The proposal RESOLVE focused on the development and preclinical validation of a more effective and less toxic anti-stroke therapy based on nanotechnological tools. Currently, the standard of care for the treatment of acute ischemic stroke requires the intravenous infusion of clot-busting molecules (thrombolysis), the mechanical retrieval of large clots via image-guided intravascular catheters (thrombectomy), or the combination of the two approaches. This standard protocol comes with considerable side effects, as highlighted in several clinical studies. In thrombolysis, the life-saving molecule tissue plasminogen activator (tPA), which is the sole molecule so far approved, has been shown to benefit only a limited cohort of stroke patients (~ 5%). Indeed, to avoid severe side effects, tPA can be only administered in patients with no cerebral bleeding within 4.5 hours post the onset of the symptoms, and delayed administration is associated with intracranial hemorrhages and exacerbate neuronal damage. Therefore, to increase the clinical potential of thrombolysis, RESOLVE has rationally designed discoidal polymeric nanoconstructs (DPN) carrying the molecule tPA. As compared to the free thrombolytic molecule, this novel anti-stroke medicine (tPA-DPN) showed a faster blood clot dissolution, higher biochemical stability, and reduced side effects in preclinical models of the disease. Importantly, under conditions well known to be associated with tPA-induced neurotoxicity, the delayed intravascular administration of tPA-DPN returned normal neuroscores. These results are expected to extend the use of thrombolytic therapy well beyond the current standard and benefit a larger cohort of patients.
