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

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          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.

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          Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors.

          This study explored the possibility of utilizing iron oxide nanoparticles as a drug delivery vehicle for minimally invasive, MRI-monitored magnetic targeting of brain tumors. In vitro determined hydrodynamic diameter of approximately 100 nm, saturation magnetization of 94 emicro/g Fe and T2 relaxivity of 43 s(-1)mm(-)(1) of the nanoparticles suggested their applicability for this purpose. In vivo effect of magnetic targeting on the extent and selectivity of nanoparticle accumulation in tumors of rats harboring orthotopic 9L-gliosarcomas was quantified with MRI. Animals were intravenously injected with nanoparticles (12 mg Fe/kg) under a magnetic field density of 0 T (control) or 0.4 T (experimental) applied for 30 min. MR images were acquired prior to administration of nanoparticles and immediately after magnetic targeting at 1h intervals for 4h. Image analysis revealed that magnetic targeting induced a 5-fold increase in the total glioma exposure to magnetic nanoparticles over non-targeted tumors (p=0.005) and a 3.6-fold enhancement in the target selectivity index of nanoparticle accumulation in glioma over the normal brain (p=0.025). In conclusion, accumulation of iron oxide nanoparticles in gliosarcomas can be significantly enhanced by magnetic targeting and successfully quantified by MR imaging. Hence, these nanoparticles appear to be a promising vehicle for glioma-targeted drug delivery.
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            Wireless magnetothermal deep brain stimulation.

            Wireless deep brain stimulation of well-defined neuronal populations could facilitate the study of intact brain circuits and the treatment of neurological disorders. Here, we demonstrate minimally invasive and remote neural excitation through the activation of the heat-sensitive capsaicin receptor TRPV1 by magnetic nanoparticles. When exposed to alternating magnetic fields, the nanoparticles dissipate heat generated by hysteresis, triggering widespread and reversible firing of TRPV1(+) neurons. Wireless magnetothermal stimulation in the ventral tegmental area of mice evoked excitation in subpopulations of neurons in the targeted brain region and in structures receiving excitatory projections. The nanoparticles persisted in the brain for over a month, allowing for chronic stimulation without the need for implants and connectors.
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              Iron Oxide Nanoparticles for Magnetically-Guided and Magnetically-Responsive Drug Delivery

              In this review, we discuss the recent advances in and problems with the use of magnetically-guided and magnetically-responsive nanoparticles in drug delivery and magnetofection. In magnetically-guided nanoparticles, a constant external magnetic field is used to transport magnetic nanoparticles loaded with drugs to a specific site within the body or to increase the transfection capacity. Magnetofection is the delivery of nucleic acids under the influence of a magnetic field acting on nucleic acid vectors that are associated with magnetic nanoparticles. In magnetically-responsive nanoparticles, magnetic nanoparticles are encapsulated or embedded in a larger colloidal structure that carries a drug. In this last case, an alternating magnetic field can modify the structure of the colloid, thereby providing spatial and temporal control over drug release.

                Author and article information

                Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry
                21 December 2017
                January 2018
                : 23
                : 1
                [1 ]Department of Neuroscience, University of Turin, 10124 Turin, Italy; federico.dagata@ 123456unito.it (F.D.); federicoalessandro.ruffinatti@ 123456unito.it (F.A.R.); silvia.boschi@ 123456unito.it (S.B.); innocenzo.rainero@ 123456unito.it (I.R.)
                [2 ]Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, 50139 Florence, Italy
                [3 ]Department of Clinical and Biological Sciences, University of Turin, 10124 Turin, Italy; ilaria.stura@ 123456unito.it
                [4 ]Department of Chemistry, University of Turin, 10124 Turin, Italy; ornella.abollino@ 123456unito.it
                [5 ]Department of Drug Science and Technology, University of Turin, 10124 Turin, Italy; roberta.cavalli@ 123456unito.it
                Author notes
                [* ]Correspondence: caterina.guiot@ 123456unito.it ; Tel.: +39-011-670-8166

                These authors contributed equally to this work.

                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).



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