This is a resubmission of a competing renewal proposal of grant RO1 EB000246-17 for the continuation of our studies on the fundamental understanding of transmucosal delivery of drugs, peptides and proteins using a series of novel biopolymeric complexation carriers with unique properties and in advanced controlled release systems. It has generally been believed that peptides and proteins such as insulin cannot be administered via the oral route because of their degradation by the proteolytic enzymes in the gastrointestinal tract and their extremely slow rate of transport across the mucosal membrane. A successful oral delivery system for protein drugs could lead to the development of new therapeutics with increased patient compliance and efficacy. Our group has developed a new class of polymeric complexation hydrogels comprised of poly (ethylene glycol) (PEG) chains grafted on poly (methacrylic acid) (PMAA) backbone chain. The new systems, henceforth designated as P (MAA-g-EG), have shown extreme promise as oral delivery vehicles for insulin, calcitonin, and growth hormone. Prior studies have established that these systems are promising candidates for oral delivery of insulin. Yet, our more recent work and attention is now focused on continued strategies for enhancing the bioavailability of oral delivered proteins, in addition to insulin. The methodologies we intend to pursue in this competing renewal proposal include: (i) developing further strategies for protection of the protein in the GI lumen;(ii) enhancing transport of the proteins across the GI lumen;and (iii) increasing the residence times in the upper small intestine through enhanced bioadhesion. While some strategies have been previously investigated with moderate success using insulin, in this work, we will pursue novel strategies that may provide significant advances over our prior studies with insulin. Additionally, we intend to further develop these complexation hydrogels for oral delivery of other therapeutic proteins such as calcitonin and growth hormone.
There is a general scientific belief that oral delivery of protein drugs such as insulin, calcitonin, and growth hormone is impossible due to the protective nature of the GI tract and extensive proteolytic activity of enzymes in the GI tract. We have developed a novel, complexation hydrogel system that has been engineered to protect the protein drugs in the GI tract and enhance transport of the drugs into the bloodstream. A successful oral delivery system for protein drugs could lead to the development of new therapeutics with increased patient compliance and efficacy.
|Koetting, Michael Clinton; Guido, Joseph Frank; Gupta, Malvika et al. (2016) pH-responsive and enzymatically-responsive hydrogel microparticles for the oral delivery of therapeutic proteins: Effects of protein size, crosslinking density, and hydrogel degradation on protein delivery. J Control Release 221:18-25|
|Horava, Sarena D; Peppas, Nicholas A (2016) Design of pH-Responsive Biomaterials to Enable the Oral Route of Hematological Factor IX. Ann Biomed Eng 44:1970-82|
|Spencer, David S; Puranik, Amey S; Peppas, Nicholas A (2015) Intelligent Nanoparticles for Advanced Drug Delivery in Cancer Treatment. Curr Opin Chem Eng 7:84-92|
|Carrillo-Conde, Brenda R; Brewer, Erik; Lowman, Anthony et al. (2015) Complexation Hydrogels as Oral Delivery Vehicles of Therapeutic Antibodies: An in Vitro and ex Vivo Evaluation of Antibody Stability and Bioactivity. Ind Eng Chem Res 54:10197-10205|
|Caldorera-Moore, M; Maass, K; Hegab, R et al. (2015) Hybrid responsive hydrogel carriers for oral delivery of low molecular weight therapeutic agents. J Drug Deliv Sci Technol 30:352-359|
|Koetting, Michael C; Peters, Jonathan T; Steichen, Stephanie D et al. (2015) Stimulus-responsive hydrogels: Theory, modern advances, and applications. Mater Sci Eng R Rep 93:1-49|
|Slaughter, Brandon V; Blanchard, Aaron T; Maass, Katie F et al. (2015) Dynamic swelling behavior of interpenetrating polymer networks in response to temperature and pH. J Appl Polym Sci 132:|
|Brewer, Erik; Lowman, Anthony M (2014) Assessing the transport of receptor-mediated drug-delivery devices across cellular monolayers. J Biomater Sci Polym Ed 25:455-73|
|Gaharwar, Akhilesh K; Peppas, Nicholas A; Khademhosseini, Ali (2014) Nanocomposite hydrogels for biomedical applications. Biotechnol Bioeng 111:441-53|
|Koetting, Michael C; Peppas, Nicholas A (2014) pH-Responsive poly(itaconic acid-co-N-vinylpyrrolidone) hydrogels with reduced ionic strength loading solutions offer improved oral delivery potential for high isoelectric point-exhibiting therapeutic proteins. Int J Pharm 471:83-91|
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