title: In vivo efficacy of a novel liposomal formulation of safingol in the treatment of acute myeloid leukemia.
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.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
authors.forename: Kuan-Boone
authors.initials: KB
authors.lastname: Tan
authors.forename: Leong-Uung
authors.initials: LU
authors.lastname: Ling
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Bunte
authors.forename: Wee-Joo
authors.initials: WJ
authors.lastname: Chng
authors.forename: Gigi N C
authors.initials: GN
authors.lastname: Chiu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D004339:Drug Compounding; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D012995:Solubility; D013110:Sphingosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D016019:Survival Analysis; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D013110:Sphingosine; C005682:safingol