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.
J Control Release. 2010 Dec 20;148(3):380-7. doi: 10.1016/j.jconrel.2010.09.016. Epub 2010 Sep 22.
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.
慢性髓性白血病（CML）的干细胞/祖细胞过度表达 Bcr-Abl，对伊马替尼的反应是增殖可逆性受阻，而没有明显的细胞凋亡。因此，由于白血病静止干细胞（QSC）的持续存在，这些细胞能够引发疾病复发，患者不太可能被治愈。以前，我们已经报道了原发性原始 CML 细胞（CD34+38(lo/-））中伊马替尼的细胞内水平明显低于 CML 祖细胞（总 CD34+）和白血病细胞系。本研究的目的是确定持续存在的白血病 QSC 中潜在的治疗浓度以下的细胞内药物浓度是否可以通过使用合成低密度脂蛋白（sLDL）颗粒进行靶向药物递送来克服。然而，为了实现这一目标，首先研究了 sLDL 被白血病细胞系和 CML 患者干细胞/祖细胞的摄取程度。结果表明，与 Bcr-Abl 阴性细胞相比，非药物负载的颗粒中 sLDL 被 Bcr-Abl 阳性细胞系的摄取增加且具有优先性。此外，与非 CML CD34+细胞相比，CML CD34+和原始 CD34+38(lo/-）细胞明显积累了更高水平的 sLDL。因此，sLDL 纳米颗粒的药物加载有可能增加原始 CML 细胞内的药物浓度，从而有助于清除这些细胞。
