Sharma Vijay, Prior Julie L, Belinsky Martin G, Kruh Gary D, Piwnica-Worms David
Molecular Imaging Center, Mallinckrodt Institute of Radiology, St. Louis, Missouri, USA.
J Nucl Med. 2005 Feb;46(2):354-64.
Overexpression of multidrug resistance (MDR1) P-glycoprotein (Pgp) remains an important barrier to successful chemotherapy in cancer patients and impacts the pharmacokinetics of many important drugs, thus evoking a need to noninvasively interrogate Pgp transport activity in vivo.
Cell tracer transport experiments as well as mouse biodistribution and microPET imaging studies were performed to characterize a nonmetabolized gallium(III) complex, gallium(III)-(bis(3-ethoxy-2-hydroxy-benzylidene)-N,N'-bis(2,2-dimethyl-3-amino-propyl)ethylenediamine) (Ga-[3-ethoxy-ENBDMPI])(+), as a candidate SPECT ((67)Ga) and generator-produced PET ((68)Ga) radiopharmaceutical recognized by MDR1 Pgp.
The (67)Ga-complex showed high membrane potential-dependent accumulation in drug-sensitive KB3-1 cells and modulator-reversible low accumulation in MDR KB8-5 cells. In KB8-5 cells, the median effective concentrations (EC(50)) of MDR modulators LY335979, PSC 833, and cyclosporin A were 69 nmol/L, 1 micromol/L, and 3 micromol/L, respectively. Using a variety of cells stably expressing MDR1 Pgp, multidrug resistance-associated proteins (MRP1-MRP6), or the breast cancer resistance protein (BCRP/MXR), the (67)Ga-complex was shown to be readily transported by MDR1 Pgp and, to a much lesser extent, by MRP1, but not MRP2-MRP6 or BCRP/MXR. In a nude mouse xenograft tumor model, the (67)Ga-complex produced a readily detected 3-fold difference between Pgp-expressing tumors and drug-sensitive tumors in the opposite flank. In mdr1a/1b(-/-) gene-deleted mice, the (67)Ga-complex showed 17-fold greater brain uptake and retention compared with wild-type mice with no net difference in blood pharmacokinetics, consistent with transport in vivo by Pgp expressed at the capillary blood-brain barrier. This could be readily observed with microPET using the (68)Ga-complex. Incidentally, wild-type mice showed heart-to-blood ratios of >100 by 1 h after injection and heart-to-liver ratios of 2.2 by 120 min.
Molecular imaging of the functional transport activity of MDR1 Pgp with ((67/68)Ga-[3-ethoxy-ENBDMPI])(+) may enable noninvasive SPECT/PET monitoring of the blood-brain barrier, chemotherapeutic regimens, and MDR1 gene therapy protocols in vivo. These Pgp-directed properties of the radiopharmaceutical may also translate favorably to myocardial perfusion imaging.
多药耐药（MDR1）P-糖蛋白（Pgp）的过表达仍然是癌症患者化疗成功的重要障碍，并影响许多重要药物的药代动力学，因此需要在体内对Pgp转运活性进行无创检测。
进行细胞示踪剂转运实验以及小鼠生物分布和微型PET成像研究，以表征一种非代谢性镓（III）配合物，即镓（III）-（双（3-乙氧基-2-羟基-亚苄基）-N，N'-双（2,2-二甲基-3-氨基丙基）乙二胺）（Ga-[3-乙氧基-ENBDMPI]）（+），作为一种可被MDR1 Pgp识别的单光子发射计算机断层扫描（SPECT）（（67）Ga）和发生器产生的正电子发射断层扫描（PET）（（68）Ga）放射性药物候选物。
（67）Ga配合物在药物敏感的KB3-1细胞中显示出高膜电位依赖性积累，在MDR KB8-5细胞中显示出调节剂可逆的低积累。在KB8-5细胞中，MDR调节剂LY335979、PSC 833和环孢菌素A的半数有效浓度（EC（50））分别为69 nmol/L、1 μmol/L和3 μmol/L。使用多种稳定表达MDR1 Pgp、多药耐药相关蛋白（MRP1-MRP6）或乳腺癌耐药蛋白（BCRP/MXR）的细胞，（67）Ga配合物显示出很容易被MDR1 Pgp转运，在较小程度上被MRP1转运，但不被MRP2-MRP6或BCRP/MXR转运。在裸鼠异种移植肿瘤模型中，（67）Ga配合物在表达Pgp的肿瘤和对侧的药物敏感肿瘤之间产生了易于检测到的3倍差异。在mdr1a/1b（-/-）基因缺失的小鼠中，（67）Ga配合物的脑摄取和滞留量比野生型小鼠高17倍，而血液药代动力学没有净差异，这与毛细血管血脑屏障表达的Pgp在体内的转运一致。使用（68）Ga配合物通过微型PET可以很容易地观察到这一点。顺便说一下，野生型小鼠在注射后1小时心脏与血液的比率>100，在120分钟时心脏与肝脏的比率为2.2。
用（（67/68）Ga-[3-乙氧基-ENBDMPI]）（+）对MDR1 Pgp的功能转运活性进行分子成像，可以在体内对血脑屏障、化疗方案和MDR1基因治疗方案进行无创SPECT/PET监测。这种放射性药物针对Pgp的特性也可能有利于心肌灌注成像。
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