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

doi:10.1161/STROKEAHA.115.011063

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

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

Authors

Miklos G Marosfoi¹, Netanel Korin¹, Matthew J Gounis¹, Oktay Uzun¹, Srinivasan Vedantham¹, Erin T Langan¹, Anne-Laure Papa¹, Olivia W Brooks¹, Chris Johnson¹, Ajit S Puri¹, Deen Bhatta¹, Mathumai Kanapathipillai¹, Ben R Bronstein¹, Ju-Yu Chueh¹, Donald E Ingber², Ajay K Wakhloo¹

Affiliations

¹ From the New England Center for Stroke Research, Department of Radiology, University of Massachusetts, Worcester (M.G.M., M.J.G., S.V., E.T.L., O.W.B., A.S.P., J.-Y.C., A.K.W.); Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA (N.K., O.U., A.-L.P., C.J., D.B., M.K., B.R.B., D.E.I.); Department of Biomedical Engineering, Technion, Israel (N.K.); Vascular Biology Program, Boston Children's Hospital and Harvard University, Boston, MA (D.E.I.); and Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA (D.E.I.).
² From the New England Center for Stroke Research, Department of Radiology, University of Massachusetts, Worcester (M.G.M., M.J.G., S.V., E.T.L., O.W.B., A.S.P., J.-Y.C., A.K.W.); Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA (N.K., O.U., A.-L.P., C.J., D.B., M.K., B.R.B., D.E.I.); Department of Biomedical Engineering, Technion, Israel (N.K.); Vascular Biology Program, Boston Children's Hospital and Harvard University, Boston, MA (D.E.I.); and Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA (D.E.I.). don.ingber@wyss.harvard.edu.

PMID: 26493676
DOI: 10.1161/STROKEAHA.115.011063

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arterial Occlusive Diseases / pathology*
Arterial Occlusive Diseases / therapy*
Cattle
Combined Modality Therapy
Endovascular Procedures / methods*
Female
Male
Nanoparticles / administration & dosage*
Nanoparticles / chemistry
Rabbits
Shear Strength*
Treatment Outcome