Targeting with nanoparticles for the therapeutic treatment of brain diseases

Abstract

Brain diseases including neurodegenerative disorders and tumours are among the most serious health problems, degrading the quality of life and causing massive economic cost. Nanoparticles that load and deliver drugs and genes have been intensively studied for the treatment of brain diseases, and have demonstrated some biological effects in various animal models. Among other efforts taken in the nanoparticle development, targeting of blood brain barrier, specific cell type or local intra-/extra-cellular space is an important strategy to enhance the therapeutic efficacy of the nanoparticle delivery systems. This review underlies the targeting issue in the nanoparticle development for the treatment of brain diseases, taking key exemplar studies carried out in various in vivo models.

Keywords: Brain diseases; blood brain barrier; in vivo models; nanoparticles; targeting.

Figure 1.

Nanoparticles with targeting ability used for the brain diseases. Nanoparticles circulating in a blood stream (a) need to cross BBB (b), and then localize to target cells (e.g. neuron, astrocyte, oligodendrocyte, microglia, tumour cells) (c), and sometimes target cellular organelles (e.g. mitochondria, synaptic cleft) (d) or extracellular molecules (e.g. amyloid beta plaques in Alzheimer’s disease) (e).

Figure 2.

Targeting BBB: (a) Engineered IDUA proteins introduce LRP1-mediated endocytosis in genetically modified cell lines. Diagram of modified human IDUA proteins (hIDUA) fused in-frame with the myc-tag and the receptor-binding domain of apoB or various peptides from apoE (apoE*). (b–d) Liver-generated IDUA fusion proteins in the circulation can be transported into the CNS and normalize the accumulation of GAG in the brain of MPS I mice. Whole brains were collected from well perfused animals 2 days after hydrodynamic injection. Samples were stained with antibodies against IDUA protein (green) and endothelial marker (CD31; red) (b), terminally differentiated neuron marker (NeuN; red) (c), or astrocyte marker (GFAP; red) (d). Reproduced with permission from Wang et al.

Figure 3.

Targeting neurons with lipid nanocarrier Squalenoyl adenosine: (A) Squalenoyl adenosine (SQAd) was prepared in a three-step synthesis, and the SQAd nanoassemblies were obtained by nanoprecipitation. (B) Ischaemic volumes in control and treated mice subjected to transient (2 h MCAo and 22 h reperfusion) and permanent (24 h MCAo) focal cerebral ischaemia were identified by reduced Nissl staining under a light microscope. A significant therapeutic effect was also observed when SQAd nanoassemblies were administered 2 h post-ischaemia in the permanent MCAo model. (C) The pharmacological efficiency of the SQAd nanoassemblies was assessed in a T9 contusion SCI model. After 72 h, the SQAd nanoassemblies-injected animals showed a complete recovery of their hindlimbs, in accordance with the absence of visible traumatic area on the cord (C, c) compared with the trauma group (C, a) and the adenosine-treated group (C, b). Reproduced with permission from Gaudin et al.

Figure 4.

Targeting of glia cells with LIF-NP through STAT-3 signalling in OPC: (a) Composition of PLGA-based NP with embedded LIF and surface avidin for attachment of biotinylated targeting antibody. (b) OPC mature into OD in response to NG2-targeted LIF-NP. Reproduced with permission from Rittchen et al.

Figure 5.

Targeting microglial activation state as an anti-inflammatory strategy in neuro-inflammatory diseases: (a) Synthesis and characterization of the D-NAC conjugate. Reaction schematic for the synthesis of the dendrimer-NAC (D-NAC) conjugate 1, starting from the free dendrimer and free NAC. (b) Inflammation on day 5 after treatment on day 1. NF-κB and TNF-α mRNA levels in the PVR of the brain. Western blot of NF-κB p65 expression was quantified and normalized to b-actin. TNF-α mRNA was quantified and normalized to GAPDH expression. (c) The periventricular white matter regions of rabbit kits on day 5 of life were stained for all microglia with tomato lectin (red) and for pro-inflammatory microglia with anti-CD11b antibody (green). Reproduced with permission from Kannan et al.

Figure 6.

Targeting brain tumours with NP: (a) Preparation of cRGD-peptide installed epirubicin-loaded polymeric micelles from a mixture (1:3) of cRGD-poly(ethylene glycol)-b-poly(hidrazinyl-aspartamide) and MeO-poly(ethylene glycol)-b-poly (hidrazinyl-aspartamide) polymer. (b) Penetration of epirubicin-loaded micelles (Epi/m) and cRGD-installed Epi/m (cRGD-Epi/m) in U87MG spheroids. Red: Fluorescence from epirubicin. (c) Antitumor activity against bioluminescent orthotopic U87-MG-luc tumours in mice injected with PBS, Epi, Epi/m and cRGD-Epi/m. Reproduced with permission from Quader et al.

Figure 7.

Targeting mitochondria with NP: (a) Design, synthesis and ROS recyclable scavenging activity of TPP-ceria nanoparticles as a therapeutic mitochondrial antioxidant for Alzheimer’s disease. (b) TPP-ceria NPs significantly inhibit Aβ-induced mitochondrial ROS in SH-SY5Y cells. (c) TPP-ceria NPs reduce reactive glial activation. Reproduced with permission from Kwon et al.

Figure 8.

Targeting neurotransmitter receptors with NP: (A) Design of hybrid nanostructured antagonist of AuM for exclusive inhibition of eNMDARs. (B) AuM is an efficient antagonist of NMDARs as demonstrated by representative calcium imaging traces from cerebrocortical neurons activated by 200 μM NMDA and inhibited by 10 nM AuM (left) or 10 μM memantine (right) (B, a), whereas AuM is not effective in inhibiting glutamatergic synaptic activity as demonstrated by representative calcium imaging traces in spontaneously active neurons in the presence of 10 nM AuM (left) and 10 μM free memantine (right) (B, b). Reproduced with permission from Savchenko et al.

Figure 9.

Targeting amyloid beta (Aβ): (A) The evaluation of the binding affinity of rHDL and GM1-rHDL to Aβ_1-42 monomers and oligomers by surface plasmon resonance analysis. (A, a and A, c) Binding of rHDL and GM1-rHDL to Aβ_1-42 monomers, respectively. (A, b and A, d) Binding of rHDL and GM1-rHDL to Aβ_1-42 oligomers, respectively. (B) Effects of rHDL and GM1-rHDL on the intracellular distribution, and degradation of Aβ_1-42 in microglia. Colocalization of FAM-Aβ_1-42 with DiI-rHDL or DiI-GM1-rHDL after 4 h of co-incubation. Arrow: FAM-Aβ_1-42 colocalized with GM1-rHDL. (C) αNAP-GM1-rHDL reduced Aβ deposition (brown signals as indicated by arrowheads) in the hippocampus of AD model mice. AD model mice were daily intranasally administrated with rHDL, GM1-rHDL and αNAP-GM1-rHDL at the lipid dose of 5 mg/kg for 2 weeks. The brain sections were immunostained with anti-Aβ antibody 6E10. Reproduced with permission from Huang et al.