A polymeric micelle magnetic resonance imaging (MRI) contrast agent reveals blood-brain barrier (BBB) permeability for macromolecules in cerebral ischemia-reperfusion injury.
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.
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.
Kouichi
K
Shiraishi
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.
Zuojun
Z
Wang
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.
Daisuke
D
Kokuryo
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.
Ichio
I
Aoki
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. Electronic address: masajun2093ryo@jikei.ac.jp.
Masayuki
M
Yokoyama
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D003287:Contrast Media / Q000008:administration & dosage / Q000493:pharmacokinetics; D005682:Gadolinium / Q000008:administration & dosage / Q000493:pharmacokinetics; D019786:Gadolinium DTPA / Q000008:administration & dosage / Q000493:pharmacokinetics; D020244:Infarction, Middle Cerebral Artery / Q000000981:diagnostic imaging / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D008823:Micelles; D010539:Permeability; D011108:Polymers / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000000981:diagnostic imaging / Q000378:metabolism*
D003287:Contrast Media; D008823:Micelles; D011108:Polymers; D005682:Gadolinium; D019786:Gadolinium DTPA
A polymeric micelle MRI contrast agent; Blood–brain barrier (BBB) permeability; Drug targeting; Focal ischemia-reperfusion injury; Magnetic resonance imaging (MRI)