Abstract
Ischemic stroke is the most common type of stroke and thrombolytic therapy is the only approved treatment. However, current thrombolytic therapy with tissue plasminogen activator (tPA) is often hampered by the increased risk of hemorrhage. Plasmin, a direct fibrinolytic, has a significantly superior hemostatic safety profile; however, if injected intravenously it becomes rapidly inactivated by anti-plasmin. Nanoformulations have been shown to increase drug stability and half-life and hence could be applied to increase the plasmin therapeutic efficacy. Here in this paper, we report a novel heparin and arginine-based plasmin nanoformulation that exhibits increased plasmin stability and efficacy. In vitro studies revealed significant plasmin stability in the presence of anti-plasmin and efficient fibrinolytic activity. In addition, these particles showed no significant toxicity or oxidative stress effects in human brain microvascular endothelial cells, and no significant blood brain barrier permeability. Further, in a mouse photothrombotic stroke model, plasmin nanoparticles exhibited significant efficacy in reducing stroke volume without overt intracerebral hemorrhage (ICH) compared to free plasmin treatment. The study shows the potential of a plasmin nanoformulation in ischemic stroke therapy.
Highlights
Stroke is a major cause of death worldwide, affecting more than fifteen million people every year
The heparin-arginine nanoparticles (HA NP) exhibited larger size compared to the heparinarginine-plasmin nanoparticles (HAP NP) as revealed by transmission electron microscopy (TEM) and dynamic light scattering (DLS) measurements (Figure 1B(i,ii)) and Table 1
The results demonstrate that treatment with HAP NPs, 3 h after middle cerebral artery occlusion (MCAO), significantly decreased stroke volume by 27% and 34% compared to free plasmin (Ctl-Plasmin) and nanoparticle controls (HA NP), respectively (Figure 7C)
Summary
Stroke is a major cause of death worldwide, affecting more than fifteen million people every year. Intravenous delivery of recombinant tPA within 4.5h after symptom onset provided better reperfusion, independence, survival and more favorable outcomes Both clinical evidence, and experimental models of ischemic stroke, demonstrate a significant increase in the incidence of hemorrhagic transformation with late thrombolytic tPA beyond the 4.5h treatment window [8,9,10,11,12,13,14]. When coated with tPA, these aggregates effectively dissolved partially occluded clots at the diseased site and showed several-fold increases in efficacy compared to the free tPA treatment All these applications of nano/micro formulations indicate their potential as effective drug depots for thrombolytic drug delivery. The study shows the potential of nanoformulations for plasmin delivery and could open new paths for efficient plasmin-based stroke therapy
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