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. 2015 Dec;46(12):3507-13.
doi: 10.1161/STROKEAHA.115.011063. Epub 2015 Oct 22.

Shear-Activated Nanoparticle Aggregates Combined With Temporary Endovascular Bypass to Treat Large Vessel Occlusion

Miklos G Marosfoi  1 , Netanel Korin  1 , Matthew J Gounis  1 , Oktay Uzun  1 , Srinivasan Vedantham  1 , Erin T Langan  1 , Anne-Laure Papa  1 , Olivia W Brooks  1 , Chris Johnson  1 , Ajit S Puri  1 , Deen Bhatta  1 , Mathumai Kanapathipillai  1 , Ben R Bronstein  1 , Ju-Yu Chueh  1 , Donald E Ingber  2 , Ajay K Wakhloo  1
Affiliations

Shear-Activated Nanoparticle Aggregates Combined With Temporary Endovascular Bypass to Treat Large Vessel Occlusion

Miklos G Marosfoi et al. Stroke. 2015 Dec.

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.

Keywords: acute ischemic stroke; endovascular treatment; nanoparticles; stent; thrombolysis.

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