Abeta-Targeted Fluorinated Liposomes for 19F MRI Detection of Abeta Pathologies in APP/PSEN1 Mice

用于 19F MRI 检测 APP/PSEN1 小鼠 Abeta 病理的 Abeta 靶向氟化脂质体

基本信息

  • 批准号:
    9034135
  • 负责人:
  • 金额:
    $ 23.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-08 至 2018-06-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the leading cause of dementia in individuals over the age of 65 and the prevalence in the United States this year is estimated at 5.2 million. 83,494 Americans died from the disease in 2010 and an estimated 70,000 more will die from AD this year, and it remains without a cure. Empirical data strongly suggest that amyloid-β (Aβ) deposition and blood-brain barrier (BBB) compromise may precede clinical manifestation of the disease by over 20 years. Methods to quantify Aβ in vivo are therefore actively investigated by the medical research community as a means of early detection. Our long term goal is to develop a magnetic resonance imaging (MRI) contrast agent for visualization of Aβ plaques in vivo. We recently showed that fluorescent Aβ-targeted liposomes cross the BBB and avidly label Aβ pathologies in the brains of APP/PSEN1 mice. In a second generation formulation, we loaded similar particles with a gadolinium contrast agent and obtained MRI data which confirm that they cross the BBB of Tg2576 mice. However, the contrast-to-noise ratio of this agent does not allow unequivocal interpretation of images due to the background signal that exists in proton-based MRI. 19F MRI presents an alternative to address this problem because there is no endogenous 19F MRI detectable signal in soft tissue. Current 1H MRI hardware can be used for 19F MRI with little modification and 19F is a stable atom with 100% natural abundance, easily available, non-radioactive, and inexpensive. Unfortunately, almost all 19F-based agents currently under use for biomedical applications utilize perfluorocarbons (PFCs) which have low aqueous solubility and not amenable to aqueous core liposome formulations protocols. We have designed and synthesized two new hydrophilic fluorinated molecules with this capacity. In this application, we propose to prepare a Aβ-targeted liposome formulation bearing one of the molecules as a 19F contrast payload and explore its potential as a tool to define and quantify noninvasively, the longitudinal accumulation of amyloid plaques (using 5, 7, 9 and 12-month old APP/PSEN1 mice) by 19F MRI. Completion of this work will result in a potential novel MRI platform for noninvasive detection and quantification of amyloid plaque burden in vivo and a potential contrast agent to other molecular imaging applications.
 描述(由申请人提供):阿尔茨海默病(AD)是65岁以上个体痴呆的主要原因,今年在美国的患病率估计为520万。2010年有83,494名美国人死于这种疾病,估计今年将有7万人死于AD,并且仍然无法治愈。经验数据强烈表明,淀粉样蛋白-β(Aβ)沉积和血脑屏障(BBB)受损可能先于疾病的临床表现超过20年。因此,医学研究界正在积极研究体内Aβ定量方法,作为早期检测的一种手段。我们的长期目标是开发一种磁共振成像(MRI)造影剂,用于体内Aβ斑块的可视化。我们最近发现,荧光Aβ靶向脂质体穿过BBB,并在APP/PSEN 1小鼠的大脑中强烈标记Aβ病理。在第二代制剂中,我们用钆造影剂装载类似的颗粒,并获得MRI数据,证实它们穿过Tg 2576小鼠的BBB。然而,由于质子基MRI中存在的背景信号,该试剂的对比度噪声比不允许对图像进行明确解释。19 F MRI提供了解决该问题的替代方案,因为在软组织中没有内源性19 F MRI可检测信号。目前的1H MRI硬件可以用于19 F MRI,只需很少的修改,19 F是一种稳定的原子,具有100%的天然丰度,易于获得,非放射性和廉价。不幸的是,目前用于生物医学应用的几乎所有基于19 F的试剂都利用全氟化碳(PFC),其具有低水溶性并且不适合水性核心脂质体制剂方案。我们设计并合成了两种具有这种能力的新型亲水性含氟分子。在本申请中,我们建议制备一种Aβ靶向脂质体制剂,其中含有一种分子作为19 F造影剂有效载荷,并探索其作为非侵入性定义和定量纵向累积的工具的潜力。 淀粉样蛋白斑块的19 F MRI(使用5、7、9和12个月大的APP/PSEN 1小鼠)。这项工作的完成将导致一个潜在的新型MRI平台,用于无创检测和定量体内淀粉样斑块负荷,以及其他分子成像应用的潜在造影剂。

项目成果

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