Shear Stress Targeted Delivery of Nitroglycerin to Brain Collaterals Improves Ischaemic Stroke Outcome.

Abstract

In patients with ischaemic stroke, retrograde perfusion of the penumbra by leptomeningeal collateral vessels (LMCs) strongly predicts clinical outcome, suggesting that enhancing LMC flow can offer a novel therapeutic approach. Using in vivo measurements and computational modelling it is shown that LMCs experience elevated fluid shear stress that is significantly higher than that in other blood vessels during ischaemic stroke in rats and humans. We exploit this to selectively enhance flow in LMCs using shear-activated nanoparticle aggregates carrying the vasodilator nitroglycerin (NG-NPAs) that specifically release drug in regions of vessels with high wall shear stress (≥100 dyne cm). NG-NPAs significantly increased LMC-mediated penumbral perfusion, decreased infarct volume, and reduced neurological deficit without altering systemic blood pressure in a rat ischaemic stroke model. NG-NPAs also avoided common side effects of systemic nitrate administration, such as systemic hypotension, cerebral vascular steal, cortical vein dilation, or intracranial pressure elevation. Systemic administration of free NG at the maximal tolerated dose, which is ten times higher than the dose of NG used in the NG-NPAs, do not enhance LMC perfusion and dropped blood pressure. Thus, packaging NG within shear-activated NPAs can potentially enable this widely available vasodilator to become a highly effective therapeutic for ischaemic stroke.