Mallinckrodt Institute of Radiology, Washington University School of Medicine, Box 8225, 510 S. Kingshighway Blvd., St. Louis, MO 63110, USA.
Dalton Trans. 2010 Jul 7;39(25):5842-50. doi: 10.1039/c002361b. Epub 2010 May 27.
The human genome is known to consist of 49 ATP-binding cassette (ABC) transporter genes. Among these ABC proteins, overexpression of multidrug resistance (MDR1) P-glycoprotein (Pgp/ABCB1) is the best characterized barrier to successful chemotherapeutic treatments, impacts pharmacokinetics of numerous recognized drugs, and is also quickly emerging as an important target in the development of neurodegenerative diseases. Therefore, there exists an urgent need to seek radiopharmaceuticals, incorporated with generator-produced radionuclides to assist their widespread deployment, for noninvasive assessment of Pgp-mediated functional transport activity in vivo.
gallium(III) complexes (5a and 5b) possessing octahedral geometry were synthesized, analytically characterized, and evaluated for their potential to serve as probes of Pgp-mediated functional transport activity in cellulo and in vivo. While unlabeled compounds (5a and 5b) were examined via cell cytotoxicity assays, the (67)Ga-labeled counterparts (6a and 6b) were evaluated via cell transport studies and quantitative biodistribution studies in mdr1a/1b((-/-)) gene-deleted mice and their wild-type (WT) counterparts.
cytotoxicity data of 5a and 5b displayed profiles modified by the expression of Pgp in drug-resistant cells. (67)Ga-metalloprobes (6a and 6b) showed high accumulation in human epidermal carcinoma drug-sensitive KB-3-1 cells (Pgp-), human breast carcinoma MCF-7 (Pgp-) cells; an inhibitor (LY335979, 1 microM) induced accumulation in multidrug resistant (MDR, Pgp+) KB-8-5, KB-8-5-11 cells, and stably transfected MCF-7/MDR1 cells, thus demonstrating their ability to interrogate Pgp-mediated functional transport activity in cellulo. In mdr1a/1b((-/-)) gene-deleted mice, the (67)Ga-metalloprobe (6b) showed 8-fold greater brain uptake and retention compared with WT counterparts and no significant difference in blood pharmacokinetics.
molecular imaging of the functional transport activity of MDR1 Pgp (ABCB1) with (67/68)Ga-metalloprobes could enable non-invasive monitoring of the blood-brain barrier, tumors, and tissues in vivo.
人类基因组已知由 49 个三磷酸腺苷结合盒（ABC）转运蛋白基因组成。在这些 ABC 蛋白中，多药耐药（MDR1）P-糖蛋白（Pgp/ABCB1）的过度表达是成功化疗治疗的最佳特征性障碍，影响许多公认药物的药代动力学，并且也迅速成为神经退行性疾病发展中的重要靶标。因此，迫切需要寻找放射性药物，与发生器产生的放射性核素结合，以协助广泛部署，用于非侵入性评估体内 Pgp 介导的功能性转运活性。
合成具有八面体几何形状的镓（III）配合物（5a 和 5b），对其进行分析表征，并评估其作为细胞内和体内 Pgp 介导的功能性转运活性探针的潜力。虽然未标记的化合物（5a 和 5b）通过细胞细胞毒性测定进行了检查，但（67）Ga 标记的对应物（6a 和 6b）通过细胞转运研究和 mdr1a/1b（-/-）基因缺失小鼠及其野生型（WT）对照的定量生物分布研究进行了评估。
5a 和 5b 的细胞毒性数据显示出由耐药细胞中 Pgp 表达修饰的谱。（67）Ga 金属探针（6a 和 6b）在人表皮癌细胞敏感 KB-3-1 细胞（Pgp-）、人乳腺癌 MCF-7（Pgp-）细胞中表现出高积累；抑制剂（LY335979，1μM）诱导在多药耐药（MDR，Pgp+）KB-8-5、KB-8-5-11 细胞和稳定转染的 MCF-7/MDR1 细胞中的积累，从而证明了它们在细胞内检测 Pgp 介导的功能性转运活性的能力。在 mdr1a/1b（-/-）基因缺失小鼠中，与 WT 对照相比，（67）Ga 金属探针（6b）在大脑中的摄取和保留增加了 8 倍，并且在血液药代动力学方面没有显着差异。
用（67/68）Ga 金属探针对 MDR1 Pgp（ABCB1）的功能性转运活性进行分子成像，可以实现对血脑屏障、肿瘤和体内组织的非侵入性监测。
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