Medical Engineering Laboratory, Research Center for Medical Sciences, The Jikei University School of Medicine, Nishi-shinbashi 3-25-8, Minato-ku, Tokyo 105-8461, Japan.
Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan.
J Control Release. 2017 May 10;253:165-171. doi: 10.1016/j.jconrel.2017.03.020. Epub 2017 Mar 18.
Blood-brain barrier (BBB) opening is a key phenomenon for understanding ischemia-reperfusion injuries that are directly linked to hemorrhagic transformation. The recombinant human tissue-type plasminogen activator (rtPA) increases the risk of symptomatic intracranial hemorrhages. Recent imaging technologies have advanced our understanding of pathological BBB disorders; however, an ongoing challenge in the pre-"rtPA treatment" stage is the task of developing a rigorous method for hemorrhage-risk assessments. Therefore, we examined a novel method for assessment of rtPA-extravasation through a hyper-permeable BBB. To examine the image diagnosis of rtPA-extravasation for a rat transient occlusion-reperfusion model, in this study we used a polymeric micelle MRI contrast-agent (Gd-micelles). Specifically, we used two MRI contrast agents at 1h after reperfusion. Gd-micelles provided very clear contrast images in 15.5±10.3% of the ischemic hemisphere at 30min after i.v. injection, whereas a classic gadolinium chelate MRI contrast agent provided no satisfactorily clear images. The obtained images indicate both the hyper-permeable BBB area for macromolecules and the distribution area of macromolecules in the ischemic hemisphere. Owing to their large molecular weight, Gd-micelles remained in the ischemic hemisphere through the hyper-permeable BBB. Our results indicate the feasibility of a novel clinical diagnosis for evaluating rtPA-related hemorrhage risks.
血脑屏障（BBB）开放是理解缺血再灌注损伤的关键现象，而缺血再灌注损伤与出血转化直接相关。重组人组织型纤溶酶原激活剂（rtPA）增加了症状性颅内出血的风险。最近的成像技术提高了我们对病理性 BBB 紊乱的认识；然而，在“rtPA 治疗前”阶段，一个持续存在的挑战是开发一种严格的出血风险评估方法。因此，我们研究了一种评估 rtPA 外渗的新方法，即通过通透性增加的 BBB。为了检查大鼠短暂闭塞再灌注模型中 rtPA 外渗的图像诊断，本研究使用了一种聚合物胶束 MRI 造影剂（Gd-胶束）。具体来说，我们在再灌注后 1 小时使用了两种 MRI 造影剂。Gd-胶束在静脉注射后 30 分钟在缺血半球的 15.5±10.3%区域提供了非常清晰的对比图像，而经典的钆螯合物 MRI 造影剂则没有提供令人满意的清晰图像。获得的图像既显示了大分子的高通透性 BBB 区域，也显示了缺血半球中大分子的分布区域。由于分子量较大，Gd-胶束通过高通透性 BBB 留在缺血半球。我们的结果表明，这种新的临床诊断方法评估 rtPA 相关出血风险是可行的。
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