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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB000246-20
Application #
8619623
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Tucker, Jessica
Project Start
1989-12-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
20
Fiscal Year
2014
Total Cost
$379,477
Indirect Cost
$77,478
Name
University of Texas Austin
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Sharpe, Lindsey A; Daily, Adam M; Horava, Sarena D et al. (2014) Therapeutic applications of hydrogels in oral drug delivery. Expert Opin Drug Deliv 11:901-15
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
Culver, Heidi; Daily, Adam; Khademhosseini, Ali et al. (2014) Intelligent recognitive systems in nanomedicine. Curr Opin Chem Eng 4:105-113
Gaharwar, Akhilesh K; Peppas, Nicholas A; Khademhosseini, Ali (2014) Nanocomposite hydrogels for biomedical applications. Biotechnol Bioeng 111:441-53
Annabi, Nasim; Tamayol, Ali; Uquillas, Jorge Alfredo et al. (2014) 25th Anniversary Article: Rational Design and Applications of Hydrogels in Regenerative Medicine. Advanced materials research 26:85-124
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
Puranik, Amey S; Dawson, Eileen R; Peppas, Nicholas A (2013) Recent advances in drug eluting stents. Int J Pharm 441:665-79
Liechty, William B; Peppas, Nicholas A (2012) Expert opinion: Responsive polymer nanoparticles in cancer therapy. Eur J Pharm Biopharm 80:241-6
Sant, Shilpa; Tao, Sarah L; Fisher, Omar Z et al. (2012) Microfabrication technologies for oral drug delivery. Adv Drug Deliv Rev 64:496-507
Caldorera-Moore, Mary E; Liechty, William B; Peppas, Nicholas A (2011) Responsive theranostic systems: integration of diagnostic imaging agents and responsive controlled release drug delivery carriers. Acc Chem Res 44:1061-70

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