CT and MR Contrast Media Research, Bayer Pharma AG, Berlin, Germany.
Invest Radiol. 2012 Jul;47(7):383-91. doi: 10.1097/RLI.0b013e31824c5a57.
Tumor imaging via molecular magnetic resonance imaging (MRI) that uses specific superparamagnetic iron oxide particles (SPIOs) has been addressed in the literature several times in the last 20 years. To our knowledge, none of the reported approaches is currently used for routine clinical diagnostic evaluation, nor are any in clinical development. This raises questions as to whether SPIO-enhanced molecular MRI is sensitive and specific enough for use in clinical practice. The aim of our preclinical study was to investigate the minimum requirements for obtaining sensitive molecular MRI for use in tumor evaluations under optimal conditions. The well-vascularized F9 teratocarcinoma tumor model, which exhibits high levels of the highly accessible target CD105 (endoglin), was used to compare the accumulation and visualization of target-specific SPIOs by MRI.
Superparamagnetic iron oxide particles were optimized in the following ways: (a) proton relaxivity was increased for higher imaging sensitivity, (b) a coating material was used for optimal loading density of the αCD105 antibody, and (c) binding activity to the target CD105 was increased. Binding activity and specificity were confirmed in vitro using enzyme-linked immunosorbent assay and in vivo using pharmacokinetic and biodistribution studies of 11 F9 teratoma-bearing mice together with micro-autoradiography. CD105 target expression was determined using immunohistochemistry and quantitative enzyme-linked immunosorbent assay. The transverse relaxation rate R2* was quantified by 3.0-T MRI in the tumors, kidneys, and muscles before and up to 60 minutes after injection in 11 mice. The use of [Fe]-labeled SPIOs for all in vivo experiments allowed for the direct correlation of the imaging results with SPIO accumulation.
High-relaxivity αCD105-polyacrylic acid-SPIOs (r2 up to 440 L mmol Fe s) with strong binding activity accumulated specifically in tumors (1.4% injected dose/g) and kidneys (4.1% injected dose/g) in a manner dependent on the target concentration. The accumulation occurred within the first 3 minutes after injection. Visualization of specific SPIOs was accomplished with MRI. In contrast to the successful use of MRI in all examined kidneys (mean ± SEM ΔR2*, 61 ± 11 s), only 6 of 11 tumors (mean ± SEM ΔR2*, 15 ± 7 s) showed a clear signal when compared with the control even though optimal conditions were used.
The accumulation of CD105-specific SPIOs in F9 mouse teratomas was robust. However, visualization of the specifically accumulated SPIOs by MRI was not reliable because of its limited signal detection sensitivity. We postulate that it will be challenging to improve the imaging properties of targeted SPIOs further. Therefore, molecular MRI by targeted SPIOs is currently not suitable for clinical tumor imaging using routinely applicable sequences and field strength.
通过使用特定的超顺磁性氧化铁颗粒（SPIOs）进行分子磁共振成像（MRI）的肿瘤成像，在过去 20 年的文献中已经多次提到。据我们所知，目前没有一种报道的方法用于常规临床诊断评估，也没有任何方法处于临床开发阶段。这引发了人们的质疑，即 SPIO 增强的分子 MRI 是否足够敏感和特异，可用于临床实践。我们的临床前研究旨在探讨在最佳条件下获得用于肿瘤评估的敏感分子 MRI 的最小要求。使用血管丰富的 F9 畸胎癌肿瘤模型，该模型表现出高水平的高度可及的靶标 CD105（内皮糖蛋白），以比较 MRI 中靶特异性 SPIOs 的积累和可视化。
对超顺磁性氧化铁颗粒进行了以下优化：（a）增加质子弛豫率以提高成像灵敏度，（b）使用涂层材料以获得最佳的 αCD105 抗体载药量，（c）增加与靶标 CD105 的结合活性。通过酶联免疫吸附试验（ELISA）体外和 11 只携带 11 F9 畸胎瘤的小鼠的药代动力学和生物分布研究以及微量放射自显影术，确认了结合活性和特异性。使用免疫组织化学和定量酶联免疫吸附试验（ELISA）测定 CD105 靶标表达。在 11 只小鼠中，在注射前和注射后长达 60 分钟内，使用 3.0-T MRI 在肿瘤、肾脏和肌肉中定量横向弛豫率 R2*。所有体内实验中使用 [Fe]标记的 SPIOs 允许直接将成像结果与 SPIO 积累相关联。
具有高弛豫率的 αCD105-聚丙烯酸-SPIOs（r2 高达 440 L mmol Fe s）具有很强的结合活性，特异性地在肿瘤（1.4%注射剂量/g）和肾脏（4.1%注射剂量/g）中积累，这与靶浓度有关。积累发生在注射后 3 分钟内。通过 MRI 实现了对特异性 SPIOs 的可视化。与所有检查的肾脏（平均 ± SEM ΔR2*，61 ± 11 s）成功使用 MRI 形成对比的是，即使使用了最佳条件，11 个肿瘤中也只有 6 个（平均 ± SEM ΔR2*，15 ± 7 s）与对照相比表现出明显的信号。
F9 小鼠畸胎瘤中 CD105 特异性 SPIOs 的积累是强大的。然而，由于其有限的信号检测灵敏度，MRI 对特异性积累的 SPIOs 的可视化不可靠。我们推测，进一步改善靶向 SPIOs 的成像特性将具有挑战性。因此，目前靶向 SPIOs 的分子 MRI 不适合使用常规应用序列和场强进行临床肿瘤成像。
