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Research ArticleArticle

Rapid Distribution of Liposomal Short-Chain Ceramide in Vitro and in Vivo

Banu S. Zolnik, Stephan T. Stern, James M. Kaiser, Yasser Heakal, Jeffrey D. Clogston, Mark Kester and Scott E. McNeil
Drug Metabolism and Disposition August 2008, 36 (8) 1709-1715; DOI: https://doi.org/10.1124/dmd.107.019679
Banu S. Zolnik
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Stephan T. Stern
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James M. Kaiser
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Yasser Heakal
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Jeffrey D. Clogston
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Mark Kester
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Scott E. McNeil
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Abstract

Ceramide, an endogenous sphingolipid, has demonstrated antieoplastic activity in vitro and in vivo. However, the chemotherapeutic utility of ceramide is limited because of its insolubility. To increase the solubility of ceramide, liposomal delivery systems have been used. The objective of the present study was to characterize the pharmacokinetics and tissue distribution of C6-ceramide and control (non-C6-ceramide) nanoliposomes in rats, using [14C]C6-ceramide and [3H]distearylphosphatidylcholine (DSPC) as tracers of the ceramide and liposome components, respectively. Ceramide liposomes were administered at 50 mg of liposomes/kg by jugular vein to female Sprague-Dawley rats. The apparent volume of distribution (Vd) of [3H]DSPC was approximately 50 ml/kg, suggesting that the liposomes were confined to the systemic circulation. In contrast, the Vd of [14C]C6-ceramide was 20-fold greater than that of liposomes, indicating extensive tissue distribution. This high Vd of [14C]C6-ceramide in relation to that of [3H]DSPC suggests that ceramide and liposomes distribute independently of each other. This disparate disposition was confirmed by tissue distribution studies, in which [14C]C6-ceramide exhibited rapid tissue accumulation compared with to [3H]DSPC. Examination of ceramide liposome blood compartmentalization in vitro also demonstrated divergent partitioning, with liposomes being confined to the plasma fraction and ceramide rapidly equilibrating between red blood cell and plasma fractions. A bilayer exchange mechanism for ceramide transfer is proposed to explain the results of the present study, as well as give insight into the documented antineoplastic efficacy of short-chain ceramide liposomes. Our studies suggest that this nanoscale PEGylated drug delivery system for short-chain ceramide offers rapid tissue distribution without adverse effects for a neoplastic-selective, insoluble agent.

Footnotes

  • This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. The project was also funded in part through the State of Pennsylvania Non-formulary Tobacco Settlement Funds. Penn State Research Foundation has licensed ceramide nanoliposomes to Tracon Pharmaceuticals, Inc. (San Diego CA). M.K. is chief medical officer for Keystone Nano, which develops a separate, nonliposomal ceramide nanotechnology.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.019679.

  • ABBREVIATIONS: PEG, polyethylene glycol; RES, reticuloendothelial system; DSPC, 1,2-distearyl-sn-glycero-3-phosphocholine; C6-ceramide, N-hexanoyl-d-erythrosphingosine; BTS-450, Beckman tissue solubilizer 450; SD, Sprague-Dawley; AUC, area under the time-concentration curve; RBC, red blood cell.

  • ↵ Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

    • Received November 6, 2007.
    • Accepted May 15, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (8)
Drug Metabolism and Disposition
Vol. 36, Issue 8
1 Aug 2008
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Research ArticleArticle

Rapid Distribution of Liposomal Short-Chain Ceramide in Vitro and in Vivo

Banu S. Zolnik, Stephan T. Stern, James M. Kaiser, Yasser Heakal, Jeffrey D. Clogston, Mark Kester and Scott E. McNeil
Drug Metabolism and Disposition August 1, 2008, 36 (8) 1709-1715; DOI: https://doi.org/10.1124/dmd.107.019679

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Research ArticleArticle

Rapid Distribution of Liposomal Short-Chain Ceramide in Vitro and in Vivo

Banu S. Zolnik, Stephan T. Stern, James M. Kaiser, Yasser Heakal, Jeffrey D. Clogston, Mark Kester and Scott E. McNeil
Drug Metabolism and Disposition August 1, 2008, 36 (8) 1709-1715; DOI: https://doi.org/10.1124/dmd.107.019679
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