimal delivery kinetics compared to 1% or 10% formulations. In addition, we show that a procedural change utilizing reduced ionic strength solutions during the drug loading imbibition step results in significantly improved delivery capability and percent release— up to an 83-fold improvement in delivery capability of sCT is observed by a 100-fold reduction in ionic strength compared to previous loading protocols. We finally discuss the effects of PEGylation of sCT on delivery capability, as we observe a small but significant decrease in release resulting from conjugation. Supported by a grant from the National Institutes of Health, R01-EB-000246-22.