Nanomaterial-Based Drug Delivery Systems for Ischemic Stroke

Abstract

Ischemic stroke is a leading cause of death and disability in the world. At present, reperfusion therapy and neuroprotective therapy, as guidelines for identifying effective and adjuvant treatment methods, are limited by treatment time windows, drug bioavailability, and side effects. Nanomaterial-based drug delivery systems have the characteristics of extending half-life, increasing bioavailability, targeting drug delivery, controllable drug release, and low toxicity, thus being used in the treatment of ischemic stroke to increase the therapeutic effects of drugs. Therefore, this review provides a comprehensive overview of nanomaterial-based drug delivery systems from nanocarriers, targeting ligands and stimulus factors of drug release, aiming to find the best combination of nanomaterial-based drug delivery systems for ischemic stroke. Finally, future research areas on nanomaterial-based drug delivery systems in ischemic stroke and the implications of the current knowledge for the development of novel treatment for ischemic stroke were identified.

Keywords: drug delivery; ischemic stroke; nanomaterials; nanoparticles; targeted therapy.

Figure 1

The possible function and mechanism of nanomaterial-based drug delivery systems in ischemic stroke. After ischemic stroke, M1 microglia and A1 astrocyte are rapidly activated in ischemic brain areas. In addition, leukocytes (including neutrophils and monocytes) in peripheral blood are recruited into the ischemic brain area. Among them, M1 microglia, A1 astrocyte, N1 neutrophils, and M1 macrophages would aggravate the neuron death through the overproduction of inflammatory molecules (i.e., TNF-α, iNOS, and IL-1β) and ROS (i.e., H₂O₂, O²⁻, ·OH, and HOCI). Based on the nanomaterial-based drug delivery systems, these harmful cell phenotypes may be shifted towards beneficial phenotypes (M2 microglia, A2 astrocyte, N2 neutrophils, and M2 macrophages) to exert the function of anti-inflammation, anti-oxidation, and anti-neuronal apoptosis, thus promoting injured neuron repair in ischemic stroke through the release of drugs or genes that are encapsulated in the nanoparticles. ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; H₂O₂, hydrogen peroxide; •OH, hydroxyl radicals; O₂, oxygen; HOCl, hypochlorous acid; TNFα, tumor necrosis factor α; iNOS, inducible nitric oxide synthase; IL-1β, interleukin-1β; Arg-1, arginase-1; IL-4, interleukin-4; BDNF, brain-derived neurotrophic factor.

Figure 2

Preparation and delivery of nanoparticles in ischemic stroke. (A) The preparation of nanoparticles mainly includes three steps, including the selection of nanocarriers, modification of surface molecules on nanocarriers, and agent encapsulation. Based on the differences in surface molecules, nanoparticles are mainly divided into ligand-modified nanoparticles and membrane-derived nanoparticles. (B) Nanoparticles enter the ischemic brain area through different injection methods, mainly including ① intravenous injection, ② intraperitoneal injection, ③ oral administration, and ④ stereotaxic injection. (C) Based on the disruption of BBB, the nanoparticles are delivered to the ischemic brain area through endothelial cell-mediated endocytosis and paracellular pathways in ischemic stroke. Among them, the overexpressed receptor located on the damaged BBB can be recognized by ligand-modified nanoparticles, and then the nanoparticles can cross the BBB through endothelial cell-mediated endocytosis. In addition, based on chemotactic characteristics of neutrophils and monocytes, neutrophil/monocytes membrane-derived nanoparticles cross the BBB through paracellular pathways. Moreover, neutrophils in peripheral blood can be bound by ligand-modified nanoparticles, and then the nanoparticles can hitchhike on neutrophils to reach the ischemic brain areas.