Boros Eszter, Bowen Alice M, Josephson Lee, Vasdev Neil, Holland Jason P
The Athinoula A. Martinos Center for Biomedical Imaging , 149 13th Street, Suite 2301 , Charlestown , Massachusetts 02129 , USA.
Department of Radiology , Massachusetts General Hospital , Harvard Medical School , 55 Fruit Street , Boston , Massachusetts 02114 , USA . Email:
Chem Sci. 2015 Jan 1;6(1):225-236. doi: 10.1039/c4sc02778g. Epub 2014 Sep 29.
A novel reaction for chelate-free, heat-induced metal ion binding and radiolabeling of ultra-small paramagnetic iron oxide nanoparticles (USPIOs) has been established. Radiochemical and non-radioactive labeling studies demonstrated that the reaction has a wide chemical scope and is applicable to p-, d- and f-block metal ions with varying ionic sizes and formal oxidation states from 2+ to 4+. Radiolabeling studies found that Zr-Feraheme (Zr-FH or Zr-ferumoxytol) can be isolated in 93 ± 3% radiochemical yield (RCY) and >98% radiochemical purity using size-exclusion chromatography. Zr-FH was found to be thermodynamically and kinetically stable using a series of ligand challenge and plasma stability tests, and using PET/CT imaging and biodistribution studies in mice. Remarkably, ICP-MS and radiochemistry experiments showed that the same reaction conditions used to produce Zr-FH can be employed with different radionuclides to yield Cu-FH (66 ± 6% RCY) and In-FH (91 ± 2% RCY). Electron magnetic resonance studies support a mechanism of binding involving metal ion association with the surface of the magnetite crystal core. Collectively, these data suggest that chelate-free labeling methods can be employed to facilitate clinical translation of a new class of multimodality PET/MRI radiotracers derived from metal-based nanoparticles. Further, this discovery is likely to have broader implications in drug delivery, metal separation science, ecotoxicology of nanoparticles and beyond.
已建立一种新型反应，用于无螯合物、热诱导的金属离子结合及超小顺磁性氧化铁纳米颗粒（USPIOs）的放射性标记。放射化学和非放射性标记研究表明，该反应具有广泛的化学适用范围，适用于p区、d区和f区金属离子，这些金属离子具有不同的离子大小和从2 +到4 +的形式氧化态。放射性标记研究发现，使用尺寸排阻色谱法可分离出Zr - Feraheme（Zr - FH或Zr - ferumoxytol），其放射化学产率（RCY）为93±3%，放射化学纯度>98%。通过一系列配体挑战和血浆稳定性测试，以及在小鼠中的PET/CT成像和生物分布研究，发现Zr - FH在热力学和动力学上是稳定的。值得注意的是，ICP - MS和放射化学实验表明，用于制备Zr - FH的相同反应条件可用于不同的放射性核素，以产生Cu - FH（66±6% RCY）和In - FH（91±2% RCY）。电子磁共振研究支持一种结合机制，即金属离子与磁铁矿晶体核心表面缔合。总体而言，这些数据表明，可采用无螯合物标记方法来促进源自金属基纳米颗粒的新型多模态PET/MRI放射性示踪剂的临床转化。此外，这一发现可能在药物递送、金属分离科学、纳米颗粒的生态毒理学及其他领域具有更广泛的意义。
