(264f) Synthesis and Characterization of pH-Responsive Hydrogels for Oral Delivery of High Isoelectric Point Therapeutic Proteins

Therapeutic proteins are widely researched and offer treatment of cancer, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, and macular degeneration, as well as many other debilitating diseases, but are currently available to patients via subcutaneous or intramuscular injection. Unfortunately, the frequent injections required for therapeutic dosage are extremely painful, often leading to low patient compliance. Oral delivery of these proteins would be highly preferred, but there are significant barriers to successful delivery to the bloodstream via this route, including the acidic environment of the stomach, enzymatic degradation in the gastrointestinal tract, and the epithelial lining of the small intestine, which tightly regulates the passage of large molecules but is where most drugs are absorbed. Bioavailability of protein drugs after oral administration is extremely low, less than one percent. Environmentally-responsive anionic hydrogels containing methacrylic acid (MAA), which protect the protein under acidic conditions but swell to release the protein at the higher pH of the small intestine, have been developed as drug delivery vehicles for therapeutic proteins and have demonstrated successful delivery of proteins such as insulin. However, higher isoelectric point (pI) proteins, suffer from limited release using these systems due to electrostatic binding resulting from their positive charge at neutral pH. Of the over 150 currently FDA-approved protein therapeutics, at least 46 exhibit high isoelectric points (likely more, as not all of the approved drugs have accepted pI values available). These therapeutics are used to treat a wide variety of diseases: breast, lung, colorectal, and head and neck cancers; rheumatoid arthritis; osteoporosis; Crohn’s disease; infertility; non-Hodgkin’s lymphoma; multiple sclerosis; macular degeneration; anemia; and growth failure, among others. Because these diseases together account for many millions of patients who may benefit from repeated administration of protein therapeutics, it is imperative that any oral delivery strategy be able to accommodate the high pI exhibited by the proteins. The aims of our work were to explore different strategies for achieving high bioavailability of therapeutic proteins delivered via the oral route, with emphasis on seeking innovations that could allow the previously studied systems to be expanded or modified to function with high pI proteins. Copolymeric systems containing itaconic acid have been synthesized and possess similar pH-dependent swelling behavior, but show potential for delivery of high pI proteins when compared to the MAA-based systems.