title: Transport across the blood-brain barrier of pluronic leptin.
abstract: Leptin is a peptide hormone produced primarily by adipose tissue that acts as a major regulator of food intake and energy homeostasis. Impaired transport of leptin across the blood-brain barrier (BBB) contributes to leptin resistance, which is a cause of obesity. Leptin as a candidate for the treatment of this obesity is limited because of the short half-life in circulation and the decreased BBB transport that arises in obesity. Chemical modification of polypeptides with amphiphilic poly(ethylene oxide)-poly(propylene oxide) block copolymers (Pluronic) is a promising technology to improve efficiency of delivery of polypeptides to the brain. In the present study, we determined the effects of Pluronic P85 (P85) with intermediate hydrophilic-lipophilic balance conjugated with leptin via a degradable SS bond [leptin(ss)-P85] on food intake, clearance, stability, and BBB uptake. The leptin(ss)-P85 exhibited biological activity when injected intracerebroventricularly after overnight food deprivation and 125I-leptin(ss)-P85 was stable in blood, with a half-time clearance of 32.3 min (versus 5.46 min for leptin). 125I-Leptin(ss)-P85 crossed the BBB [blood-to-brain unidirectional influx rate (K(i)) = 0.272 +/- 0.037 microl/g x min] by a nonsaturable mechanism unrelated to the leptin transporter. Capillary depletion showed that most of the 125I-leptin(ss)-P85 taken up by the brain reached the brain parenchyma. Food intake was reduced when 3 mg of leptin(ss)-P85 was administered via tail vein in normal body weight mice [0-30 min, p < 0.0005; 0-2 h, p < 0.001]. These studies show that the structure based Pluronic modification of leptin increased metabolic stability, reduced food intake, and allowed BBB penetration by a mechanism-independent BBB leptin transporter.
authors.affiliation: Geriatric Research, Education, and Clinical Center, VA Medical Center, John Cochran Division, 915 N. Grand Blvd., St. Louis, MO 63106, USA.
authors.forename: Tulin O
authors.initials: TO
authors.lastname: Price
authors.forename: Susan A
authors.initials: SA
authors.lastname: Farr
authors.forename: Xiang
authors.initials: X
authors.lastname: Yi
authors.forename: Serguei
authors.initials: S
authors.lastname: Vinogradov
authors.forename: Elena
authors.initials: E
authors.lastname: Batrakova
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kabanov
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D020738:Leptin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D020442:Poloxamer / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D020738:Leptin; D020442:Poloxamer; C519610:pluronic P105