Recent advances in nanomedicines for the treatment of ischemic stroke

Abstract

Ischemic stroke is a cerebrovascular disease normally caused by interrupted blood supply to the brain. Ischemia would initiate the cascade reaction consisted of multiple biochemical events in the damaged areas of the brain, where the ischemic cascade eventually leads to cell death and brain infarction. Extensive researches focusing on different stages of the cascade reaction have been conducted with the aim of curing ischemic stroke. However, traditional treatment methods based on antithrombotic therapy and neuroprotective therapy are greatly limited for their poor safety and treatment efficacy. Nanomedicine provides new possibilities for treating stroke as they could improve the pharmacokinetic behavior of drugs in vivo, achieve effective drug accumulation at the target site, enhance the therapeutic effect and meanwhile reduce the side effect. In this review, we comprehensively describe the pathophysiology of stroke, traditional treatment strategies and emerging nanomedicines, summarize the barriers and methods for transporting nanomedicine to the lesions, and illustrate the latest progress of nanomedicine in treating ischemic stroke, with a view to providing a new feasible path for the treatment of cerebral ischemia.

Keywords: AEPO, asialo-erythropoietin; APOE, apolipoprotein E; BBB, blood‒brain barrier; BCECs, brain capillary endothelial cells; Blood‒brain barrier; CAT, catalase; COX-1, cyclooxygenase-1; CXCR-4, C-X-C chemokine receptor type 4; Ce-NPs, ceria nanoparticles; CsA, cyclosporine A; DAMPs, damage-associated molecular patterns; GFs, growth factors; GPIIb/IIIa, glycoprotein IIb/IIIa; HMGB1, high mobility group protein B1; Hb, hemoglobin; ICAM-1, intercellular adhesion molecule-1; IL-1β, interleukin-1β; IL-6, interleukin-6; Ischemic cascade; LFA-1, lymphocyte function-associated antigen-1; LHb, liposomal Hb; MCAO, middle cerebral artery occlusion; MMPs, matrix metalloproteinases; MSC, mesenchymal stem cell; NF-κB, nuclear factor-κB; NGF, nerve growth factor; NMDAR, N-methyl-d-aspartate receptor; NOS, nitric oxide synthase; NPs, nanoparticles; NSCs, neural stem cells; Nanomedicine; Neuroprotectant; PBCA, poly-butylcyanoacrylate; PCMS, poly (chloromethylstyrene); PEG, poly-ethylene-glycol; PEG-PLA, poly (ethylene-glycol)-b-poly (lactide); PLGA NPs, poly (l-lactide-co-glycolide) nanoparticles; PSD-95, postsynaptic density protein-95; PSGL-1, P-selectin glycoprotein ligand-1; RBCs, red blood cells; RES, reticuloendothelial system; RGD, Arg-Gly-Asp; ROS, reactive oxygen species; Reperfusion; SDF-1, stromal cell-derived factor-1; SHp, stroke homing peptide; SOD, superoxide dismutase; SUR1-TRPM4, sulfonylurea receptor 1-transient receptor potential melastatin-4; Stroke; TEMPO, 2,2,6,6-tetramethylpiperidine-1-oxyl; TIA, transient ischemic attack; TNF-α, tumor necrosis factor-α; Thrombolytics; cRGD, cyclic Arg-Gly-Asp; e-PAM-R, arginine-poly-amidoamine ester; iNOS, inducible nitric oxide synthase; miRNAs, microRNAs; nNOS, neuron nitric oxide synthase; siRNA, small interfering RNA.

Graphical abstract

Figure 1

Molecular and cellular events involved in the ischemic cascade, including energy failure, ion imbalance and excitotoxicity, oxidative stress, cell death (apoptosis or necrosis), initiation of the inflammation and immune response. The expression of P-selectin and intercellular adhesion molecule-1 (ICAM-1) on brain capillary endothelial cells (BCECs) are up-regulated during stroke. The interaction between P-selection and P-selectin glycoprotein ligand-1 (PSGL-1) which are expressed on leukocytes promotes the binding of leukocytes on BCECs. Leukocytes realized firmer adhesion on the vascular wall through the specific binding between the ICAM-1 and lymphocyte function associated antigen-1 (LFA-1), leukocytes subsequently infiltrate into the ischemic brain parenchyma through the damaged blood‒brain barrier (BBB). TLRs, Toll-like receptors.

Figure 2

Schematic illustration of the BBB and the strategies for nanomedicines to cross the BBB.

Figure 3

Schematic diagram of targeted thrombolysis using nanovesicles inspired from activated platelets. (a) Nanovesicles bind the activated platelets in thrombus through the interaction between RGD and GPIIb-IIIa, as well as P-selectin targeting peptide and P-selectin. (b) Nanovesicles composed of glycerophospholipids achieve responsive release of drugs after locating at the target site, as the glycerophospholipids are cleaved by phospholipase A2 overproduced by activated platelets and leukocytes in thrombus. (c) Drug released from degraded nanovesicle realizes targeted fibrinolysis. PMINs: platelet microparticle-inspired nanovesicles. Reprinted with the permission from Ref. 105. Copyright © 2017, Elsevier Ltd.

Figure 4

(A) Scheme of targeted delivery of PLGA NPs coated with membrane derived from NSCs which overexpressed CXCR4 to the ischemic brain. Lentiviral transduction was applied to transform NSCs to overexpress CXCR4. PLGA NPs accumulate in the ischemic area after intravenous injection, and glyburide entrapped in NPs are released to rescue neurons. (B) The accumulation of IR-780-loaded NPs in ischemic brain (n = 3), CMNPs showed significantly higher accumulation than MNPs or NPs. (C) Infarct volume (n = 5), of MCAO mice treated with different formulations. CMNPs: CXCR4-overexpressing membrane-coated NPs; Gly: glyburide; MNPs: membrane-coated NPs. Reprinted with the permission from Ref. 75. Copyright © 2019, WILEY-VCH.

Figure 5

(A) Schematic diagram of CPLB/RAPA micelle in modulating the damaged brain suffered from ischemia: 1) micelle bind the microthrombus through the interaction between fibrin and fibrin-binding peptide; 2) micelle accumulate in the ischemic brain via crossing the damaged BBB; 3) ROS initiate the release of rapamycin, rapamycin promote the phenotypic transition of microglia from M1 to M2, thereby inhibiting the damage of neurons and reducing the inflammation response. (B) Immunostaining of M1 (red) and M2 (green) microglia treatment with different formulations (scale bar = 50 μm). (C) Representative TTC staining images of ischemic brain from rats with different treatment. RAPA: rapamycin; PLB: PEG-phenylboronic ester modified polylysine; CPLB: fibrin-binding peptide CREKA modified PLB. Reprinted with the permission from Ref. 23. Copyright © 2019, WILEY-VCH.