Simultaneous Blood–Brain Barrier Crossing and Protection for Stroke Treatment Based on Edaravone-Loaded Ceria Nanoparticles

Abstract

Cerebral vasculature and neuronal networks will be largely destroyed due to the oxidative damage by overproduced reactive oxygen species (ROS) during a stroke, accompanied by the symptoms of ischemic injury and blood-brain barrier (BBB) disruption. Ceria nanoparticles, acting as an effective and recyclable ROS scavenger, have been shown to be highly effective in neuroprotection. However, the brain access of nanoparticles can only be achieved by targeting the damaged area of BBB, leading to the disrupted BBB being unprotected and to turbulence of the microenvironment in the brain. Nevertheless, the integrity of the BBB will cause very limited accumulation of therapeutic nanoparticles in brain lesions. This dilemma is a great challenge in the development of efficient stroke nanotherapeutics. Herein, we have developed an effective stroke treatment agent based on monodisperse ceria nanoparticles, which are loaded with edaravone and modified with Angiopep-2 and poly(ethylene glycol) on their surface (E-A/P-CeO). The as-designed E-A/P-CeO features highly effective BBB crossing via receptor-mediated transcytosis to access brain tissues and synergistic elimination of ROS by both the loaded edaravone and ceria nanoparticles. As a result, the E-A/P-CeO with low toxicity and excellent hemo/histocompatibility can be used to effectively treat strokes due to great intracephalic uptake enhancement and, in the meantime, effectively protect the BBB, holding great potentials in stroke therapy with much mitigated harmful side effects and sequelae.

Camouflaging Nanoparticles with Brain Metastatic Tumor Cell Membranes: A New Strategy to Traverse Blood–Brain Barrier for Imaging and Therapy of Brain Tumors

“…[ 2,11–13 ] Recently, several target ligands including transferrin, lactoferrin, and angiopep‐2 have been exploited to cross BBB by receptor‐mediated transcytosis. [ 12,14–16 ] However, the less than 1.0% of the brain accumulation rate of these nanoparticles cannot meet the requirements of clinical use, which is due to the low efficiency of ligand upload on nanoparticles, weak binding ability with receptors, and the competition of high concentration of endogenous ligands in the blood. [ 5,6 ] Therefore, it is still challenging to develop a strategy to endow nanoparticles with essential functions such as BBB‐crossing ability, high tumor accumulation, and immune escape for the treatment of brain diseases.…”

“…[2,[11][12][13] Recently, several target ligands including transferrin, lactoferrin, and angiopep-2 have been exploited to cross BBB by receptor-mediated transcytosis. [12,[14][15][16] However, the less than 1.0% of the brain accumulation rate of these nanoparticles cannot meet the requirements of clinical use, which is due to the low efficiency of ligand upload on nanoparticles, weak binding ability with receptors, and the…”

Advanced Functional Materials and Cell‐Based Therapies for the Treatment of Ischemic Stroke and Postischemic Stroke Effects

“…One of the most used biomaterial‐based nanostructures in the combinational studies are the polymeric ones. These nanostructures find several uses as supportive scaffolds for the delivery of MSCs, as nanoparticles for drug and gene delivery or as coatings for inorganic nanoparticles . Each of these nanostructures is able to encapsulate a variety of therapeutics, including antioxidants such as catalase,86a nanoceria, and edaravone, growth factors such as VEGF, and other neuroprotectants such as glyburide86b and the NR2B9C therapeutic peptide 86c.…”

“…These nanostructures find several uses as supportive scaffolds for the delivery of MSCs, as nanoparticles for drug and gene delivery or as coatings for inorganic nanoparticles . Each of these nanostructures is able to encapsulate a variety of therapeutics, including antioxidants such as catalase,86a nanoceria, and edaravone, growth factors such as VEGF, and other neuroprotectants such as glyburide86b and the NR2B9C therapeutic peptide 86c. In addition, these nanostructures can be modified with specific targeting ligands, including peptides such as angiopep‐2, N ‐acetyl Pro‐Gly‐Pro (Ac‐PGP),86a organic compounds such as AMD3100,86b and proteins such as wheat germ agglutinin (WGA)86c and laminin, aiming at improving their uptake both by the BBB cells as well as by the ischemic tissue.…”

Intelligent Nanocomposites with Intrinsic Blood–Brain‐Barrier Crossing Ability Designed for Highly Specific MR Imaging and Sonodynamic Therapy of Glioblastoma

“…to the cerebrum, thereby compromising the outcomes of diagnosis and therapy . With the increasing development of nanomaterials, receptor‐mediated transcytosis (RMT) has become one of the most promising protocols to overcome the BBB through receptors that are highly expressed on BBB endothelial cells, among which transferrin receptor (TfR) is a promising candidate . Moreover, TfR is also present in substantial quantities on GBM cells due to their high proliferation rate and iron demand .…”