This research plan will enable patients to take protein medications orally. Although patients are most willing and able to take their medications by mouth, this is not currently possible for protein therapeutics like insulin. The most significant challenge preventing oral protein delivery is that the protein drugs are too large to exit the small intestine and enter the bloodstream where they take effect. This research will overcome that challenge by creating chemically modified proteins that temporarily make the intestines more porous so that the protein drug can be absorbed. The chemical modification will consist of polymer chains extending from the surface of the protein. We will learn how the chemistry of the polymer improves the transport of the medicine into the bloodstream and optimize the chemistry for the maximum therapeutic effect. Results will be published for public dissemination. The proposed outreach plan will benefit students of all age levels, including over 1500 K-12 Pittsburgh students who will learn from hands-on science demonstrations. Undergraduate and graduate students will be trained as the next generation of engineers, with an emphasis on research opportunities for women and underrepresented minorities.
This research plan will establish a new paradigm for oral protein delivery therapeutics. Oral protein delivery is one of the most pressing unmet needs in medicine today, and its realization would have dramatic effects on patient compliance and the accessibility of protein therapeutics. Unfortunately, oral protein delivery has not yet been realized due to several challenges, the most significant of which is the inability of therapeutic proteins to cross the intestinal epithelium into the bloodstream. This work will enable oral protein delivery through the engineering of protein-polymer conjugates that selectively enhance intestinal protein permeability. Polymers containing permeation-enhancing side chains will be grown from the surface of the therapeutically relevant enzyme, asparaginase. The side chains will contain piperazine derivatives, a class of molecules previously shown by the PI to offer excellent permeation enhancement without cytotoxicity. The proposed research will determine structure-function relationships to aid in rational design and elucidate the molecular mechanisms of permeation enhancement. At the end of the NSF grant period, this first-of-its-kind platform technology will be well-poised for application to additional therapeutic proteins, including enzymes and antibodies. Results will be published for public dissemination. The proposed outreach plan will benefit students of all age levels, including over 1500 K-12 Pittsburgh students each year who will learn from hands-on drug delivery modules. Undergraduate and graduate students will be groomed as productive, influential future engineers through technical training in biological transport and drug delivery mechanisms, with an emphasis on research opportunities for women and underrepresented minorities.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
