Versluis A J, Rensen P C, Rump E T, Van Berkel T J, Bijsterbosch M K
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, University of Leiden, The Netherlands.
Br J Cancer. 1998 Dec;78(12):1607-14. doi: 10.1038/bjc.1998.730.
Many tumours express relatively high levels of low-density lipoprotein (LDL) receptors on their membranes. The LDL receptor is, therefore, an attractive target for the selective delivery of antineoplastic drugs to tumour cells. We reported previously on the synthesis of small apolipoprotein E (apoE)-containing liposomes that behave in vivo in a very similar way to native LDL. In this study, we examined the interaction of this liposomal carrier with cultured B16 melanoma cells. Binding of apoE liposomes to the cells is saturable, with a maximum binding of approximately 90000 particles per cell. Cross-competition studies indicated that apoE liposomes are bound by the LDL receptor. Association of apoE liposomes to B16 cells is strictly Ca2+ dependent, which forms additional evidence for a role of the LDL receptor. The affinity of apoE liposomes for the LDL receptor on B16 cells is 15-fold higher than that of LDL (0.77 vs 11.5 nM respectively). ApoE is essential for the LDL receptor recognition because liposomes lacking apoE were, in competition studies, 20- to 50-fold less effective than apoE-containing liposomes. We examined in B16 tumour-bearing mice the tumour-localizing properties of apoE liposomes and the disposition of an incorporated lipophilic derivative of daunorubicin (LAD). Tissue distribution studies showed that LAD-loaded apoE liposomes were taken up and processed by the major LDL receptor-expressing organs (i.e. adrenals, liver and spleen). Of all other tissues, the tumour showed the highest uptake. The distribution patterns of LAD-loaded apoE liposomes and native LDL in the tumour-bearing mice were very similar, which supports the role of the LDL receptor in the disposition of the prodrug-loaded particles. The disposition of LAD followed the pattern of the liposomal carrier. We conclude that apoE liposomes enable LDL receptor-mediated specific delivery of antineoplastic (pro)drugs to tumours, and, therefore, constitute an attractive novel option for anti-tumour chemotherapy.
许多肿瘤细胞膜上表达相对高水平的低密度脂蛋白（LDL）受体。因此，LDL受体是将抗肿瘤药物选择性递送至肿瘤细胞的一个有吸引力的靶点。我们之前报道了含小载脂蛋白E（apoE）的脂质体的合成，其在体内的行为与天然LDL非常相似。在本研究中，我们检测了这种脂质体载体与培养的B16黑色素瘤细胞的相互作用。apoE脂质体与细胞的结合是可饱和的，每个细胞的最大结合量约为90000个颗粒。交叉竞争研究表明，apoE脂质体被LDL受体结合。apoE脂质体与B16细胞的结合严格依赖Ca2+，这为LDL受体的作用提供了额外证据。apoE脂质体对B16细胞上LDL受体的亲和力比LDL高15倍（分别为0.77 nM和11.5 nM）。apoE对于LDL受体识别至关重要，因为在竞争研究中，不含apoE的脂质体比含apoE的脂质体效果低20至50倍。我们在荷B16肿瘤的小鼠中检测了apoE脂质体的肿瘤定位特性以及柔红霉素脂质衍生物（LAD）的处置情况。组织分布研究表明，载有LAD的apoE脂质体被主要表达LDL受体的器官（即肾上腺、肝脏和脾脏）摄取和处理。在所有其他组织中，肿瘤的摄取量最高。荷瘤小鼠中载有LAD的apoE脂质体和天然LDL的分布模式非常相似，这支持了LDL受体在载有前药颗粒处置中的作用。LAD的处置遵循脂质体载体的模式。我们得出结论，apoE脂质体能够实现LDL受体介导的抗肿瘤（前）药物向肿瘤的特异性递送，因此，构成了抗肿瘤化疗的一个有吸引力的新选择。
