Shear-activated nanoparticle aggregates combined with temporary endovascular bypass to treat large vessel occlusion

Miklos G. Marosfoi, Netanel Korin, Matthew J. Gounis, Oktay Uzun, Srinivasan Vedantham, Erin T. Langan, Anne Laure Papa, Olivia W. Brooks, Chris Johnson, Ajit S. Puri, Deen Bhatta, Mathumai Kanapathipillai, Ben R. Bronstein, Ju Yu Chueh, Donald E. Ingber, Ajay K. Wakhloo

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Background and Purpose - The goal of this study is to combine temporary endovascular bypass (TEB) with a novel shear-activated nanotherapeutic (SA-NT) that releases recombinant tissue-type plasminogen activator (r-tPA) when exposed to high levels of hemodynamic stress and to determine if this approach can be used to concentrate r-tPA at occlusion sites based on high shear stresses created by stent placement. Methods - A rabbit model of carotid vessel occlusion was used to test the hypothesis that SA-NT treatment coupled with TEB provides high recanalization rates while reducing vascular injury. We evaluated angiographic recanalization with TEB alone, intra-arterial delivery of soluble r-tPA alone, or TEB combined with 2 doses of intra-arterial infusion of either the SA-NT or soluble r-tPA. Vascular injury was compared against stent-retriever thrombectomy. Results - Shear-targeted delivery of r-tPA using the SA-NT resulted in the highest rate of complete recanalization when compared with controls (P=0.0011). SA-NT (20 mg) had a higher likelihood of obtaining complete recanalization as compared with TEB alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), intra-arterial r-tPA alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), or TEB with soluble r-tPA (2 mg; odds ratio 18.78, 95% confidence interval 1.28, 275.05; P=0.0322). Histological analysis showed circumferential loss of endothelium restricted to the area where the TEB was deployed; however, there was significantly less vascular injury using a TEB as compared with stent-retriever procedure (odds ratio 12.97, 95% confidence interval 8.01, 21.02; P<0.0001). Conclusions - A novel intra-arterial, nanoparticle-based thrombolytic therapy combined with TEB achieves high rates of complete recanalization. Moreover, this approach reduces vascular trauma as compared with stent-retriever thrombectomy.

Original languageEnglish (US)
Pages (from-to)3507-3513
Number of pages7
JournalStroke
Volume46
Issue number12
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

Keywords

  • acute ischemic stroke
  • endovascular treatment
  • nanoparticles
  • stent
  • thrombolysis

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

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