Magnetic Nanoparticles in the Central Nervous System: Targeting Principles, Applications and Safety Issues

Abstract

One of the most challenging goals in pharmacological research is overcoming the Blood Brain Barrier (BBB) to deliver drugs to the Central Nervous System (CNS). The use of physical means, such as steady and alternating magnetic fields to drive nanocarriers with proper magnetic characteristics may prove to be a useful strategy. The present review aims at providing an up-to-date picture of the applications of magnetic-driven nanotheranostics agents to the CNS. Although well consolidated on physical ground, some of the techniques described herein are still under investigation on in vitro or in silico models, while others have already entered in-or are close to-clinical validation. The review provides a concise overview of the physical principles underlying the behavior of magnetic nanoparticles (MNPs) interacting with an external magnetic field. Thereafter we describe the physiological pathways by which a substance can reach the brain from the bloodstream and then we focus on those MNP applications that aim at a nondestructive crossing of the BBB such as static magnetic fields to facilitate the passage of drugs and alternating magnetic fields to increment BBB permeability by magnetic heating. In conclusion, we briefly cite the most notable biomedical applications of MNPs and some relevant remarks about their safety and potential toxicity.

Keywords: blood brain barrier; central nervous system; delivery; magnetic nanoparticles; targeting.

Figure 1

Schematic representation of two strategies for drug delivery through magnetic nano-carriers. (A) The magnetic element is the core of the nanoparticles, while the active compound is linked to the protective coating surfacing the core; (B) In this case, the magnetic element consists of a number of iron nanoparticles attached to the surface of a nano-bubble structure that can be internally loaded with drug compounds.

Figure 2

Comparison between the structure of the Blood-Brain Barrier (BBB) and the blood-CSF barrier. (Left) BBB separates the lumen of the brain capillaries from the brain parenchyma. The main contribution to the BBB property of reduced permeability comes from the tight junctions (drawn in violet) among endothelial cells lining the capillaries. The so-called neurovascular unit also comprises the pericytes, a basement membrane surrounding both pericytes and endothelial cells and astrocyte end-feet processes from nearby astrocytes. As well as the undisputed role of the tight junctions in sealing the interendothelial cleft, all the elements of the neurovascular unit are likely to contribute to some extent to the augmented selectivity of the BBB. That said, their role is still controversial; (Right) The Blood-CSF barrier is found in the choroid plexus of each ventricle of the brain. Unlike the endothelium in the brain parenchyma, capillaries of the choroid plexus have no tight junctions and are fenestrated. However, the choroid plexus is delimited overall by a monolayer of tight-junctioned epithelial cells. This particular epithelium is in direct continuity with the ependymal layer lining the ventricle, though the rest of the ependymal layer is much more permeable. Therefore, unlike the BBB, the blood-CSF barrier is located at epithelial level, while capillaries are relatively leaky and permeable to small molecules, thus allowing, among other processes, the rapid delivery of water through the bloodstream to the surrounding epithelial cells for CSF production in the choroid plexus. Similarly, to what can be found in other tissues of the body, also in the choroid plexus pericytes and a basement membrane wrap around the endothelial cells. Although in principle both the barriers serve the same defensive purpose for the CNS, their distinct structure allows the interchange of different substances between bloodstream and brain. (Upper part) Top view; (Lower part) Section view.

Figure 3

Schematic enumeration of the many pathways which a compound can use to cross the blood-brain barrier, depending on its chemico-physical properties. (A) Drugs can cross the barrier simply by passive diffusion if they are sufficiently lipid soluble (or have been made lipophilic by appropriate chemical modifications); (B) Carrier protein-Mediated active Transport (CMT) can allow many essential compounds such as glucose and amino acids to enter the endothelial cytoplasm and then be released into the brain at the abluminal side. In addition, artificial compounds mimicking those endogenous ligands have been developed to take advantage of the carrier-mediated transport mechanisms; (C) Drugs or even NPs can enter the brain through a paracellular route only when the tight junction system is disrupted. In particular, BBB permeability can be temporarily induced in several ways: by local temperature increases (38–39 °C), by osmotic alterations (e.g., infusion of hypertonic solutions of mannitol), by adenosine receptor activation, by Focused Ultrasound (FUS) bombardment or by electromagnetic radiations; (D) The binding of specific ligands to the receptors mediating the endocytosis (e.g., transferrin and insulin receptors) allows the uptake of large compounds and NPs conveniently functionalized. By a subsequent exocytosis process, vesicles can then release their content at the abluminal side (RMT); (E) If the compound has sufficient cationic charge, it can induce a localized electrostatic disruption of membrane phospholipids resulting in the so-called Adsorptive-Mediated Transcytosis (AMT); (F) If the drug is carried by NPs exhibiting magnetic properties (such as IONs) a localized magnetic field, generated by an external electromagnet, can be used to produce a driving force enabling the passage of such NPs from the bloodstream to a targeted region of the brain (through both paracellular and transcellular routes).