In vivo efficacy of a novel liposomal formulation of safingol in the treatment of acute myeloid leukemia
Tan, K.-B. Ling, L.-U. Bunte, R.M. Chng, W.-J. Chiu, G.N.C.
Tan, K.-B.
Ling, L.-U.
Chng, W.-J.
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Alternative Title
Abstract
Prognosis of patients with acute myeloid leukemia (AML) remains poor despite the use of first-line induction chemotherapy. Therefore, it is imperative to find effective treatment for AML patients. Safingol is a bioactive sphingolipid which has demonstrated promising in vitro anti-leukemic properties; however, translation into clinical use is hampered by its low water solubility and dose-limiting hemolysis. The present study is the first to describe a rationally designed liposome formulation of safingol and demonstrate the anti-leukemic potential using a panel of human AML cell lines and patient samples as well as a human xenograft model in SCID mice. Encapsulation efficiency of safingol into liposomes was approximately 100%, and the release of drug followed square-root-of-time release model. The presence of a transmembrane pH gradient completely abolished the biological activity of liposomal safingol. A positive zeta potential, which influenced cellular accumulation of liposomal safingol, was crucial to the anti-leukemic activity. Liposomal safingol was effective against a wide range of AML subtypes with minimal hemolytic toxicity, and was able to extend the median survival time of the U937-inoculated mice to 31 days as compared to 23 days by free drug. The increase in therapeutic efficacy could be related to the increase in systemic drug exposure as a result of liposome encapsulation. © 2011 Elsevier B.V.
Keywords
Acute myeloid leukemia, Hemolysis, Liposome, Safingol, Sphingolipid, Zeta potential
Source Title
Journal of Controlled Release
Publisher
Series/Report No.
Collections
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Date
2012-06-10
DOI
10.1016/j.jconrel.2011.11.002
Type
Article