Sillerud Laurel O, Neuwelt Alexander J, Staquicini Fernanda I, Arap Wadih, Pasqualini Renata
Department of Neurology, UNM BRaIN Center, University of New Mexico School of Medicine, Albuquerque, NM 87106, USA.
Division of Hematology, Oncology and Palliative Care, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Cancers (Basel). 2021 Jul 28;13(15):3802. doi: 10.3390/cancers13153802.
Tumor-associated macrophages (TAMs) in breast cancer regulate inflammation, immunosuppression, angiogenesis, and metastasis. However, TAM imaging remains a clinical challenge. Ferumoxytol has long been an FDA-approved superparamagnetic iron oxide nanoparticle (SPION) preparation used as an intravenous (IV) treatment for iron-deficiency anemia. Given its high transverse relaxivity, ferumoxytol produces a negative image contrast upon cellular uptake in T-weighted magnetic resonance imaging (MRI) studies. Here we evaluated ferumoxytol as a contrast agent to image/quantify TAMs in an aggressive mouse model of breast cancer: We developed [Fe]MRI to measure the 5-dimensional function c(x,y,z,t), where c is the concentration of nanoparticle iron and {x,y,z,t} is the 4-dimensional set of tumor space-time coordinates. Ferumoxytol SPIONs are readily phagocytosed (10/cell) by the F4/80CD11b TAMs within breast tumors. Quantitative [Fe]MRIs served to determine both the spatial and the temporal distribution of the SPION iron, and hence to measure [Fe] = c(x,y,z,t), a surrogate for TAM density. In single-dose pharmacokinetic studies, after an IV dose of 5 mg/Kg iron, [Fe]MRI measurements showed that c(x,y,z,t) within breast tumors peaked around [Fe] = 70 μM at 42 h post-administration, and decayed below the [Fe]MRI detection limit (2 μM) by day 7. There was no SPION uptake in control organs (muscle and adipose tissue). Optical microscopy of tissue sections confirmed that F4/80CD11b TAMs infiltrated the tumors and accumulated SPION iron. Our methodology and findings have translational applications for breast cancer patients.
乳腺癌中的肿瘤相关巨噬细胞（TAM）可调节炎症、免疫抑制、血管生成和转移。然而，TAM成像仍然是一项临床挑战。长期以来， ferumoxytol一直是美国食品药品监督管理局（FDA）批准的超顺磁性氧化铁纳米颗粒（SPION）制剂，用于静脉注射（IV）治疗缺铁性贫血。鉴于其高横向弛豫率，在T加权磁共振成像（MRI）研究中，ferumoxytol在细胞摄取后会产生负性图像对比度。在此，我们评估了ferumoxytol作为一种造影剂，用于在侵袭性乳腺癌小鼠模型中对TAM进行成像/定量：我们开发了[Fe]MRI来测量五维函数c(x,y,z,t)，其中c是纳米颗粒铁的浓度，{x,y,z,t}是肿瘤时空坐标的四维集合。Ferumoxytol SPIONs很容易被乳腺肿瘤内的F4/80CD11b TAM吞噬（10个/细胞）。定量[Fe]MRI用于确定SPION铁的空间和时间分布，从而测量[Fe]=c(x,y,z,t)，作为TAM密度的替代指标。在单剂量药代动力学研究中，静脉注射5 mg/Kg铁后，[Fe]MRI测量显示，给药后42小时，乳腺肿瘤内的c(x,y,z,t)在[Fe]=70 μM左右达到峰值，并在第7天下降至[Fe]MRI检测限（2 μM）以下。对照器官（肌肉和脂肪组织）未摄取SPION。组织切片的光学显微镜检查证实，F4/80CD11b TAM浸润肿瘤并积累SPION铁。我们的方法和发现对乳腺癌患者具有转化应用价值。
