Detection of cell death in tumors by using MR imaging and a gadolinium-based targeted contrast agent
Detection of cell death in tumors by using MR imaging and a gadolinium-based targeted contrast agent
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DOI：
10.1148/radiol.2463070471
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发表时间：
2008-03-01
期刊：
影响因子：
19.7
通讯作者：
Brindle, Kevin M.
中科院分区：
文献类型：
--
作者：
Krishnan, Anant S.;Neves, Andre A.;Brindle, Kevin M.
目的：在动物模型中前瞻性地确定突触结合蛋白 I C2A 结构域的离子钆 (Gd3+) 螯合物是否可以与磁共振 (MR) 成像一起使用，以无创地检测体内肿瘤细胞死亡。 材料和方法：动物实验经当地伦理审查委员会批准。 Gd3+ 螯合物和荧光探针连接到谷胱甘肽-S-转移酶-C2A 融合蛋白的赖氨酸ε-氨基上。使用表面等离子共振表征与磷脂酰丝氨酸 (PS) 的结合，并使用流式细胞术和 MR 成像表征体外与死亡细胞的结合。通过 T1 映射和 T1 加权 MR 成像检测体内与垂死肿瘤细胞的结合，并在药物治疗的动物中进行比较 (n = 10)；在注射了定点突变体的动物中，该突变体在 PS 结合中不活跃（PS 无活性）并且与垂死细胞的结合较少（n = 6）；以及在未治疗的 Ps 活性动物（n = 6）中注射 PS 无活性（n = 6）造影剂。组间差异显着，通过方差分析和 Dun nett 事后分析进行分析。 结果：造影剂对 PS 具有相对较高的亲和力（解离常数 = 333 nmol/L +/- 85 [平均值 +/- 平均值的标准误差]；n = 3），并且与凋亡和坏死结合，但是；细胞在体外无法存活。相比之下，PS活性造影剂的肿瘤积聚量更大。药物治疗动物中的 PS 无活性造影剂 (P < .05) 并与注射 PS 活性和 PS 无活性造影剂的未治疗动物进行比较（两者均 P < .01）。结论：相对较小（约 100 kDa）的 G(3+) 基造影剂在 AIR 图像上提供正对比度，可用于检测体内特纳细胞死亡，并且 if 的未来衍生物可用于评估早期肿瘤对治疗的反应。
Purpose: To prospectively determine in an animal model whether an ionic gadolinium (Gd3+) chelate conjugate of the C2A domain of synaptotagmin I can be used with magnetic resonance (MR) imaging to detect tumor cell death noninvasively in vivo.Materials and Methods: Animal experiments were approved by a local ethics review committee. Gd3+ chelates and fluorescent probes were attached to the lysine epsilon-amino groups of a glutathione-S-transferase-C2A fusion protein. Binding to phosphatidylserine (PS) was characterized by using surface plasmon resonance, and binding to dying cells in vitro was characterized by using flow cytometry and MR imaging. Binding to dying tumor cells in vivo was detected with T1 mapping and T1-weighted MR imaging and compared in drug-treated animals (n = 10); in animals injected with a site-directed mutant, which was inactive in PS binding (PS inactive) and which showed lesser binding to dying cells (n = 6); and in untreated animals Ps-active (n = 6) injected with PS-inactive (n = 6) contrast agents. Among groups, differences that were significant were analyzed by using analysis of variance and Dun nett post hoc analysis.Results: The contrast agent had a relatively high affinity for PS (dissociation constant = 333 nmol/L +/- 85 [mean +/- standard error of the mean]; n = 3) and bound to apoptotic and necrotic, but; not viable, cells in vitro. There was a greater tumor accumulation of the PS-active contrast agent compared with. the PS-inactive contrast agent in drug-treated animals (P < .05) and compared with untreated animals injected with the PS-active and PS-inactive contrast agents (P < .01 for both).Conclusion: A relatively small (approximately 100 kDa) G(3+)-based contrast agent, which gives positive contrast on AIR images, can be used to detect turner cell death in vivo, and future derivatives of if may be used to assess early tumor responses to treatment.