Recent advances in the development of nanomedicines for the treatment of ischemic stroke

Abstract

Ischemic stroke is still a serious threat to human life and health, but there are few therapeutic options available to treat stroke because of limited blood-brain penetration. The development of nanotechnology may overcome some of the problems related to traditional drug development. In this review, we focus on the potential applications of nanotechnology in stroke. First, we will discuss the main molecular pathological mechanisms of ischemic stroke to develop a targeted strategy. Second, considering the important role of the blood-brain barrier in stroke treatment, we also delve mechanisms by which the blood-brain barrier protects the brain, and the reasons why the therapeutics must pass through the blood-brain barrier to achieve efficacy. Lastly, we provide a comprehensive review related to the application of nanomaterials to treat stroke, including liposomes, polymers, metal nanoparticles, carbon nanotubes, graphene, black phosphorus, hydrogels and dendrimers. To conclude, we will summarize the challenges and future prospects of nanomedicine-based stroke treatments.

Keywords: Blood-brain barrier; Nanomaterials; Stroke.

Graphical abstract

Fig. 1

Nano-medicine for the treatment of ischemic stroke.

Fig. 2

Schematic of neurotoxicity induced by changes in inflammatory cytokines and immune cells after cerebral ischemia. Reprinted with permission from Ref. [12]. Copyright 2017 SPRINGER.

Fig. 3

Schematic illustration of the main structural components of the BBB. Reprinted with permission from Ref. [44]. Copyright 2018 MDPI.

Fig. 4

Schematic diagram of different liposome membrane functionalization strategies. Reprinted with permission from Ref. [83]. Copyright 2019 PERGAMON-ELSEVIER.

Fig. 5

Polymeric nanoparticles, polymeric vesicles and polymeric micelles all formed from various cetyl poly(ethylenimine) amphiphiles. Reprinted with permission from Ref. [96]. Copyright 2013 Springer Science+Business Media New York.

Fig. 6

Schematic diagram of preparation of PEG-MWCNTs (multiwalled carbon nanotubes) Reprinted with permission from ref[171]. Copyright 2018 MDPI.

Fig. 7

Schematic diagram of rGO opening BBB. Reprinted with permission from ref. [63] Copyright 2015 BMC.

Fig. 8

A1-A6. The therapeutic performance of GO-based drugs on stroke. (A1) Experimental setup. (A2) Photoacoustic vessel cross-section images of vasodilatation under irradiation with an 808 nm laser in a PTI rat treated with (i–iii) Ru–CO–GO (group 1) and (iv–vi) GO (control). The enhanced photoacoustic signal of the experimental group indicates that the released CO can effectively promote vasodilation. (A3)The intensity of photoacoustic signals of group 1 and control at different time points indicated the rapid therapeutic. (A4)The infarct volume of 1 mm coronal brain sections of rats at +1.5 to −0.5 mm to the Bregma, by TTC staining. (A5) Raman spectroscopy of brain slides. (A6) Raman imaging of brain slides (+0.5 mm) (i–iii and vii) Ru–CO–GO and (iv–vi and viii) GO. Scale bar: 0.4 cm. Reprinted with permission from Ref. [244]. Copyright 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. *Region of depth scan. (B1–B4): BBB crossing of magnetic nanoparticles in the magnetic field. (B1) Images of mouse brain sections treated without magnetic nanoparticles (left); with magnetic field, but without magnetic nanoparticles (middle); with magnetic fields and magnetic nanoparticles (right). Scale bar, 20 μm (B2) Relative fluorescence intensity of brain sections in B1. The enrichment of magnetic nanoparticles increased 26-fold after the treatment with the magnetic field. (B3) Confocal image of extravasation of magnetic nanoparticles in the vessels. Scale bar, 50 μm (B4) Image of brain sections showing aggregation of magnetic nanoparticles around blood vessels. Scale bar, 20 μm. Reprinted with permission from ref [56]. Copyright 2012 PERGAMON-ELSEVIER. (C1–C2): In vitro and in vivo BBB penetration of BP. (C1) bEnd.3 cell monolayer was seeded in transwells to obtain an in vitro BBB model, as shown in the inset. 48% of BP was transported from the upper chamber to the lower chamber in the control group (no bEnd.3 cell). With bEnd.3 cell monolayer, only 3.5% of BP spontaneously traversed to the lower chamber, while the delivery of BP was increased by 6-fold under the illumination. (C2) The images of mouse brains with Evans blue staining show obvious BBB crossing ability of BP under the irradiation. (1) BP (2) NIR, (3) BP + NIR. Reprinted with permission from ref [64]. Copyright 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 9

The potential application of injectable hydrogels in stroke treatment. (a) injecting bio functional hydrogels into infarcted areas can induce endogenous repair mechanisms, such as angiogenesis and neurogenesis. (b) injectable hydrogel can be used as a cell delivery carrier to provide a three-dimensional environment in the infarcted area. Then, coated exogenous cells can release therapeutic nutrients to the surrounding environment to help regeneration. (c) injectable hydrogel can be used as a reservoir for drug/biological agents in the infarct area for controlled and sustained administration. The goal of promoting regeneration includes increasing neural precursor cell migration from the SVZ, reducing inflammation and attenuating the immune response. (d) It may also be a dual function method to combine the delivery of exogenous cells and drug/biological agents. Reprinted with permission from Ref. [254]. Copyright 2019 ROYAL SOC CHEMISTRY.