Abstract

This proposal is a competing continuation of the NIH grant R01 NS051335. The long term goal is to produce polypeptides that could cross the blood-brain barrier (BBB) and so be developed as central nervous system (CNS) therapeutics. The goal is achieved by modification of polypeptides with Pluronic copolymers (poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide)). The studies have focused on leptin, a candidate for the treatment of epidemic obesity. Leptin failure is mostly due to peripheral resistance - a loss of its ability to cross the BBB necessary to reach its receptors in the arcuate nucleus of the hypothalamus. The previous work produced a conjugate of leptin with Pluronic P85 that is centrally active, has a long half-life in blood, is enzymatically resistant, crosses the BBB by a non-saturable mechanism independently of the leptin transporter, and can exert effects on feeding and body weight after peripheral administration. This proposal will: 1). optimize modifications to produce superior leptin analogs with maximal BBB permeability, improved half-life in blood and high enzymatic resistance in brain and blood;2). identify mechanisms underlying enhanced permeability of leptin analogs in BBB;3). determine the permeability of modified leptin analogs across the BBB to select the best analogs for activity testing;and 4) determine the biological activity after intravenous injection of the best leptin analogs 3 in leptin sensitive (ob/ob) and leptin resistant (dietary obese) mouse models of obesity. Analogs completing this development will be a) active in brain, b) have favorable pharmacokinetics, c) be able to cross the BBB in obese mice, and d) reverse obesity after iv injection. Such analogs are candidates for clinical trials in human obesity.

Public Health Relevance

The long term goal is to produce polypeptides that could cross the blood-brain barrier (BBB) and so be developed as central nervous system (CNS) therapeutics. The goal is achieved by modification of polypeptides with Pluronic copolymers (poly(ethylene oxide)- b-poly(propylene oxide)-b-poly(ethylene oxide)).

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS051334-08
Application #
8445267
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2005-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
8
Fiscal Year
2013
Total Cost
$334,428
Indirect Cost
$42,088

  Institution

Name
University of North Carolina Chapel Hill
Department
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Yuan, Dongfen; Yi, Xiang; Zhao, Yuling et al. (2017) Intranasal delivery of N-terminal modified leptin-pluronic conjugate for treatment of obesity. J Control Release 263:172-184
Jiang, Yuhang; Brynskikh, Anna M; S-Manickam, Devika et al. (2015) SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature. J Control Release 213:36-44
Yi, Xiang; Yuan, Dongfen; Farr, Susan A et al. (2014) Pluronic modified leptin with increased systemic circulation, brain uptake and efficacy for treatment of obesity. J Control Release 191:34-46
Erickson, Michelle A; Morofuji, Yoichi; Owen, Joshua B et al. (2014) Rapid transport of CCL11 across the blood-brain barrier: regional variation and importance of blood cells. J Pharmacol Exp Ther 349:497-507
Yi, Xiang; Manickam, Devika S; Brynskikh, Anna et al. (2014) Agile delivery of protein therapeutics to CNS. J Control Release 190:637-63
Tong, Jing; Yi, Xiang; Luxenhofer, Robert et al. (2013) Conjugates of superoxide dismutase 1 with amphiphilic poly(2-oxazoline) block copolymers for enhanced brain delivery: synthesis, characterization and evaluation in vitro and in vivo. Mol Pharm 10:360-77
Yi, Xiang; Kabanov, Alexander V (2013) Brain delivery of proteins via their fatty acid and block copolymer modifications. J Drug Target 21:940-55
Klyachko, Natalia L; Manickam, Devika S; Brynskikh, Anna M et al. (2012) Cross-linked antioxidant nanozymes for improved delivery to CNS. Nanomedicine 8:119-29
Luxenhofer, Robert; Han, Yingchao; Schulz, Anita et al. (2012) Poly(2-oxazoline)s as polymer therapeutics. Macromol Rapid Commun 33:1613-31
Banks, William A (2012) Role of the blood-brain barrier in the evolution of feeding and cognition. Ann N Y Acad Sci 1264:13-9

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