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Review
. 2022 Apr 11:16:868323.
doi: 10.3389/fncel.2022.868323. eCollection 2022.

Progresses and Prospects of Neuroprotective Agents-Loaded Nanoparticles and Biomimetic Material in Ischemic Stroke

Junfa Chen  1 , Jing Jin  2 , Kaiqiang Li  3 , Lin Shi  1 , Xuehua Wen  1 , Fuquan Fang  4
Affiliations
Review

Progresses and Prospects of Neuroprotective Agents-Loaded Nanoparticles and Biomimetic Material in Ischemic Stroke

Junfa Chen et al. Front Cell Neurosci. .

Abstract

Ischemic stroke remains the leading cause of death and disability, while the main mechanisms of dominant neurological damage in stroke contain excitotoxicity, oxidative stress, and inflammation. The clinical application of many neuroprotective agents is limited mainly due to their inability to cross the blood-brain barrier (BBB), short half-life and low bioavailability. These disadvantages can be better eliminated/reduced by nanoparticle as the carrier of these drugs. This review expounded the currently hot researched nanomedicines from the perspective of the mechanism of ischemic stroke. In addition, this review describes the bionic nanomedicine delivery strategies containing cells, cell membrane vesicles and exosomes that can effectively avoid the risk of clearance by the reticuloendothelial system. The potential challenges and application prospect for clinical translation of these delivery platforms were also discussed.

Keywords: biomimetic material; blood-brain barrier; ischemic stroke; nanoparticles; neuroprotection.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Major active cells and molecules during ischemic stroke. Upregulation of glutamate (glu) and increased NMDA (N-methyl-D-aspartate) receptors lead to intracellular calcium (Ca2+) and sodium (Na+) loading; Increased intracellular Ca2+ induce cell membrane degradation and mitochondrial damage, followed by apoptosis or death; DAMPs (Damage-associated molecular patterns) trigger microglial activation to release chemokines, which can induce neutrophil invasion; Ischemia leads to endothelial damage, resulting in increased vascular permeability and inflammatory cell migration. MMPs, matrix metalloproteinase; Ros, reactive oxygen species; NETs, neutrophil extracellular traps; TNF, Tumor Necrosis Factor.
FIGURE 2
FIGURE 2
Blood–brain barrier (BBB) transport mechanisms for brain delivery of nanoparticles (NPs). The BBB is highly selective and has specific transport mechanisms allowing a close control of molecules/cells that enter the brain parenchyma. Loosened tight junctions (TJs) allow the cross of NPs through the BBB, either by the presence of a surfactant in NPs able to disrupt the TJs or by BBB impairment due to pathological conditions. Receptor-mediated transcytosis is the most common type of transport for NP entry into the brain. NPs can be functionalized with different types of ligands (such as insulin, transferrin, lactoferrin or antibodies against some endothelial receptors), or surfactants like polysorbate 80 [that adsorbs plasma proteins, namely apolipoprotein E enabling their binding to the lipoprotein receptor-related proteins (LRPs)]. The interaction between NP ligands and respective receptors in the endothelial cell (luminal side) surface triggers plasma membrane invaginations followed by pinch free forming vesicles, which facilitates the release of the NPs in the opposite site of the membrane (parenchymal side). NPs coated with molecules such as albumin or chitosan can cross the BBB by adsorptive transcytosis. Efflux pumps may reduce the amount of NPs retained in brain parenchyma (Saraiva et al., 2016).
FIGURE 3
FIGURE 3
Main nanoparticle (NP) features influencing systemic delivery and blood brain barrier (BBB) passage. NPs can be classified into natural, when molecules such as proteins (albumin), polysaccharides, chitosan, among others are used, or synthetic. Synthetic NPs can be made of very common polymers such as poly(lactic-co-glycolic acid) (PLGA), poly(ethylenimine) (PEI), polyesters [poly(lactic acid)] (PLA), or from inorganic agents like gold, silica or alumina. NPs can vary in their size (1–1000 nm) and are able to deliver drugs into cells by entrapping, adsorbing or covalently bounding them. NPs can assume different shapes (spherical, cubic, and rod-like) and charges (negative, zwitterionic, and positive); negatively charged spheres are widely used in intravenous applications. Another important feature of NPs is the possibility of functionalization with different types of ligands. Ligands are distributed into four major categories: (i) capable of mediating protein adsorption [e.g., poly(sorbate) 80 (P-80)]; (ii) able to interact directly with the BBB (e.g., transferrin proteins, antibody or peptides); (iii) capable of increasing hydrophobicity (e.g., amphiphilic peptides); and (iv) able to improve blood circulation [e.g., poly(ethylene glycol) (PEG)] (Saraiva et al., 2016).
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