MRI of tumor-associated macrophages with clinically applicable iron oxide nanoparticles.
MRI of tumor-associated macrophages with clinically applicable iron oxide nanoparticles.
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DOI：
10.1158/1078-0432.ccr-10-3420
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发表时间：
2011-09-01
期刊：
影响因子：
--
通讯作者：
Coussens LM
中科院分区：
文献类型：
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作者：
Daldrup-Link HE;Golovko D;Ruffell B;Denardo DG;Castaneda R;Ansari C;Rao J;Tikhomirov GA;Wendland MF;Corot C;Coussens LM
乳腺癌中肿瘤相关巨噬细胞（TAM）的存在与不良结局密切相关。本研究的目的是开发一种基于磁共振（MR）成像和临床适用的氧化铁纳米颗粒的临床适用的非侵入性诊断检测方法，用于乳腺癌中TAM的选择性靶向和可视化。将F4/80阴性乳腺癌细胞和F4/80阳性TAM与氧化铁纳米颗粒一起孵育，并比较MR信号变化和铁摄取。携带乳腺癌的MMTV-PyMT转基因小鼠经历纳米颗粒增强MR长达1小时（h）和注射后24小时（p.i.）。MR图像上的肿瘤增强与共聚焦显微镜上TAM和纳米颗粒的存在和位置相关。体外研究表明，氧化铁纳米颗粒优先被TAM吞噬，但不被恶性肿瘤细胞吞噬。在体内，所有肿瘤在造影后立即MR图像上显示出初始造影剂灌注，并逐渐经内皮渗漏到肿瘤组织中。在感染后24小时，所有肿瘤在MR扫描上显示出持续的信号下降。通过α CSF 1 mAb的TAM消耗导致肿瘤纳米颗粒增强的显著抑制。使用DAB增强的普鲁士蓝染色检测铁，和免疫检测的CD 68本地化氧化铁纳米粒子到TAM，表明MR信号的延迟MR图像的影响主要是由于TAM介导的造影剂的摄取。这些数据表明，使用临床适用的氧化铁纳米颗粒增强肿瘤可能作为长期预后，相关治疗决策和新免疫靶向治疗评估的新生物标志物。
The presence of tumor-associated macrophages (TAMs) in breast cancer correlates strongly with poor outcome. The purpose of this study was to develop a clinically applicable, non-invasive diagnostic assay for selective targeting and visualization of TAMs in breast cancer, based on magnetic resonance (MR) imaging and clinically applicable iron oxide nanoparticles. F4/80-negative mammary carcinoma cells and F4/80-positive TAMs were incubated with iron oxide nanoparticles and were compared regarding MR signal changes and iron uptake. MMTV-PyMT transgenic mice harboring mammary carcinomas underwent nanoparticle-enhanced MR up to 1 hour (h) and at 24 h post injection (p.i.). The tumor enhancement on MR images was correlated with the presence and location of TAMs and nanoparticles on confocal microscopy. In vitro studies revealed that iron oxide nanoparticles are preferentially phagocytosed by TAMs, but not by malignant tumor cells. In vivo, all tumors demonstrated an initial contrast agent perfusion on immediate postcontrast MR images with gradual transendothelial leakage into the tumor interstitium. At 24 h p.i., all tumors demonstrated a persistent signal decline on MR scans. TAM-depletion via αCSF1 mAb lead to significant inhibition of tumor nanoparticle enhancement. Detection of iron using DAB-enhanced Prussian Blue staining, and immunodetection of CD68 localized iron oxide nanoparticles to TAMs, indicating that the MR signal effects on delayed MR images were largely due to TAM-mediated uptake of contrast agent. These data indicate that tumor-enhancement with clinically applicable iron oxide nanoparticles may serve as a new biomarker for long-term prognosis, related treatment decisions and the evaluation of new immune-targeted therapies.