靶向纳米铁磁共振造影剂特异性标记阿尔茨海默病鼠脑内老年斑

Study of specially labeling amyloid plaques in vivo in Alzheimer transgenic mice with targeted magnetic nano-iron contrast agent

目的开发具有高度特异性的靶向磁共振对比剂，验证其特异性显示阿尔茨海默病（AD）脑内老年斑的可能性及有效性。方法利用热分解法获得水相的磁性纳米四氧化三铁颗粒（MNPs），经过表面官能化学修饰，完成MNPs与13淀粉样蛋白肽段140（Aβ40）及蛋白质转导结合域（protein transduction domain, Tat-PTD）的连接后，制备出特异性与老年斑相结合的靶向纳米铁造影剂Aβ40-MNPs-TatPTD，通过尾静脉注射入20只AD鼠和20只阴性对照C57小鼠（4、6、9、12月龄各5只）体内，不同的时间点采用7．0T动物磁共振检测获得磁共振图像，观察靶向纳米造影剂对脑实质内老年斑信号的强化效果，继之处死小鼠后灌流取脑做连续冰冻切片，进行铁染色和Thioflavine S染色组织学验证。结果所获得的靶向纳米颗粒Aβ40-MNPs—TatPTD能够在体外进入细胞内进而改变细胞磁共振T2信号强度。尾静脉注射入AD鼠体内后能特异性负性强化AD鼠脑内老年斑病变，经组织学验证，能够与老年斑染色及铁染色相对应。结论特异靶向性的磁性纳米铁造影剂Aβ40-MNPs—TatPTD能特异性地针对小鼠脑内的老年斑病变进行负性强化和标记。

Objective To develop specific targeted magnetic biomarkers which can selectively mark the senile plaques in Alzheimer＇ s disease （AD） and verify its feasibility and validity. Methods Aβ1-40 peptide and Tat-PTD （Tat-protein transduction domain ） was binded with dextran-coated ultrasmall superparamagnetic iron oxide （USPIO） particles. Visualization of plaques in vivo in Alzheimer transgenic mice was investigated at 7.0 Tesla using T2 sequences after intravenous administration of the targeted nanoiron contrast agent and verified by histological staining. Results The targeted nano-iron contrast agent could enter the cultured neural stem cells, and was able to accelerate T2 relaxation rates of water protons in the cells and negatively reinforce the T2 signal intensity in the labeled cells. Plaques were specifically detected in vivo by magnetic resonance imaging （MRI） and correlated well with histological staining after injection of nano-iron contrast agent into the APP/PS1 mice. Conclusion The targeted nano-iron contrast agent has the ability of selectively labeling the senile plaques in AD brain tissues in vivo, which might enable the early detection of plaques by MRI and can be further applied in the studies of early diagnosis of AD.