Uptake of synthetic Low Density Lipoprotein by leukemic stem cells--a potential stem cell targeted drug delivery strategy.
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+38(lo/⁻)), are significantly lower than in CML progenitor cells (total CD34+) 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+ and primitive CD34+38(lo/⁻) cells accumulated significantly higher levels of sLDL when compared with non-CML CD34+ cells. Thus, drug-loading the sLDL nanoparticles could potentially enhance intracellular drug concentrations in primitive CML cells and thus aid their eradication.
Zhou
Peixun
P
Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G120NY, United Kingdom.
Hatziieremia
Sophia
S
Elliott
Moira A
MA
Scobie
Linda
L
Crossan
Claire
C
Michie
Alison M
AM
Holyoake
Tessa L
TL
Halbert
Gavin W
GW
Jørgensen
Heather G
HG
D018952:Antigens, CD34 / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism*
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D008077:Lipoproteins, LDL