Protein drugs are currently administered systemically by injections. For individuals requiring chronic therapy, self administration with a needle is an unpleasant everyday experience. Development of injectable biodegradable polymers, e.g. poly(lactic-co-glycolic acid) (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 stablization approaches. In this proposal, the pH in the polymer will be manipulated to improve the stability of model proteins and peptides encapsulated in PLGA. This and other stabilization approaches will be applied to therapeutic proteins that promote angiogenesis. Slow-release angiogenic agents have important applications for patients with ischemic heart disease (responsible for >600,000 deaths annually in the US). 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. Considering the potential impact of PLGA delivery systems that slowly release native therapeutic proteins, such as those that promote angiogenesis, could have on human heath, the importance in resolving the poor instability of proteins encapsulated in PLGAs becomes unmistakeable. This proposal will test the following hypothesis: Moisture combined with uncontrolled and frequently acidic pH inside PLGAs are the two most common stresses responsible for instability of proteins in PLGA delivery systems, including microspheres. Development of methods to control polymer microclimate pH will become a widely applicable method 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 and peptides in PLGA delivery systems, 3) application of the stabilization methodology to the delivery of 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 #
5R01HL068345-09
Application #
7929585
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Lundberg, Martha
Project Start
2001-02-15
Project End
2012-05-31
Budget Start
2010-09-01
Budget End
2011-05-31
Support Year
9
Fiscal Year
2010
Total Cost
$275,145
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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Holpuch, Andrew S; Phelps, Maynard P; Desai, Kashappa-Goud H et al. (2012) Evaluation of a mucoadhesive fenretinide patch for local intraoral delivery: a strategy to reintroduce fenretinide for oral cancer chemoprevention. Carcinogenesis 33:1098-105

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