Magnetic Nanoparticles Cross the Blood-Brain Barrier: When Physics Rises to a Challenge

Abstract

The blood-brain barrier is a physical and physiological barrier that protects the brain from toxic substances within the bloodstream and helps maintain brain homeostasis. It also represents the main obstacle in the treatment of many diseases of the central nervous system. Among the different approaches employed to overcome this barrier, the use of nanoparticles as a tool to enhance delivery of therapeutic molecules to the brain is particularly promising. There is special interest in the use of magnetic nanoparticles, as their physical characteristics endow them with additional potentially useful properties. Following systemic administration, a magnetic field applied externally can mediate the capacity of magnetic nanoparticles to permeate the blood-brain barrier. Meanwhile, thermal energy released by magnetic nanoparticles under the influence of radiofrequency radiation can modulate blood-brain barrier integrity, increasing its permeability. In this review, we present the strategies that use magnetic nanoparticles, specifically iron oxide nanoparticles, to enhance drug delivery to the brain.

Keywords: IONs; blood-brain barrier; magnetic nanoparticles.

Figure 1

Magnetic regimes of ferromagnetic materials as a function of their size (superparamagnetic, single domain, multidomain).

Figure 2

After disrupting the blood-brain barrier (BBB), nanoparticles (NPs) can accumulate at the tumor site. Receptor-mediated endocytosis of the functionalized NPs by cells overexpressing a receptor can retain NPs inside the tumor.

Figure 3

Cellular model for checking the passage of drugs or NPs across the BBB. The Transwell filter consists of a porous membrane support submerged in a culture medium. Two different Transwell co-culture modes exist: non-contact and contact culture. In non-contact culture, the cells (for instance, brain endothelial cells and astrocytes) are co-cultured in two different compartments (insert membrane in well). In contact culture, astrocytes are first seeded onto the abluminal side of the inverted Transwell filter, and after adhering, the filter is flipped back, and the astrocytes are cultured for 2 days. At the end of the second day, brain cells are seeded onto the luminal side of the Transwell filter and co-cultured with astrocytes for an additional 3–4 days. The number of NPs is determined in both compartments. Superparamagnetic IONs (SPIONs) are depicted as red dots. The passage through the BBB model can be mediated by the effect of a magnet located underneath the plate.

Figure 4

Magnetically vectored magnetic nanoparticles (MNPs) accumulate in the brain. (A) A small magnet was implanted in the right hemisphere of the brains of mice by stereotactic injection. (Blue represents the inserted magnet and green shade represents MNPs in cartoon). One week after implantation, MNPs were administered by IV injection. Confocal analysis demonstrated accumulation of the MNPs in the ipsilateral hemisphere, whereas a background level of MNPs was found in the contralateral hemisphere. Scale bar: 500 μm. (B) Confocal analysis of coronal sections of brain demonstrated enrichment of the MNPs near the magnet. Scale bar: 100 μm. Reproduced with permission of [59]. Copyright Elsevier Science, 2012.