| 20053933 |
Price TO, Farr SA, Yi X, Vinogradov S, Batrakova E, Banks WA, Kabanov AV: Transport across the blood-brain barrier of pluronic leptin. . J Pharmacol Exp Ther. 2010 Apr;333(1):253-63. Epub 2010 Jan 6.
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. |
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