Novel carriers for oral delivery of hemophiliac factor IX

Current treatments for hemophilia B, a hereditary bleeding disorder characterized by the deficiency of coagulation factor IX (FIX), rely on injection-based administration that cause pain and discomfort, leading to noncompliance and risk of subsequent bleeding episodes. A non-invasive protein replacement therapy using an oral delivery system can both overcome such issues and improve access to treatment in developing countries. Oral delivery is a desirable route for protein therapeutics; however, two main challenges—increasing bioavailability and maintaining protein functionality—need to be addressed when designing a delivery platform. The overarching goal of this work presented here is to develop an oral delivery system for human factor IX (hFIX) as a convenient prophylactic treatment. Complexation hydrogels have been engineered to protect biologics from the harsh environment of the GI tract and deliver them to the small intestine for absorption. We have successfully developed pH-responsive hydrogel networks based on poly(methacrylic acid)-grafted-poly(ethylene glycol) [P(MAA-g-EG)] as delivery vehicles for hFIX. We have focused on optimizing the drug loading and release, as well as evaluating in vitro drug absorption and in vivo biocompatibility and biodistribution of the microcarrier. Tailoring the networks of P(MAA-g-EG) hydrogels improved the loading of hFIX within the microcarriers, which is critical for minimizing protein degradation. Optimizing the loading conditions by increasing the incubation time and using a reduced ionic strength buffer further improved the delivery potential of the microcarriers. The presence of the microcarriers significantly improved the in vitro absorption of hFIX. As an alternative strategy designed to further increase the delivery potential, we incorporated an enzymatically degradable component into the P(MAA-g-EG) microcarrier system. Evaluation of this degradable system demonstrated the increased levels of hFIX in intestinal conditions, which has the potential to promote the oral bioavailability of hFIX. We performed stability testing of lyophilized hFIX-loaded microparticles to determine the effects of storage conditions on hFIX release and activity. Lastly, in vivo biocompatibility and biodistribution studies were performed to establish the safety of multiple oral doses of P(MAA-g-EG) microparticles and to determine the residence time and clearance of these microcarriers. In vivo preclinical studies were critical for clinical applications of these drug delivery systems. This works shows that P(MAA-g-EG) microcarriers are promising candidates for the oral delivery of hFIX for treating hemophilia B.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Chemical Engineering

Grantor

The University of Texas at Austin

Year dc:date.issued

2016

Author dc:creator

• Horava, Sarena DelVecchio

Advisor dc:contributor.advisor

• Peppas, Nicholas A., 1948-

Committee members dc:contributor.committeemember

• Croyle, Maria
• Freeman, Benny
• Maynard, Jennifer A
• Paul, Donald R

• Drug delivery
• Hydrogels
• Factor IX

Language dc:language.iso

en

Identifier

doi:10.15781/T21N7Z59R

OAI identifier oai:identifier

oai:repositories.lib.utexas.edu:2152/68376