Progress and perspectives on targeting nanoparticles for brain drug delivery

Abstract

Due to the ability of the blood-brain barrier (BBB) to prevent the entry of drugs into the brain, it is a challenge to treat central nervous system disorders pharmacologically. The development of nanotechnology provides potential to overcome this problem. In this review, the barriers to brain-targeted drug delivery are reviewed, including the BBB, blood-brain tumor barrier (BBTB), and nose-to-brain barrier. Delivery strategies are focused on overcoming the BBB, directly targeting diseased cells in the brain, and dual-targeted delivery. The major concerns and perspectives on constructing brain-targeted delivery systems are discussed.

Keywords: Blood–brain barrier; Brain targeting; Dual targeting; Intranasal delivery; Nanoparticles.

Graphical abstract

Figure 1

Inhibition of brain tumor growth in NRG-SCID mice. (A) Treatment schedule with saline (200 μL), doxorubincin (Dox) (10 mg/kg; 200 μL), or Dox-loaded NPs (10 mg/kg Dox; 200 μL). Treatments were administered on day 0 and 14. (B) In vivo images of brain tumor bioluminescence. (C) Fold increase in the average tumor radiance as measured by in vivo bioluminescence imaging. Data presented as mean±SEM (n=5 for saline; n=7 for free Dox and Dox-NP). Statistical significance of P<0.05 denoted by asterisk (*). This study demonstrated that polysorbate 80 modification could enhance the brain-targeted delivery of NPs, resulting in an improved anti-brain tumor effect. Reprinted from Ref. with permission of the copyright holder, American Chemical Society. Dox, doxorubicin; NP, nanoparticle.

Figure 2

Schematic illustration of paclitaxel (PTX)-loaded R8-RGD-modified liposomes (PTX-R8-RGD-lipo). Liposomes could specifically bind to integrin α_vβ₃ receptors expressed on brain capillary endothelial cells and be transported across the blood–brain barrier (BBB) through a synergistic effect. Liposomes could accumulate in the glioma tissue selectively, penetrate into the core region of tumor and release drug. Reprinted from Ref. with permission of the copyright holder, Elsevier, Amsterdam.

Figure 3

Brain drug delivery via nanoagonist (NA)-mediated adenosine receptor signaling. (A) In vivo SPECT/CT images of mouse brain when radioactive model drug (3.7×10⁷ Bq/mouse) was injected at 30 min postinjection (PI) of 10 nmol NA, regadenoson (Reg), or saline via i.v. Confocal fluorescence microscopic images of brain sections presenting cortex, striatum, and cerebellum areas when model drug was injected at 30 min PI of dendrimer (Den)-Reg16 (B) or Den-PEG (C). CD31 immunofluorescence indicating brain vasculature is displayed in green; model drug is displayed in red and DAPI-stained nuclei are blue. Yellow areas present the co-localized vessel and model drugs. Arrows point to the leaky vessels, and arrowheads point to the extravasated model drug. Scale bar, 50 μm. This study demonstrated that the administration of nanoagonists could temporarily open BBB and improve the brain-targeted delivery of several model drugs. Reprinted from Ref. with permission of the copyright holder, American Chemical Society. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Figure 4

In vivo and ex vivo imaging. (A) Fluorescent imaging of glioma-bearing mice 2 h after administered DiR-loaded IL-13p-modified NPs (ILNPs). (B) Fluorescent imaging of glioma-bearing mice 2 h after administration of DiR-loaded NPs. (C) Ex vivo imaging of brains 2 h after administration of DiR-loaded ILNPs and NPs. (D) Semi-quantitative results of fluorescence intensity of gliomas, ^**P<0.01 vs. control. This study demonstrated that modification with IL-13p could specifically enhance the brain tumor–targeting delivery of NPs. Reprinted from Ref. with permission of the copyright holder, Huile Gao.

Figure 5

(A) The in vivo imaging of DiR-loaded NPs, AS1411 conjugated NPs (AsNPs), AsTNPs and TGN modified NPs (TNP) in the brain glioma-bearing nude mice at several time points with ex vivo imaging of the brain at 24 h. (B) Brain and glioma fluorescent intensity at 24 h. (C) The T/N ratio of the brains 24 h after treatment with different formulations. This study demonstrated that the dual targeting delivery strategy could not only increase the brain targeting efficiency but also improve the selectivity to brain tumor cells. Reprinted from Ref. with permission of the copyright holder, Elsevier, Amsterdam.