title: Pluronic modified leptin with increased systemic circulation, brain uptake and efficacy for treatment of obesity.
abstract: Modification of hydrophilic proteins with amphiphilic block copolymers capable of crossing cell membranes is a new strategy to improve protein delivery to the brain. Leptin, a candidate for the treatment of epidemic obesity, has failed in part because of impairment in its transport across the blood-brain barrier (BBB) that develops with obesity. We posit that modification of leptin with poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide), Pluronic P85 (P85) might permit this protein to penetrate the BBB independently of its transporter, thereby overcoming peripheral leptin resistance. Here we report that peripherally administered leptin-P85 conjugates exhibit biological activity by reducing food intake in mouse models of obesity (ob/ob, and diet-induced obese mouse). We further generated two new leptin-P85 conjugates: one, Lep(ss)-P85(L), containing one P85 chain and another, Lep(ss)-P85(H), containing multiple P85 chains. We report data on their purification, analytical characterization, peripheral and brain pharmacokinetics (PK). Lep(ss)-P85(L) crosses the BBB using the leptin transporter, and exhibits improved peripheral PK along with increased accumulation in the brain compared to unmodified leptin. Lep(ss)-P85(H) also has improved peripheral PK but in a striking difference to the first conjugate penetrates the BBB independently of the leptin transporter via a non-saturable mechanism. The results demonstrate that leptin analogs can be developed through chemical modification of the native leptin with P85 to overcome leptin resistance at the level of the BBB, thus improving the potential for the treatment of obesity.
authors.affiliation: Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: xiang_yi@unc.edu.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yi
authors.affiliation: Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Dongfen
authors.initials: D
authors.lastname: Yuan
authors.affiliation: Research and Development, VA Medical Center and Division of Geriatrics, St. Louis University School of Medicine, St. Louis, MI, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Farr
authors.affiliation: Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98108, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
authors.affiliation: Research Computer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Chi-Duen
authors.initials: CD
authors.lastname: Poon
authors.affiliation: Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Faculty of Chemistry, M.V. Lomonosov Moscow State University, 119899 Moscow, Russia. Electronic address: kabanov@unc.edu.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kabanov
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D004337:Drug Carriers; D004355:Drug Stability; D004435:Eating / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D020738:Leptin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D010539:Permeability; D011060:Poloxalene / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D019440:Anti-Obesity Agents; D004337:Drug Carriers; D020738:Leptin; C422648:pluronic block copolymer p85; D011060:Poloxalene
keywords: Blood–brain barrier; Brain pharmacokinetics; Leptin; Obesity; Pluronic block copolymer; Protein–polymer conjugation