Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.
J Control Release. 2012 Apr 30;159(2):302-8. doi: 10.1016/j.jconrel.2011.12.036. Epub 2011 Dec 30.
Alzheimer's disease is a neurodegenerative disease characterized pathologically by amyloid-β (Aβ) aggregates in the brain. Notwithstanding many promising therapeutics that are under development, early diagnosis of Alzheimer's disease is limited. By targeting the Aβ aggregates, diagnosis can be improved and disease progression reduced. Molecular imaging using monoclonal antibodies to target specific isoforms of Aβ aggregates offer increased specificity in comparison to conventional imaging tracers; however, antibodies that are widely used in histology do not necessarily show similar binding in a dynamic in vivo environment. In this study, the diffusion and binding were studied of a classical monoclonal antibody, 6E10, in the brain of the TgCRND8 mouse model of AD. After intracranial injection of fluorescent 6E10, we observed broad and rapid labelling of Aβ deposits in the cortex and corpus callosum within 4h. Aβ plaques were detected up to 2.5mm away from the injection site in TgCRND8 mice and not in wild type mice at all, demonstrating specificity of binding. The apparent diffusivity and elimination constant of the anti-Aβ antibody were found to be independent of both the age of the animal and the accumulation of Aβ in the extracellular space, suggesting broad applicability of this targeting molecule. Mathematical modelling of the diffusion profiles of the anti-Aβ antibody in the brain parenchyma provides insights into the utility of antibodies as molecular imaging tools and targeted therapeutics.
阿尔茨海默病是一种神经退行性疾病，其病理特征是大脑中存在淀粉样蛋白-β（Aβ）聚集体。尽管有许多有前途的治疗方法正在开发中，但阿尔茨海默病的早期诊断仍然受到限制。通过针对 Aβ 聚集体，可以改善诊断并减少疾病进展。使用针对特定 Aβ 聚集体亚型的单克隆抗体进行分子成像与传统成像示踪剂相比具有更高的特异性；然而，在组织学中广泛使用的抗体在动态体内环境中不一定表现出相似的结合。在这项研究中，研究了经典单克隆抗体 6E10 在 AD 的 TgCRND8 小鼠模型中的大脑中的扩散和结合情况。在颅内注射荧光 6E10 后，我们观察到在 4 小时内大脑皮层和胼胝体中的 Aβ 沉积物广泛且快速标记。在 TgCRND8 小鼠中，Aβ 斑块可检测到距离注射部位 2.5mm 处，而在野生型小鼠中根本无法检测到，表明结合具有特异性。抗 Aβ 抗体的表观扩散率和消除常数与动物的年龄和细胞外空间中 Aβ 的积累无关，表明这种靶向分子具有广泛的适用性。对脑实质中抗 Aβ 抗体扩散分布的数学建模为抗体作为分子成像工具和靶向治疗药物的应用提供了深入的了解。
