Nanomaterial-based blood-brain-barrier (BBB) crossing strategies

Abstract

Increasing attention has been paid to the diseases of central nervous system (CNS). The penetration efficiency of most CNS drugs into the brain parenchyma is rather limited due to the existence of blood-brain barrier (BBB). Thus, BBB crossing for drug delivery to CNS remains a significant challenge in the development of neurological therapeutics. Because of the advantageous properties (e.g., relatively high drug loading content, controllable drug release, excellent passive and active targeting, good stability, biodegradability, biocompatibility, and low toxicity), nanomaterials with BBB-crossability have been widely developed for the treatment of CNS diseases. This review summarizes the current understanding of the physiological structure of BBB, and provides various nanomaterial-based BBB-crossing strategies for brain delivery of theranostic agents, including intranasal delivery, temporary disruption of BBB, local delivery, cell penetrating peptide (CPP) mediated BBB-crossing, receptor mediated BBB-crossing, shuttle peptide mediated BBB-crossing, and cells mediated BBB-crossing. Clinicians, biologists, material scientists and chemists are expected to be interested in this review.

Keywords: Blood-brain barrier (BBB); Central nervous system (CNS); Drug delivery systems; Nanomaterials.

Figure 1.

Schematic illustration of the BBB.

Figure 2.

Permeation mechanism of the BBB.

Figure 3.

(A) The models for studying the BBB crossing of nanocarriers. (B) Building process for in vivo BBB models.

Figure 4.

Delivery of nanoparticles to the brain detected by fluorescence microscopy [110]. (A) Size distribution of PBCA nanoparticles determined by dynamic light scattering. (a) FITC-dextran-loaded nanoparticles, (b) rhodamine-123-loaded nanoparticles, (c) doxorubicin-loaded nanoparticles. (B) Cerebral distribution of administrated FITC-dextran-loaded nanoparticles through the carotic artery in the brain of rat. (a) Uncoated nanoparticles and administration of Tween 80-coated PBCA nanoparticles at (b) 20 min with fluorescence mainly shown in the lumina of brain capillaries, (c) 30 min with nanoparticles fluorescence mainly shown in brain capillary endothelial cells, and (d) 60 min with fluorescence spread distributed in brain, which indicates the BBB-crossing of nanoparticles. (C) Cerebral distribution of administrated rhodamine-123 labelled nanoparticles through a tail vein in the brain of rat. (a) no fluorescence signal in brain could be observed at 60 and 120 min after administration of uncoated PBCA nanoparticles (one time point was shown). (b) Fluorescence signal can be observed in the brain capillary lumen, the endothelial cells and the perivascular brain tissue at 60 min after administration of polysorbate 80-coated nanoparticles. Including, the red circles indicated the identified nanoparticles. (c) The fluorescence signal could be observed throughout the brain tissue after nanoparticles has been administrated for 2 hours. Copyright 2008, Elsevier.

Figure 5.

Drug delivery to the brain with intranasal administration (A) Schematic of the drug delivery to the brain from the nasal cavity. (B) concentration-time profile of OND loaded NLC in (a) Blood and (b) Brain with intranasal and intravenous administration (n = 3). Higher concentration of OND loaded NLC in brain with intranasal administration than that of intravenous administration [113]. Copyright 2014, Elsevier. (C) Maximum possible effect (MPE %) of antinociceptive effect by loperamide in mouse with administration of PLGA and R8-PLGA nanoparticles (a) intranasally and (b) intravenously. R8-PLGA versus control, i.n. P < 0.05 and i.v. P < 0.05 at t = 60 min [112]. Copyright 2015, Wiley-blackwell. (D) Lamotrigine (LTG) concentrations up to 4 h post-dosing in plasma and different brain regions of mice after intranasal (IN) and intravenous (IV) administration (4 mg/kg, n = 4). Statistical significant differences between IN and IV administrations are marked with (*) for p < 0.05, (#) for p < 0.01 and (§) for p < 0.001. After IN administration, higher LTG concentrations in the olfactory bulb relatively to other areas of the brain was found, which indicates a potential direct nose-to-brain transport pathway for IN administration of LTG [117]. (E) Relationship between tissue-to-plasma and tissue-to-remaining portion in the brain of mice with LTG concentration ratios obtained at 0.083 h and 0.167 h after IN and IV administration (4 mg/kg). Including, B/P is remaining portion of the brain / plasma ratio; FC/B is frontal cortex / remaining portion of the brain; FC/P is frontal cortex / plasma ratio; OB/B is olfactory bulb / remaining portion of the brain ratio; OB/P is olfactory bulb / plasma ratio. The result indicates that a direct transport from nose to brain for LTG may be involved [117]. Copyright 2015, Elsevier.

Figure 6.

BBB disruption: (A) The transgene expression of TPP1 affected by the increasing mannitol induced BBB disruption was shown in immunoperoxidase staining images. Each mouse was administrated with 3.18×10¹⁰ gc of AAVrh.10CLN2 after (a) 125 μl, (b) 250 μl, (c) 500 μl, or (d) 750 μl of mannitol, respectively. At 125 μl, no transgene expression is seen. At 250 μl, some transgene expression production can be seen in deeper brain structures and increasing staining production could be observed in cortical structures with the mannitol dose reaching to 500 μl and 750 μl [121]. Copyright 2014, Elsevier. (B) Schematic synthetic protocol of ultrasmall superparamagnetic iron oxide-loaded microbubbers (USPIO-MB) [133]. (C) Extravasation and penetration of FITC-dextran (green). FITC-dextran extravasation crossing the rhodamine lectin-stained vessels (red) as shown in 2D fluorescence (2D-FM) and 3D two-photon microscopy (3D-2PM) images, which indicating efficient transport of macromolecular drug crossing the BBB with the combination of USPIO-MB within 5 and 30 min of US [133]. Copyright 2015, Wiley-blackwell.

Figure 7.

A multitheragnostic nanobubble system to induce BBB disruption with magnetically guided (MG) focused ultrasound. (A) Schematic diagram of the experimental setup to demonstrate the concept of disrupting the BBB with the locally accumulated magnetically guidable theranostic nanobubbles (MNBs) in a specific brain area after applying magnetic guidance in vivo and the local accumulation of MNBs in the vasculature to perform dual targeting of the BBB disruption. (B) The schematic of the synthesis of MNBs and the interfacial structure of the SPIO/silica. (a) The fabrication procedure involved a mixture of silane monomers of TEOS, OTES, and APTES. (b) Monodispersed positively charged PS particles were mixed with negatively charged SPIO, and then (c) a silica shell was grown onto the PS core particles and mixed with SPIO nanoparticles. (d) Hollow MNBs formed after treatment with THF overnight. (e) The silica shell presented as a nanoporous structure with embedded SPIO nanoparticles. (f) The OTES was very compatible with the oleic acid-conjugated SPIO and the OTES polymerized with TEOS to form the shell on the PS core. (C) (a) and (b) represents the efficiency of MG on 500 nm MNB-mediated FUS-BBB disruption as evaluated by the representative images of T2* gradient echo coronal sections and their corresponding EB dye-stained images, the scale bar is 1 cm. Representative images of T2*-MRI sections and their corresponding H&E stained slices were used to investigate the BBB permeability and hemorrhagic damage from c) MG-assisted FUS-exposure with 2000 nm MNBs, d) 1000 nm MNBs. e) 500 nm MNBs, and f) 200 nm MNBs, respectively. Including, tissue destruction and hemorrhage were found in the mouse striatum where SPIO-embedded 2000 nm, 1000 nm, and 500 nm MNBs [132]. Copyright 2015, Wiley-blackwell.

Figure 8.

Transportation of nanoparticles into CNS with CED infusions. (A) the implanted cannula guide cylinders were shown in 3D MR image (left and the tip of the reflux-resistant injection cannula was shown in photography (right). (B) the growing distribution volume of the viral vector during the medial thalamic infusion in NHP-H as shown in a set of real-time MR images of coronal sections. (C) Showing the reconstruction (red) of the MR volume of the spread of viral vector with CED infusion [142]. Copyright 2018, Elsevier. (D)Real-time (14 min) MRI convection-enhanced delivery in the NHP cerebellum with infusion of AAV5-GFP/Gd, shown as hyper-intense regions indicative of MRI contrast, denote placement of cannula tip within the cerebellar cortex. Obvious increase in infusate size was obtained accompanying with the extending of infusion time and increasing of delivered volume [144]. Copyright 2018, Mary Ann Liebert.

Figure 9.

CPP-mediated transportation of nanoparticles across BBB. (A) preparation schematic of stealth magnetic PLGA/Lipid nanoparticles (MPLs) with conjugation of TAT peptide onto MPLs. (B) Localization of QDs encapsulated TAT peptide modified MPLs in brain endothelial cells. Cells were cultured in FITC-labeled QDs-loaded NPs-containing medium for 0.5, 3, and 12 h, respectively, and DAPI treating was performed for these cells before observation with a confocal microscopy. High fluorescence signal was observed in the cytoplasm and cell nucleus for the sample administrated with TAT-MPLs, which indicates effective delivery of QDs to bEnd.3 cells for these nanoparticles. (C) Quantitation of QD-loaded FITC-MPLs and QD-loaded FITC-TAT-MPLs in brain endothelial cells. Cells were cultured in a 24-well plate for lysed, and the fluorescence intensity of FITC (a) and QDs (b) in cells were measured with a microplate spectrophotometer at 0.5 h, 3 h, and 12 h, respectively. conjugation of TAT peptide on MPLs could significantly improve the cellular uptake of cargoes in bEnd.3 cells through penetrating the cell membrane. This is a promising strategy in designing nanocarriers for crossing the BBB and transporting drugs into the CNS [158]. Copyright 2014, Public Library of Science.

Figure 10.

Receptor-mediated nanoparticles crossing the BBB. (A) The transportation mechanism of Tf-containing gold nanoparticles with an acid-cleavable linkage across the BBB and preparation of acid-cleavable Tf/Ab-DAK-PEG-OPSS ligand and the targeted gold nanoparticles. Disruption of the linkage between Tf and the nanoparticle core after being uptake by brain endothelial cells through endocytosis pathway due to the acidification in the endosome, which enable the free transport of the nanoparticle into the CNS across BBB. (B) The percentage of various nanoparticles reaching the basal well of bEnd.3 coated transwells 8 h after administration. 120Tf-C and 200Tf-C show greater ability to cross the transwells compared with 200Tf-N, whereas both Ab-C nanoparticles did not show a significant increase compared with equivalent Ab-N formulations. (C) The percentage of Tf-containing nanoparticles crossed the BBB model over time. Note that most crossing behavior happened within the first 2 h for all Tf-C nanoparticles. *P < 0.001. (D) The gold nanoparticles accumulated in the brain parenchyma were evaluated with silver enhancement of brain sections. The result indicates that addition of acid-cleavable linkage DAK could improve the transport effective of high-avidity Tf-containing nanoparticles entering into the brain [167]. Copyright 2015, National Academy of Sciences.

Figure 11.

(a): Design and synthesis of the Fenton-reaction-acceleratable magnetic nanoparticles, i.e., cisplatin-loaded Fe₃O₄/Gd₂O₃ hybrid nanoparticles with conjugation of LF and RGD2 (FeGd-HN@Pt@LF/RGD2). (b): Mechanism illustration for the ferroptosis therapy (FT) of orthotopic brain tumors with self-MRI-monitoring [175]. Copyright 2018, American Chemical Society.

Figure 12.

Glucose transporter isoform 1 (GLUT1) mediated BBB-crossing for nanodevices. (A)The mechanism of the smart therapeutic nanocarrier with cooperative dual characteristics of high tumor-targeting ability and selectively controlling drug deposition in tumor cells was developed. The disulfide linkage contributes a reductive-sensitive characteristic for the nanodevice, which shield the loaded drug from leaking in blood. Dehydroascorbic acid (DHA) was modified on the surface of nanodevice for tumor-specific targeting via binding to GLUT1, a glucose transporter abundant expressed on tumor cells. (B) Different transportation characteristics of D-glucose and DHA by GLUT 1. A “two-way” transportation of D-glucose to keep its stable concentration in cells. DHA rapidly reduced to ascorbate, which effectively is “trapped” within the cell. (C) The Kaplan-Meier survival curves and body weight of glioma-bearing mice treated with different PTX formulations at days 12, 15, and 18 postimplantation (n = 15), which indicates that this nanodevice could be a promising potential platform for the treatment of glioma [200]. Copyright 2014, American Chemical Society.

Figure 13.

The BBB shuttle peptides mediated BBB-crossing. (A) Ex vivo imaging of dissected tissues of different organs and the fluorescence intensity of brain in the mice 8 h after injection of plain liposomes, ^LCDX-liposomes, and ^DCDX-liposomes, respectively. (B) Kaplan-Meier survival curves of intracranial U87 glioblastoma beared mice, which shows that the mice administrated with DOX-loaded ^DCDX or ^LCDX-liposomes survived much longer than the control groups that administrated with saline, free DOX, and DOX-loaded plain liposome. These results showed that ^DCDX transport could be developed as a good shuttle for brain targeted drug delivery [207]. Copyright 2015, Wiley-VCH. (C) MiniAp-4 was designed as a BBB shuttle. a) MiniAp-4 was conjugated onto the protein and nanoparticles as a shuttle. b) the permeability of MiniAp-4 modified protein and nanoparticles was improved comparing with that of non-MiniAp-4 modification in the human-cell-based in vitro BBB model (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001). + + indicates the quantification limit. c) higher fluorescence signal (green) was shown in the representative confocal microscopy images of brain slices in mice administrated with Cy5.5–MiniAp-4 (top) than that of Cy5.5–CA (bottom). Scale bars represent 10 mm [204]. Copyright 2016, Wiley-VCH. (D). CF signal in RBE4 cells with incubation of (a): GSH-PEG liposomes at 37°C, (b): PEG liposomes at 37 °C, (c): GSH-PEG liposomes at 4 °C, respectively. More uptake of the GSH-PEG liposomes in cells comparing with that of PEG liposomes at 37 °C was obtained as conformed from the fluorescent signal due to the targeting effect of GSH. Moreover, the decreased uptake at 4 °C demonstrates an active uptake mechanism for the GSH-included liposome [209]. Copyright 2014, Taylor & Francis.