Transport across the blood-brain barrier of pluronic leptin

Tulin O. Price, Susan A. Farr, Xiang Yi, Serguei V Vinogradov, Elena Batrakova, William A. Banks, Alexander V. Kabanov

Research output: Contribution to journalArticle

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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 bloodbrain 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 (Ki) = 0.272 ± 0.037 μl/g · 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.

Original languageEnglish (US)
Pages (from-to)253-263
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume333
Issue number1
DOIs
StatePublished - Apr 1 2010

Fingerprint

Poloxamer
Leptin
Blood-Brain Barrier
Eating
Obesity
Brain
Food Deprivation
Ideal Body Weight
Ethylene Oxide
Peptides
Peptide Hormones

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Price, T. O., Farr, S. A., Yi, X., Vinogradov, S. V., Batrakova, E., Banks, W. A., & Kabanov, A. V. (2010). Transport across the blood-brain barrier of pluronic leptin. Journal of Pharmacology and Experimental Therapeutics, 333(1), 253-263. https://doi.org/10.1124/jpet.109.158147

Transport across the blood-brain barrier of pluronic leptin. / Price, Tulin O.; Farr, Susan A.; Yi, Xiang; Vinogradov, Serguei V; Batrakova, Elena; Banks, William A.; Kabanov, Alexander V.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 333, No. 1, 01.04.2010, p. 253-263.

Research output: Contribution to journalArticle

Price, TO, Farr, SA, Yi, X, Vinogradov, SV, Batrakova, E, Banks, WA & Kabanov, AV 2010, 'Transport across the blood-brain barrier of pluronic leptin', Journal of Pharmacology and Experimental Therapeutics, vol. 333, no. 1, pp. 253-263. https://doi.org/10.1124/jpet.109.158147
Price, Tulin O. ; Farr, Susan A. ; Yi, Xiang ; Vinogradov, Serguei V ; Batrakova, Elena ; Banks, William A. ; Kabanov, Alexander V. / Transport across the blood-brain barrier of pluronic leptin. In: Journal of Pharmacology and Experimental Therapeutics. 2010 ; Vol. 333, No. 1. pp. 253-263.
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