The long-term research objectives of this proposal are the formulation and synthesis of biodegradable polymeric matrices which can incorporate and stabilize macromolecules (MW>1000) and release them in a controlled fashion as bioactive agents for up to 1 month. Macromolecules, such as peptides and proteins, are becoming increasingly important for use in biopharmaceutical research and as potential therapeutic agents. However, their complex three-dimensional structures and large size generally results in easy inactivation, poor oral bioavailability and rapid metabolism, limiting their use to short-term parenteral settings. Controlled release polymer systems potentially offer many advantages which may overcome these obstacles. For example, protection during storage and delivery, maintenance of drug levels without peaks and troughs, reduced dosages, increased dosing intervals, localized delivery, and improved patient comfort and compliance. Delivery systems for low molecular weight molecules are being widely used both experimentally, to study chemotactic agents, cell extracts and others, and clinically, to treat prostate cancer using Lupron Depot or deliver contraceptives using Norplant. In spite of these advances, no clinically available controlled release system for large molecular weight compounds exists. This is because of both formulation (polymer) and stability (protein) issues. The candidate's hypothesis is that biodegradable controlled release polymers can be developed for the long-term delivery of bioactive macromolecules, such as peptides and proteins, at efficacious levels. She has chosen PLGA [poly(lactide-co-glycolide)], a biodegradable copolymer with FDA approval for biomedical application, as a release matrix. Atrial natriuretic peptide (ANP), a 3000 MW molecule with therapeutic potential in hypertension and congestive heart failure, will serve as a model compound. The hypothesis will be tested through the following specific aims. 1) To design a biodegradable controlled release system by optimizing the performance properties of PLGA for the delivery of ANP over one month, and study the role of polymer erosion in drug delivery using both theoretical and experimental approaches; 2) To examine protein stability as it relates to PLGA preparation, storage, and release and develop strategies to preserve ANP bioactivity: 3) To evaluate the pharmacokinetics of the PLGA delivery system and the efficacy of the controlled release form of ANP using cell culture and animal model bioassays. The candidate states her belief that the successful completion of these objectives will greatly facilitate, first the investigations, and ultimately, the clinical applications of large, bioactive protein macromolecules.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL003698-03
Application #
2900983
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (F1))
Project Start
1997-04-04
Project End
2002-03-31
Budget Start
1999-05-06
Budget End
2000-03-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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Rupnick, Maria A; Panigrahy, Dipak; Zhang, Chen-Yu et al. (2002) Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci U S A 99:10730-5
Dallabrida, S M; Rupnick, M A (2002) Vascular endothelium in tissue remodeling: implications for heart failure. Cold Spring Harb Symp Quant Biol 67:417-27