Brain Targeting Nanomedicines: Pitfalls and Promise

Abstract

Brain diseases are the most devastating problem among the world's increasingly aging population, and the number of patients with neurological diseases is expected to increase in the future. Although methods for delivering drugs to the brain have advanced significantly, none of these approaches provide satisfactory results for the treatment of brain diseases. This remains a challenge due to the unique anatomy and physiology of the brain, including tight regulation and limited access of substances across the blood-brain barrier. Nanoparticles are considered an ideal drug delivery system to hard-to-reach organs such as the brain. The development of new drugs and new nanomaterial-based brain treatments has opened various opportunities for scientists to develop brain-specific delivery systems that could improve treatment outcomes for patients with brain disorders such as Alzheimer's disease, Parkinson's disease, stroke and brain tumors. In this review, we discuss noteworthy literature that examines recent developments in brain-targeted nanomedicines used in the treatment of neurological diseases.

Keywords: blood-brain barrier; brain delivery; cancer; nanoparticle; neurodegenerative diseases; stroke; targeted delivery.

Figure 1

Schematic structure of the blood-brain barrier (BBB) (A) and transport mechanisms of nanoparticles (NPs) through the BBB (B). NPs can cross the BBB by paracellular pathway, passive transcellular diffusion, carrier-mediated transport, receptor-mediated transcytosis, adsorptive-mediated transcytosis, and cell-mediated transport.

Figure 2

Application of nanomaterials against Alzheimer’s diseases. (A) W20/XD4-SPION attenuated Aβ pathology in the brains of AD mice. Adapted from Liu X-G, Zhang L, Lu S, et al. Superparamagnetic iron oxide nanoparticles conjugated with Aβ oligomer-specific scFv antibody and class A scavenger receptor activator show therapeutic potentials for Alzheimer’s Disease. J Nanobiotechnology. 2020;18(1):160. Creative Commons. Schematic illustration and morphology (TEM, scale bar 50 nm) of W20/XD4-SPION (left). 6E10 immunostaining for plaques in the brains of AD mice treated with SPION reduced Aβ burden (right). Scale bars 400 μm. (B) Significantly reduced Aβ deposition after treatment by curcumin-loaded and decorated with BBB-crossing (CRTIGPSVC) and Aβ targeting (QSHYRHISPAQV) peptides SPION in double transgenic mice (APP/PS1 mice). Adapted from Ruan Y, Xiong Y, Fang W, et al. Highly sensitive Curcumin-conjugated nanotheranostic platform for detecting amyloid-beta plaques by magnetic resonance imaging and reversing cognitive deficits of Alzheimer’s disease via NLRP3-inhibition. J Nanobiotechnol. 2022;20(1):322. Creative Commons. (C) Schematic illustration and TEM image of the MCPZFS NPs; scale bar: 200 nm (left). MCPZFS NP treatment could significantly attenuate cognitive and memory impairment of AD transgenic mice as demonstrated by Morris water maze test (middle and right). Adapted from Liu R, Yang J, Liu L, et al. An “Amyloid-β Cleaner” for the Treatment of Alzheimer’s Disease by Normalizing Microglial Dysfunction. Adv Sci (Weinh). 2019;7(2):1901555. Creative Commons. Data are presented as the mean ± SD. *P < 0.05, ***P < 0.001.

Figure 3

Application of nanomaterials against Alzheimer’s diseases. (A) Schematic diagram of mannose-guided nanoparticles (NPs) reaching the brain via oral administration and (B) organ biodistribution of (a) only PEGylated NPs, (b) mannose functionalized NPs and (c) mannose functionalized in combination with glucose control strategy by administering glucose 1 h after NP administration. Reprinted from Lei T, Yang Z, Jiang C, et al. Mannose-Integrated Nanoparticle Hitchhike Glucose Transporter 1 Recycling to Overcome Various Barriers of Oral Delivery for Alzheimer’s Disease Therapy. ACS Nano. 2024;18(4):3234–3250. Copyright © 2024 American Chemical Society. By implementing a glucose control strategy, NP accumulation at AD lesions was enhanced, resulting in highly efficient oral brain-targeting. (C-D) Delivery of the nerve growth factor (NGF) gene through the blood–brain barrier resulted in a notable reduction in Aβ accumulation in mice with Alzheimer’s disease (AD) carrying the APP/PS1 mutation. Liposomes decorated with penetratin and transferrin (PenTf), exhibited effective transfection capabilities. This formulation demonstrated a remarkable capacity to significantly decrease Aβ levels in the brains of APP/PS1 mice. Reprinted from Rodrigues BDS, Kanekiyo T, Singh J. Nerve growth factor gene delivery across the blood–brain barrier to reduce beta amyloid accumulation in AD mice. Mol Pharm. 2020;17(6):2054–2063. Copyright © 2020 American Chemical Society. Data are expressed as mean ± SEM (n = 14/group). Statistically significant differences (p < 0.05) are shown as (*). (E) Liposomes decorated with rabies virus glycoprotein peptide (CCP) and mannose showcased exceptional permeability across the blood-brain barrier (BBB) for gene delivery. Following a single tail vein administration in C57BL/6 mice, these specialized liposomes demonstrated a remarkable twofold increase in Apolipoprotein E expression in the brain. Reprinted from Arora S, Layek B, Singh J. Design and validation of liposomal ApoE2 gene delivery system to evade blood–brain barrier for effective treatment of Alzheimer’s disease. Mol Pharm. 2021;18(2):714–725. American Chemical Society.

Figure 4

Application of brain-targeted nanomedicines for brain cancer. (A) L-histidine (His) functionalized and pH-responsive acid-cleavable angiopep-2 (ANG2) NPs showed superiors BBB-permeability and brain accumulation in comparison to non-functionalized or non-cleavable NPs. Adapted from Martins C, Araújo M, Malfanti A, et al. Stimuli-Responsive Multifunctional Nanomedicine for Enhanced Glioblastoma Chemotherapy Augments Multistage Blood-to-Brain Trafficking and Tumor Targeting. Small. 2023;19(22):2300029. © 2023 The Authors. Small published by Wiley-VCH GmbH. (B) Schematic illustration of the biomimetic nanomedicine penetrating the BBB and targeting the tumor site via the specific recognition of apolipoprotein E peptide and the multiple low-density lipoprotein receptor (eg, LDLR, LRP1, and LRP2) overexpressed in the BBB endothelial cells and glioblastoma (GBM) cells (upper). Evaluation of the tumor inhibition rate after five successive injections of NPs (bottom). Data are presented as the mean ± SD (*p < 0.05 and ***p < 0.001). Adapted from He W, Li X, Morsch M, et al. Brain-Targeted Codelivery of Bcl-2/Bcl-xl and Mcl-1 Inhibitors by Biomimetic Nanoparticles for Orthotopic Glioblastoma Therapy. ACS Nano. 2022;16(4):6293–6308. Copyright © 2022 American Chemical Society. (C) Angiopep-2-conjugated hybrid nanovehicles targeted glioma cells and delivered arsenic trioxide reducing necrosis of tumor tissue in the brain. Reprinted from Tao J, Fei W, Tang H, et al. Angiopep-2-conjugated “core–shell” hybrid nanovehicles for targeted and pH-triggered delivery of arsenic trioxide into glioma. Mol Pharm. 2019;16(2):786–797. Copyright © 2019 American Chemical Society.

Figure 5

Brain-targeted nanomedicines against stroke. (A) Schematic illustration of brain-targeted micelles releasing a long PEG chain to expose triphenylphosphine at pH 5.0 (upper). By T2-weighted magnetic resonance imaging (MRI), the recovery of brain injury was remarkably enhanced after treatment with resveratrol-loaded micelles, reducing the infarct area by 65.7% than in the saline group (bottom). Adapted from Wang Z, Pan J, Yuan R, Chen M, Guo X, Zhou S. Shell-Sheddable Polymeric Micelles Alleviate Oxidative Stress and Inflammation for Enhanced Ischemic Stroke Therapy. Nano Lett. 2023;23(14):6544–6552. Copyright © 2023 American Chemical Society. Data are presented as mean ± SD. One-way ANOVA was used to calculate P values (*P < 0.05, **P < 0.01, ***P < 0.001). (B) The nanocarrier composed of a dextran polymer core modified with ROS-responsive boronic ester (PHB) and a red blood cell (RBC) membrane shell with stroke homing peptide (SHp) inserted (scheme design upper panel), enhance targeting of ischemic area and reduce ischemic brain damage (lower panel). Adapted from Lv W, Xu J, Wang X, Li X, Xu Q, Xin H. Bioengineered boronic ester modified dextran polymer nanoparticles as reactive oxygen species responsive nanocarrier for ischemic stroke treatment. ACS nano. 2018;12(6):5417–5426. Copyright © 2018 American Chemical Society. Statistical analysis used one-way ANOVA test (**P < 0.01). (C) Ceria NPs, which were loaded with edaravone and modified with Angiopep-2 and PEG on their surface (E-A/P-CeO2), demonstrated great intracephalic uptake, and ability to prevent the injuries on both brain tissues and BBB in strokes. Adapted from Bao Q, Hu P, Xu Y, et al. Simultaneous blood–brain barrier crossing and protection for stroke treatment based on edaravone-loaded ceria nanoparticles. ACS Nano. 2018;12(7):6794–6805. Copyright © 2018 American Chemical Society.