Journal
JOURNAL OF CONTROLLED RELEASE
Volume 253, Issue -, Pages 165-171Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2017.03.020
Keywords
Blood-brain barrier (BBB) permeability; Drug targeting; Magnetic resonance imaging (MRI); A polymeric micelle MRI contrast agent; Focal ischemia-reperfusion injury
Funding
- Ministry of Health, Labour and Welfare, Japan
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) Japan
- Grants-in-Aid for Scientific Research [17K01372] Funding Source: KAKEN
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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 1 h after reperfusion. Gd-micelles provided very clear contrast images in 15.5 +/- 10.3% of the ischemic hemisphere at 30 min 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. (C) 2017 Elsevier B.V. All rights reserved.
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