Effective MR Molecular Imaging of Triple Negative Breast Cancer With an EDB-Fibronectin-Specific Contrast Agent at Reduced Doses
Effective MR Molecular Imaging of Triple Negative Breast Cancer With an EDB-Fibronectin-Specific Contrast Agent at Reduced Doses
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DOI：
10.3389/fonc.2019.01351
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发表时间：
2019-12-03
影响因子：
4.7
通讯作者：
Lu, Zheng-Rong
中科院分区：
文献类型：
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作者：
Ayat, Nadia R.;Vaidya, Amita;Lu, Zheng-Rong
肿瘤微环境中丰富的致癌生物标志物的磁共振分子成像（MRMI）有可能提供高分辨率的精确癌症成像。外域- b纤维连接蛋白（EDB-FN）是一种致癌细胞外基质蛋白，在侵袭性三阴性乳腺癌中高度表达。研究了一种靶向EDB-FN的靶向大环钆基造影剂（GBCA） ZD2-N-3-Gd(HP-DO3A) (MT218)，用于侵袭性乳腺癌的MRMI。在MDA-MB-231和Hs578T人三阴性乳腺癌模型中检测不同剂量MT218对MRMI的有效性。在临床剂量为0.1 mmol Gd/kg和亚临床剂量为0.04 mmol Gd/kg时，MT218在注射后1-30分钟内迅速与细胞外基质EDB-FN结合，并在两种肿瘤模型中产生强大的肿瘤对比增强。MT218剂量低至0.02 mmol Gd/kg时，两种模型均出现明显的肿瘤增强，明显优于临床用药Gd（HP-DO3A）剂量为0.1 mmol Gd/kg时。在所有测试剂量下，MT218在肝脏、脾脏和大脑等正常组织中几乎没有观察到非特异性增强，肾脏在30分钟内清除。这些结果表明，减少MT218剂量的MRMI对侵袭性乳腺癌的敏感和特异性成像是安全有效的。
MR molecular imaging (MRMI) of abundant oncogenic biomarkers in tumor microenvironment has the potential to provide precision cancer imaging in high resolution. Extradomain-B fibronectin (EDB-FN) is an oncogenic extracellular matrix protein, highly expressed in aggressive triple negative breast cancer. A targeted macrocyclic gadolinium-based contrast agent (GBCA) ZD2-N-3-Gd(HP-DO3A) (MT218), specific to EDB-FN, was developed for MRMI of aggressive breast cancer. The effectiveness of different doses of MT218 for MRMI was tested in MDA-MB-231 and Hs578T human triple negative breast cancer models. At clinical dose of 0.1 and subclinical dose of 0.04 mmol Gd/kg, MT218 rapidly bound to the extracellular matrix EDB-FN and produced robust tumor contrast enhancement in both the tumor models, as early as 1-30 min post-injection. Substantial tumor enhancement was also observed in both the models with MT218 at doses as low as 0.02 mmol Gd/kg, which was significantly better than the clinical agent Gd(HP-DO3A) at 0.1 mmol Gd/kg. Little non-specific enhancement was observed in the normal tissues including liver, spleen, and brain for MT218 at all the tested doses, with renal clearance at 30 min. These results demonstrate that MRMI with reduced doses of MT218 is safe and effective for sensitive and specific imaging of aggressive breast cancers.