From the Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA (R.R., L.P., F.P., L.K., H.E.D.-L.); and Department of Pediatrics, Hematology/Oncology, Stanford University School of Medicine, Stanford, CA (H.E.D.-L.).
Invest Radiol. 2024 May 1;59(5):391-403. doi: 10.1097/RLI.0000000000001030. Epub 2023 Oct 9.
A novel clinically translatable iron oxide nanoparticle (IOP) is currently being tested in phase 2 clinical trials as a magnetic resonance imaging (MRI) contrast agent for hepatocellular carcinoma diagnosis. The purpose of our study is to evaluate if this IOP can detect activation of tumor-associated macrophages (TAMs) due to CD47 mAb-targeted immunotherapy in 2 mouse models of osteosarcoma.
The toxicity, biodistribution, and pharmacokinetics of IOP were evaluated in 77 female and 77 male rats. Then, 24 female BALB/c mice with intratibial murine K7M2 tumors and 24 female NOD scid gamma mice with intratibial human 143B osteosarcoma xenografts were treated with either CD47 mAb (n = 12) or control antibody (n = 12). In each treatment group, 6 mice underwent MRI scans before and after intravenous infusion of either IOP or ferumoxytol (30 mg Fe/kg). Tumor T2* values and TAM markers F4/80, CD80, CD206, and Prussian blue staining were compared between different experimental groups using exact 2-sided Wilcoxon rank sum tests.
Biodistribution and safety evaluations of IOP were favorable for doses of less than 50 mg Fe/kg body weight in female and male rats. Both IOP and ferumoxytol caused negative enhancement (darkening) of the tumor tissue. Both murine and human osteosarcoma tumors treated with CD47 mAb demonstrated significantly shortened T2* relaxation times after infusion of IOP or ferumoxytol compared with controls (all P 's < 0.05). Higher levels of F4/80 + CD80 + were found in murine and human osteosarcomas treated with CD47 mAb compared with sham-treated controls (all P 's < 0.05). In addition, murine CD47 mAb-treated tumors after infusion of either IOP or ferumoxytol showed significantly higher numbers of Prussian blue-positive cells compared with controls ( P < 0.05). There was no significant difference of F4/80 + CD206 + cells among any of the groups (all P 's > 0.05).
Iron oxide nanoparticle-enhanced MRI can be used to diagnose CD47 mAb-mediated TAM-activation in osteosarcomas.
一种新型临床转化氧化铁纳米颗粒（IOP）目前正在进行 2 期临床试验，作为用于肝细胞癌诊断的磁共振成像（MRI）造影剂。本研究的目的是评估该 IOP 是否可检测到 CD47 mAb 靶向免疫疗法引起的骨肉瘤中肿瘤相关巨噬细胞（TAM）的激活。
在 77 只雌性和 77 只雄性大鼠中评估了 IOP 的毒性、生物分布和药代动力学。然后，24 只雌性 BALB/c 小鼠胫骨内有鼠源性 K7M2 肿瘤，24 只雌性 NOD scid gamma 小鼠胫骨内有人源性 143B 骨肉瘤异种移植物，用 CD47 mAb（n=12）或对照抗体（n=12）治疗。在每个治疗组中，6 只小鼠在静脉内输注 IOP 或 ferumoxytol（30mgFe/kg）前后进行 MRI 扫描。使用精确的双侧 Wilcoxon 秩和检验比较不同实验组之间的肿瘤 T2*值和 TAM 标志物 F4/80、CD80、CD206 和普鲁士蓝染色。
IOP 的生物分布和安全性评估在雌性和雄性大鼠中，50mgFe/kg 以下的剂量是有利的。IOP 和 ferumoxytol 均导致肿瘤组织的负性增强（变暗）。与对照相比，用 CD47 mAb 治疗的鼠源性和人源性骨肉瘤肿瘤在输注 IOP 或 ferumoxytol 后 T2*弛豫时间明显缩短（均 P'<0.05）。与假对照相比，用 CD47 mAb 治疗的鼠源性和人源性骨肉瘤中发现 F4/80+CD80+水平更高（均 P'<0.05）。此外，在输注 IOP 或 ferumoxytol 后，用 CD47 mAb 治疗的鼠源性肿瘤中的普鲁士蓝阳性细胞数量明显高于对照（P<0.05）。各组之间的 F4/80+CD206+细胞无显著差异（均 P'>0.05）。
氧化铁纳米颗粒增强 MRI 可用于诊断 CD47 mAb 介导的骨肉瘤中 TAM 激活。
