Department of Biochemistry, Genetics and Microbiology, Institute of Sustainable Malaria Control, University of Pretoria, Pretoria, South Africa.
Preclinical Imaging Facility, The South African Nuclear Energy Corporation SOC Ltd (Necsa), Pelindaba, South Africa.
Mol Imaging Biol. 2020 Feb;22(1):115-123. doi: 10.1007/s11307-019-01360-3.
Nuclear imaging is an important preclinical research tool to study infectious diseases in vivo and could be extended to investigate complex aspects of malaria infections. As such, we report for the first time successful radiolabeling of a novel antibody specific to Plasmodium-infected erythrocytes (IIIB6), its in vitro assessment and molecular imaging in nude mice.
In vitro confocal microscopy was used to determine the stage-specificity of Plasmodium-infected erythrocytes recognised by IIIB6. To enable micro-positron emission tomography (PET)/X-ray computed tomography (CT) imaging, IIIB6 was conjugated to Bz-DFO-NCS and subsequently radiolabeled with zirconium-89. Healthy nude mice were injected with [Zr]IIIB6, and pharmacokinetics and organ uptake were monitored over 24 h. This was followed by post-mortem animal dissection to determine the biodistribution of [Zr]IIIB6.
IIIB6 recognised all the relevant stages of Plasmodium falciparum-infected erythrocytes (trophozoites, schizonts and gametocytes) that are responsible for severe malaria pathology. [Zr]IIIB6-radiolabeling yields were efficient at 84-89 %. Blood pool imaging analysis indicated a pharmacological half-life of 9.6 ± 2.5 h for [Zr]IIIB6. The highest standard uptake values were determined at 2-6 h in the liver followed by the spleen, kidneys, heart, stomach and lung, respectively. Minimal activity was present in muscle and bone tissues.
In vitro characterization of IIIB6 and pharmacokinetic characterization of [Zr]IIIB6 revealed that this antibody has potential for future use in Plasmodium-infected mouse models to study malaria in a preclinical in vivo setting with PET/CT imaging.
核成像技术是研究体内传染病的重要临床前研究工具，也可用于研究疟疾感染的复杂方面。因此，我们首次成功地报告了一种新型抗疟原虫感染红细胞的抗体（IIIB6）的放射性标记、体外评估及其在裸鼠中的分子成像。
采用共聚焦显微镜检测 IIIB6 识别的疟原虫感染红细胞的阶段特异性。为了实现微正电子发射断层扫描（PET）/X 射线计算机断层扫描（CT）成像，将 IIIB6 与 Bz-DFO-NCS 偶联，随后用锆-89 进行放射性标记。将[Zr]IIIB6 注射到健康的裸鼠体内，在 24 小时内监测其药代动力学和器官摄取情况。随后进行动物解剖，以确定[Zr]IIIB6 的生物分布。
IIIb6 可识别恶性疟原虫感染红细胞的所有相关阶段（滋养体、裂殖体和配子体），这些阶段是导致严重疟疾病理的原因。[Zr]IIIB6 的放射性标记产率为 84-89%。血池成像分析表明，[Zr]IIIB6 的药代动力学半衰期为 9.6±2.5 h。肝脏的标准摄取值最高，分别在 2-6 小时后依次为脾脏、肾脏、心脏、胃和肺。肌肉和骨骼组织的活性最低。
IIIb6 的体外特性和[Zr]IIIB6 的药代动力学特性表明，该抗体具有在未来用于感染疟原虫的小鼠模型的潜力，可通过 PET/CT 成像在临床前体内环境中研究疟疾。
