Although protein therapeutics now account for over $100 billion annually in sales, therapy comes with high cost and poor delivery options. The vast majority of protein therapeutics are delivered by injection, an unfavorable method that leads to low patient compliance. The preferred oral route has been unused due to digestive enzymes and harsh conditions in the gastrointestinal tract that prevent proteins from reaching their target site. pH-Responsive delivery vehicles based on poly(methacrylic acid) grafted with poly(ethylene glycol) (P(MAA-g-EG)) or poly(methacrylic acid-co-N-vinylpyrrolidone) (P(MAA-co-NVP)) hydrogels have previously been shown to be capable of protecting proteins through the stomach and releasing proteins in the small intestine for uptake into the bloodstream. We aim to expand on this technology to enable the oral delivery of high isoelectric point-exhibiting proteins such as salmon calcitonin to improve treatment compliance and patient quality of life. We show a 10-fold improvement in time-sensitive pH-responsive swelling resulting from changing the pH-responsive moiety to itaconic acid (IA), as well as sufficient delivery potential from P(IA-co-NVP) microparticles for transition to a standard-sized pill. Additionally, using peptide-crosslinked degradable hydrogels targeted for degradation in the small intestine, we demonstrate nearly complete release of encapsulated salmon calcitonin in simulated intestinal fluid, thus showing two promising vehicle designs for overcoming the limitations imposed by the oral pathway.Supported by a grant from the National Institutes of Health R01-EB-000246-20.

Stimuli-responsive hydrogels for oral delivery of high isoelectric point-exhibiting therapeutic proteins

247th National Meeting (2014)

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