Adiseshaiah Pavan, Dellinger Anthony, MacFarland Darren, Stern Stephan, Dobrovolskaia Marina, Ileva Lilia, Patri Anil K, Bernardo Marcelino, Brooks D Bradford, Zhou Zhiguo, McNeil Scott, Kepley Christopher
From the *Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD; †Luna nanoWorks, Luna Innovations, Inc, Danville, VA; ‡Department of Nanoscience, Joint School of Nanoscience and Nanoengineering, Greensboro, NC; §Small Animal Imaging Program, Laboratory Animal Sciences Program, SAIC-Frederick, Inc, Frederick National Laboratory for Cancer Research, Frederick; and ∥Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
Invest Radiol. 2013 Nov;48(11):745-54. doi: 10.1097/RLI.0b013e318294de5d.
Macromolecular contrast agents for magnetic resonance imaging (MRI) are useful blood-pool agents because of their long systemic half-life and have found applications in monitoring tumor vasculature and angiogenesis. Macromolecular contrast agents have been able to overcome some of the disadvantages of the conventional small-molecule contrast agent Magnevist (gadolinium-diethylenetriaminepentaacetic acid), such as rapid extravasation and quick renal clearance, which limits the viable MRI time. There is an urgent need for new MRI contrast agents that increase the sensitivity of detection with a higher relaxivity, longer blood half-life, and reduced toxicity from free Gd3+ ions. Here, we report on the characterization of a novel water-soluble, derivatized, gadolinium-enclosed metallofullerene nanoparticle (Hydrochalarone-1) in development as an MRI contrast agent.
The physicochemical properties of Hydrochalarone-1 were characterized by dynamic light scattering (hydrodynamic diameter), atomic force microscopy (particle height), ζ potential analysis (surface charge), and inductively coupled plasma-mass spectrometry (gadolinium concentration). The blood compatibility of Hydrochalarone-1 was also assessed in vitro through analysis of hemolysis, platelet aggregation, and complement activation of human blood. In vitro relaxivities, in vivo pharmacokinetics, and a pilot in vivo acute toxicity study were also performed.
An extensive in vitro and in vivo characterization of Hydrochalarone-1 is described here. The hydrodynamic size of Hydrochalarone-1 was 5 to 7 nm depending on the dispersing media, and it was negatively charged at physiological pH. Hydrochalarone-1 showed compatibility with blood cells in vitro, and no significant hemolysis, platelet aggregation, or complement activation was observed in vitro. In addition, Hydrochalarone-1 had significantly higher r1 and r2 in vitro relaxivities in human plasma in comparison with Magnevist and was not toxic at the doses administered in an in vivo pilot acute-dose toxicity study in mice.In vivo MRI pharmacokinetic analysis after a single intravenous injection of Hydrochalarone-1 (0.2 mmol Gd/kg) showed that the volume of distribution at steady state was approximately 100 mL/kg, suggesting prolonged systemic circulation. Hydrochalarone-1 also had a long blood half-life (88 minutes) and increased relaxivity, suggesting application as a promising blood-pool MRI contrast agent.
The evidence suggests that Hydrochalarone-1, with its long systemic half-life, may have significant utility as a blood-pool MRI contrast agent.
用于磁共振成像（MRI）的大分子造影剂因其较长的全身半衰期而成为有用的血池造影剂，并已在监测肿瘤血管生成和血管新生方面得到应用。大分子造影剂能够克服传统小分子造影剂马根维显（钆-二乙烯三胺五乙酸）的一些缺点，如快速外渗和肾快速清除，这限制了可行的MRI检查时间。迫切需要新型MRI造影剂，它们能以更高的弛豫率、更长的血液半衰期和降低游离钆离子的毒性来提高检测灵敏度。在此，我们报告一种正在研发用作MRI造影剂的新型水溶性、衍生化、包钆金属富勒烯纳米颗粒（Hydrochalarone-1）的特性。
通过动态光散射（流体动力学直径）、原子力显微镜（颗粒高度）、ζ电位分析（表面电荷）和电感耦合等离子体质谱（钆浓度）对Hydrochalarone-1的物理化学性质进行表征。还通过分析人血的溶血、血小板聚集和补体激活在体外评估Hydrochalarone-1的血液相容性。也进行了体外弛豫率、体内药代动力学和一项体内急性毒性预试验研究。
本文描述了对Hydrochalarone-1广泛的体外和体内特性研究。Hydrochalarone-1的流体动力学尺寸根据分散介质不同为5至7纳米，且在生理pH值下带负电荷。Hydrochalarone-1在体外与人血细胞具有相容性，在体外未观察到明显的溶血、血小板聚集或补体激活。此外，与马根维显相比，Hydrochalarone-1在人血浆中的体外弛豫率r1和r2显著更高，并且在小鼠体内急性剂量毒性预试验研究中所用剂量下无毒。单次静脉注射Hydrochalarone-1（0.2 mmol钆/千克）后的体内MRI药代动力学分析表明，稳态分布容积约为100 mL/千克，表明全身循环时间延长。Hydrochalarone-1还具有较长的血液半衰期（88分钟）和增加的弛豫率，表明其有望用作血池MRI造影剂。
证据表明，具有较长全身半衰期的Hydrochalarone-1可能作为血池MRI造影剂具有重要用途。
