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Rationale for a nanomedicine approach to thrombolytic therapy.

Stroke is the third-leading cause of death and most common etiology for long-term adult disability. Of the approximate 700 000 individuals experiencing new or recurrent stroke annually, less than 5% of these individuals receive thrombolytic therapy.1–3 Intravenous recombinant tissue plasminogen activator (rt-PA) is an approved pharmacological treatment for acute ischemic stroke, but the window of opportunity is considered to be 3 hours from the onset of symptoms following a diagnostic imaging study to rule out hemorrhage. At the thrombolytic dosages approved, the incidence of intracranial hemorrhage in Europe and North America has been 6.4%.4 More recently, this time-window guideline has been liberalized to 3 to 6 hours, primarily because very few patients present for treatment within 3 hours.5 However, this change could bring a potential increase in the complication rate. The potential impact and value of a nanomedicine approach to this problem becomes apparent after examination of the alternatives that have been explored.

Neuroprotective approaches to stroke treatment have generated considerable interest because of the low effective use rate of thrombolytic therapies and, if successful, would extend the therapeutic window. However, hundreds of compounds and thousands of articles have been written on neuroprotecting agents to be administered in the advent of a cerebral vascular accident, but none has achieved regulatory-approved status.6 The evidence from PET studies has revealed that early reperfusion, either spontaneous or chemically initiated, primarily determines the final size of brain infarction; these hypoperfused regions account for 70% of the final infarct volume.

Reperfusion of the ischemic brain is the most effective therapy for acute stroke, restoring nutrition and oxygen-rich blood flow to threatened tissues. Endogenous enzymes such as rt-PA and urokinase control the conversion of plasminogen to plasmin and the ultimate digestion of fibrin. A number of circulating proteins neutralize plasmin; the best …