Protein drugs are currently administered systemically by injections. For individuals requiring chronic therapy, self-administration with a needle is an unpleasant everyday experience. However, development of injectable biodegradable polymers (e.g., poly(lactide-co-glycolides), PLGA) capable of slowly and continuously releasing proteins for months between injections may provide a realistic alternative to painful daily injections. PLGA delivery systems are also used for local therapy and for delivery of vaccines. The primary obstacle to develop PLGA delivery systems for proteins is the irreversible instability of these agents prior to their release in vivo. The overall goal of these studies is to determine the underlying molecular mechanisms responsible for the instability of proteins in PLGA and to use this information to develop widely applicable stabilization approaches. In this proposal, the pH in the polymer will be manipulated with antacid excipients to improve the stability of model proteins encapsulated in PLGA. This general stabilization approach will then be tested with therapeutic proteins that promote angiogenesis. Slow-release angiogenic agents have important applications for patients with ischemic heart disease (responsible for about 5OO,OOO deaths annually in the U. S.). The ensuing site-specific neovascularization would facilitate myocardial perfusion and reduce cardiac complications such as myocardial infarction, angina pectoris, heart failure, and/or sudden cardiac death. Slow-release growth factors may also be useful to improve survival of tissues after implantation of tissue engineering scaffolds. Considering the potential impact of PLGA delivery systems that slowly release native therapeutic proteins, such as those that promote angiogenesis, could have on human health, the importance in resolving the poor instability of proteins encapsulated in PLGAs becomes unmistakable. This proposal will test the following hypothesis: Moisture and acidic pH inside PLGAs during protein release are the two most common stresses responsible for instability of proteins in PLGA delivery systems, including microspheres. Development of methods to regulate pH in the polymer as well as aqueous protein solubility will become widely applicable techniques to stabilize encapsulated proteins. This hypothesis will be tested in the following specific aims: (1) Characterization of physical chemical processes in the polymer microclimate that influence stability and release of encapsulated proteins; (2) Investigation of stability of model proteins in PLGA delivery systems; (3) Application of the stabilization methodology to the delivery of therapeutic angiogenic proteins; and (4) In vivo assessment of the controlled release of biologically active angiogenic proteins.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068345-03
Application #
6629146
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Lundberg, Martha
Project Start
2001-02-15
Project End
2006-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
3
Fiscal Year
2003
Total Cost
$194,673
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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