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

Peixun Zhou, Sophia Hatziieremia, Moira A Elliott, Linda Scobie, Claire Crossan, Alison M Michie, Tessa L Holyoake, Gavin W Halbert, Heather G Jørgensen

Research output: Contribution to journalArticle

19 Citations (Scopus)

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+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.
Original languageEnglish
Pages (from-to)380-387
Number of pages8
JournalJournal of Controlled Release
Volume148
Issue number3
Early online date22 Sep 2010
DOIs
Publication statusPublished - 20 Dec 2010

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
LDL Lipoproteins
Stem Cells
Pharmaceutical Preparations
Myeloid Cells
Cell Line
Myeloid Progenitor Cells
Myeloid Leukemia
Nanoparticles
Apoptosis
Recurrence

Keywords

  • antigens
  • antineoplastic agents
  • cell line
  • cell membrane permeability
  • cells
  • drug delivery systems
  • hematopoietic stem cells
  • leukemia
  • leukocytes
  • lipoproteins
  • neoplastic stem cells
  • low density lipoprotein
  • chronic myeloid leukemia
  • CD34+
  • hemopoietic stem cells
  • nanoparticle

Cite this

Zhou, Peixun ; Hatziieremia, Sophia ; Elliott, Moira A ; Scobie, Linda ; Crossan, Claire ; Michie, Alison M ; Holyoake, Tessa L ; Halbert, Gavin W ; Jørgensen, Heather G. / Uptake of synthetic low density Lipoprotein by leukemic stem cells--a potential stem cell targeted drug delivery strategy. In: Journal of Controlled Release. 2010 ; Vol. 148, No. 3. pp. 380-387.
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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+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.",
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Uptake of synthetic low density Lipoprotein by leukemic stem cells--a potential stem cell targeted drug delivery strategy. / Zhou, Peixun; Hatziieremia, Sophia; Elliott, Moira A; Scobie, Linda; Crossan, Claire; Michie, Alison M; Holyoake, Tessa L; Halbert, Gavin W; Jørgensen, Heather G.

In: Journal of Controlled Release, Vol. 148, No. 3, 20.12.2010, p. 380-387.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Uptake of synthetic low density Lipoprotein by leukemic stem cells--a potential stem cell targeted drug delivery strategy

AU - Zhou, Peixun

AU - Hatziieremia, Sophia

AU - Elliott, Moira A

AU - Scobie, Linda

AU - Crossan, Claire

AU - Michie, Alison M

AU - Holyoake, Tessa L

AU - Halbert, Gavin W

AU - Jørgensen, Heather G

N1 - Copyright © 2010 Elsevier B.V. All rights reserved.

PY - 2010/12/20

Y1 - 2010/12/20

N2 - 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.

AB - 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.

KW - antigens

KW - antineoplastic agents

KW - cell line

KW - cell membrane permeability

KW - cells

KW - drug delivery systems

KW - hematopoietic stem cells

KW - leukemia

KW - leukocytes

KW - lipoproteins

KW - neoplastic stem cells

KW - low density lipoprotein

KW - chronic myeloid leukemia

KW - CD34+

KW - hemopoietic stem cells

KW - nanoparticle

U2 - 10.1016/j.jconrel.2010.09.016

DO - 10.1016/j.jconrel.2010.09.016

M3 - Article

VL - 148

SP - 380

EP - 387

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

IS - 3

ER -