Uptake of synthetic low density lipoprotein by leukemic stem cells — a potential stem cell targeted drug delivery strategy

Zhou, P., Hatziieremia, S., Elliott, M. A., Scobie, L., Crossan, C., Michie, A. M. , Holyoake, T. L., Halbert, G. W. and Jorgensen, H. G. (2010) Uptake of synthetic low density lipoprotein by leukemic stem cells — a potential stem cell targeted drug delivery strategy. Journal of Controlled Release, 148(3), pp. 380-387. (doi: 10.1016/j.jconrel.2010.09.016)

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Publisher's URL: http://dx.doi.org/10.1016/j.jconrel.2010.09.016

Abstract

Chronic Myeloid Leukemia (CML) stem/progenitor cells, which over-express Bcr-Abl, respond to imatinib by a reversible block in proliferation without significant apoptosis. As a result, patients are unlikely to be cured owing to the persistence of leukemic quiescent stem cells (QSC) capable of initiating relapse. Previously, we have reported that intracellular levels of imatinib in primary primitive CML cells (CD34<sup>+</sup>38<sup>lo/−</sup>), are significantly lower than in CML progenitor cells (total CD34<sup>+</sup>) and leukemic cell lines. The aim of this study was to determine if potentially sub-therapeutic intracellular drug concentrations in persistent leukemic QSC may be overcome by targeted drug delivery using synthetic Low Density Lipoprotein (sLDL) particles. As a first step towards this goal, however, the extent of uptake of sLDL by leukemic cell lines and CML patient stem/progenitor cells was investigated. Results with non-drug loaded particles have shown an increased and preferential uptake of sLDL by Bcr-Abl positive cell lines in comparison to Bcr-Abl negative. Furthermore, CML CD34<sup>+</sup> and primitive CD34<sup>+</sup>38<sup>lo/−</sup> cells accumulated significantly higher levels of sLDL when compared with non-CML CD34<sup>+</sup> cells. Thus, drug-loading the sLDL nanoparticles could potentially enhance intracellular drug concentrations in primitive CML cells and thus aid their eradication.

Item Type:Articles
Additional Information:NOTICE: this is the author’s version of a work that was accepted for publication in <i>Journal of Controlled Release</i>. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in <i>Journal of Controlled Release</i>, [148, 3, (2010)] DOI:10.1016/j.jconrel.2010.09.016
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Michie, Dr Alison and Holyoake, Professor Tessa and Crossan, Miss Claire and Jorgensen, Dr Heather and Zhou, Mr Peixun and Scobie, Dr Linda and Hatziieremia, Dr Sophia
Authors: Zhou, P., Hatziieremia, S., Elliott, M. A., Scobie, L., Crossan, C., Michie, A. M., Holyoake, T. L., Halbert, G. W., and Jorgensen, H. G.
Subjects:R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Journal of Controlled Release
Publisher:Elsevier
ISSN:0168-3659
ISSN (Online):1873-4995
Published Online:22 September 2010
Copyright Holders:Copyright © 2010 Elsevier
First Published:First published in Journal of Controlled Release 148(3):380-387
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
444831Defining the cellular origin of chronic lymphocytic leukaemiaAlison MichieMedical Research Council (MRC)G0601099Institute of Cancer Sciences