Edaravone-Encapsulated Agonistic Micelles Rescue Ischemic Brain Tissue by Tuning Blood-Brain Barrier Permeability

Abstract

Thrombolysis has been a standard treatment for ischemic stroke. However, only 2-7% patients benefit from it because the thrombolytic agent has to be injected within 4.5 h after the onset of symptoms to avoid the increasing risk of intracerebral hemorrhage. As the only clinically approved neuroprotective drug, edaravone (EDV) rescues ischemic brain tissues by eradicating over-produced reactive oxygen species (ROS) without the limitation of therapeutic time-window. However, EDV's short circulation half-life and inadequate cerebral uptake attenuate its therapeutic efficacy. Here we developed an EDV-encapsulated agonistic micelle (EDV-AM) to specifically deliver EDV into brain ischemia by actively tuning blood-brain barrier (BBB) permeability. The EDV-AM actively up-regulated endothelial monolayer permeability in vitro. HPLC studies showed that EDV-AM delivered more EDV into brain ischemia than free EDV after intravenous injection. Magnetic resonance imaging also demonstrated that EDV-AM more rapidly salvaged ischemic tissue than free EDV. Diffusion tensor imaging indicated the highest efficiency of EDV-AM in accelerating axonal remodeling in the ipsilesional white matter and improving functional behaviors of ischemic stroke models. The agonistic micelle holds promise to improve the therapeutic efficiency of ischemic stroke patients who miss the thrombolytic treatment.

Antioxidant Alternatives in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review

“…Edaravone easily crosses the blood-brain-barrier and displays a high brain penetration capacity (Jin et al, 2017). Its amphiphilic capacity allows edaravone to scavenge both lipid and water soluble peroxyl radicals and chain-carrying lipid peroxyl radicals (Nagase et al, 2016) (Table 1).…”

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“…One study developed drug-conjugated cationic bovine serum albumin (CBSA) micelles to augment crossing of the BBB, while another study had conjugated ligands onto micelle surfaces to bind to adenosine 2A receptors (A 2A R) on the BBB lumen to improve uptake. 82,83 One study had even combined the encapsulation of lexiscan and surface conjugation with chlorotoxin which together improved BBB uptake and delivery to the ischemic region. 84 However, a strategy that is different from liposomes is the use of engineered degradation for intracellular release.…”

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“…Furthermore, a potential amelioration of inflammation by limiting the production of several proinflammatory cytokines can also be achieved . Both antioxidant substances, including curcumin, quercetin, and edaravone, as well as antioxidant enzymes (superoxide dismutase and catalase) were encapsulated inside polymer matrices and were used as curatives for cerebral ischemia. Their encapsulation inhibited limitations such as short half‐life, fast RES clearance, and nonspecific selectivity toward brain tissues, enhancing, as in the case of lipid‐based nanostructures, their therapeutic effect.…”

“…Their encapsulation inhibited limitations such as short half‐life, fast RES clearance, and nonspecific selectivity toward brain tissues, enhancing, as in the case of lipid‐based nanostructures, their therapeutic effect. In all the reported studies, these antioxidants resulted into a reduction of ROS and to therapeutic outcomes such as BBB preservation and reduction of neuroinflammation,33c activation and mobilization of progenitor stem cells, improved axonal remodeling, and inhibition of apoptosis with simultaneous induction of angiogenesis . It has to be noted that surface functionalization with specific moieties has also been performed.…”

“…It has to be noted that surface functionalization with specific moieties has also been performed. Ligands such as the triphenylphosphonium (TPP) cation that targets the mitochondria, or the adenosine 2A receptor agonistic agent that has the ability to open the BBB tight junctions, have been attached to poly(lactic‐ co ‐glycolic) acid (PLGA) and polyethylene glycol (PEG)‐poly(lactic) acid nanoparticles, respectively. Another targeting moiety worth to be mentioned is the chlorotoxin, that has the ability to target MMP‐2, which is overexpressed in ischemic stroke .…”