Abstract
Ischemic stroke is still one of the leading causes of high mortality and severe disability worldwide. Therapeutic options for ischemic stroke and subsequent cerebral ischemia/reperfusion injury remain limited due to challenges associated with drug permeability through the blood-brain barrier (BBB). Neuroprotectant delivery with nanoparticles, including liposomes, offers a promising solution to address this problem, as BBB disruption following ischemic stroke allows nanoparticles to pass through the intercellular gaps between endothelial cells. To ameliorate ischemic brain damage, a number of nanotherapeutics encapsulating neuroprotective agents, as well as surface-modified nanoparticles with specific ligands targeting the injured brain regions, have been developed. Combination therapy with nanoparticles encapsulating neuroprotectants and tissue plasminogen activator (t-PA), a globally approved thrombolytic agent, has been demonstrated to extend the narrow therapeutic time window of t-PA. In addition, the design of biomimetic drug delivery systems (DDS) employing circulating cells (e.g., leukocytes, platelets) with unique properties has recently been investigated to overcome the injured BBB, utilizing these cells’ inherent capability to penetrate the ischemic brain. Herein, we review recent findings on the application and utility of nanoparticle DDS, particularly liposomes, and various approaches to developing biomimetic DDS functionalized with cellular membranes/membrane proteins for the treatment of ischemic stroke.
Highlights
Introduction published maps and institutional affilIschemic stroke, which accounts for approximately 60% of cerebrovascular disorders, is caused by obstruction of the blood supply into the brain due to thrombi and leads to brain cell damage [1]
Due to the risk of cerebral hemorrhage induced by damage to brain endothelial cells, and potential neurotoxic effects resulting from intravenously infused tissue plasminogen activator (t-PA), the therapeutic time window (TTW; within 4.5 h after onset of an ischemic stroke) is very narrow, which significantly limits the use of t-PA reperfusion therapy in eligible stroke patients [4,5]
Liposomes and other synthetic nanoparticles can carry therapeutic drugs that exhibit a number of different physical properties, such as one of a range of molecular sizes and hydrophilicity/hydrophobicity, by encapsulation or surface modification, which brings about efficient delivery of the drugs to diseased areas and an increase in their therapeutic effects
Summary
The blood-brain barrier (BBB) plays a pivotal role in maintaining homeostasis associated with normal functioning of the central nervous system (CNS), and in regulating molecular transport between the blood and the brain. Kikuchi et al reported the use of liposomes encapsulating the NMDAR antagonist ifenprodil, which can be efficiently loaded into liposomes using a pH gradient between internal and external water phases [37] Both liposomal neuroprotective agents targeting NMDAR signaling exhibited superior therapeutic effects on cerebral I/R injury compared to free drugs in t-MCAO rats. Other examples that have been reported of liposomes encapsulating therapeutic drugs with neuroprotective activities against ischemic stroke include liposomal formulations of simvastatin (3-hydroxy-r-methylglutaryl coenzyme A reductase inhibitor) and cytidine-50 -diphosphocholine (citicoline; a vital component of neuronal membranes) [40,41] Taken together, these findings suggest that the use of liposomes to deliver cerebroprotective agents to the lesioned area offers a promising approach for the treatment of ischemic stroke.
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