Liposomal Codelivery of A Synergistic Combination of Bioactive Lipids in The Treatment of Acute Myeloid Leukemia

Abstract

Aim: The aim of this work was to develop a liposomal formulation to facilitate delivery of a synergistic safingol/C2-ceramide combination in the treatment of acute myeloid leukemia (AML). Materials & methods: Liposomes were prepared using the extrusion method and the bioactive lipids were encapsulated passively. Drug concentrations were determined by liquid chromatography tandem mass spectrometry. Antileukemic activity was evaluated using human leukemic cell lines, patient samples and U937 leukemic xenograft models. Results: A stable liposome formulation was developed to coencapsulate safingol and C2-ceramide at 1:1 molar ratio with >90% encapsulation efficiency. The liposomal safingol/C2-ceramide was effective in AML cell lines, patient samples and murine xenograft models of AML, compared with liposomal safingol or liposomal C2-ceramide alone despite a dose reduction of 33%. Conclusion: Our study provided proof-of-concept evidence to deliver synergistic combination of bioactive lipid to achieve complete remission in AML.

Original submitted: 27 February 2013; Revised submitted: 25 June 2013

Keywords::

• acute myeloid leukemia
• C2-ceramide
• hemolysis
• liposome
• safingol
• sever combined immunodeficiency mouse
• sphingolipid
• synergistic combination
• U937
• zeta-potential

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Financial & competing interests disclosure

This work was supported by Singapore‘s Ministry of Education through the National University of Singapore Academic Research Fund FRC-Tier 1 grant (R-148-000-098-112). KB Tan is supported by National University of Singapore graduate research scholarship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was supported by Singapore‘s Ministry of Education through the National University of Singapore Academic Research Fund FRC-Tier 1 grant (R-148-000-098-112). KB Tan is supported by National University of Singapore graduate research scholarship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.