Occlusion of Animal Model Arteriovenous Malformations Using Vascular Targeting
| Autor: | Vivienne S. Lee, Vaughan Moutrie, Marcus A. Stoodley, Lucinda S. McRobb, Andrew J. Gauden, Sinduja Subramanian, Zhenjun Zhao |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Intracranial Arteriovenous Malformations Phosphatidylserines Anastomosis Radiosurgery Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Fibrinolytic Agents medicine.artery Occlusion Medicine Animals Thrombolytic Therapy Common carotid artery Annexin A5 Dose Modification Intracerebral hemorrhage medicine.diagnostic_test business.industry General Neuroscience Thrombin Arteriovenous malformation medicine.disease Thrombosis Disease Models Animal 030104 developmental biology Angiography Neurology (clinical) Cardiology and Cardiovascular Medicine business Nuclear medicine 030217 neurology & neurosurgery |
| Zdroj: | Translational stroke research. 11(4) |
| ISSN: | 1868-601X |
| Popis: | Brain arteriovenous malformations (AVMs) are a significant cause of intracerebral hemorrhage in children and young adults. Currently, one third of patients have no viable treatment options. Vascular targeting agents (VTAs) are being designed to deliver pro-thrombotic molecules to the abnormal AVM vessels for rapid occlusion and cure. This study assessed the efficacy of a pro-thrombotic VTA targeting phosphatidylserine (PS) in a radiation-primed AVM animal model. The model AVM was surgically created in rats by anastomosis of the left external jugular vein to the adjacent common carotid artery. After 6 weeks, the AVM was irradiated (20 Gy) using gamma knife surgery (GKS). A PS-targeting VTA was created by conjugation of annexin V with human thrombin and administered intravenously 3 weeks post-GKS or sham. Unconjugated thrombin was used as a non-targeting control. AVM thrombosis and occlusion was monitored 3 weeks later by angiography and histology. Preliminary experiments established a safe dose of active thrombin for systemic administration. Subsequently, a single dose of annexin V–thrombin conjugate (0.77 mg/kg) resulted in angiographic AVM occlusion in sham (75%) and irradiated (63%) animals, while non-targeted thrombin did not. Lowering the conjugate dose (0.38 mg/kg) decreased angiographic AVM occlusion in sham (13%) relative to irradiated (80%) animals (p = 0.03) as did delivery of two consecutive doses of 0.38 mg/kg, 2 days apart (sham (0%); irradiated (78%); p = 0.003). These findings demonstrate efficacy of the PS-targeting VTA and the feasibility of a vascular targeting approach for occlusion of high-flow AVMs. Targeting specificity can be enhanced by radiation–sensitization and VTA dose modification. |
| Databáze: | OpenAIRE |
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