2129Nanomedicine (Lond.) (2015) 10(14), 2129–2131 ISSN 1743-5889

part of

Editorial

10.2217/NNM.15.85 © 2015 Future Medicine Ltd

Nanomedicine (Lond.)

Editorial 2015/06/3010

14

2015

Keywords:  alternating magnetic field • blood–brain barrier • drug delivery • hyperthermia • induction heating • magnetic nanoparticles 

The blood–brain barrier (BBB) prevents the entry of 98% of drugs to the CNS, which poses an enormous challenge for cerebral disease treatment. A study now demonstrates a new safe technique to temporally open the BBB and deliver drugs into the CNS.

The demanding function of the neural tis-sue in the brain requires an extremely stable environment. In fact, any small change in the composition of the interstitial fluid in the CNS plays a predominant role in regulating the brain microenvironment and neuronal activity. Therefore, the brain is conceived to protect itself from frequent fluctuations of extracellular concentration of hormones, amino acids and potassium levels that occur after meals, exercise, or stress – as well as from toxic pathogens that may be circulating in the blood stream. This preventive defense mechanism is known as the BBB and it con-sists mainly of tightly interconnected endo-thelial cells that carpet the inner surface of most blood vessels in the brain [1]. While the BBB provides a stable neuronal environment for a healthy brain, it represents an insur-mountable challenge for neuropharmacolo-gists to combat brain-related chronic disor-ders. According to Pardridge [2], more than 98% of all drug molecules are not able to cross this barrier. A recent effort provides evi-dence for the emergence of a novel approach to overcome this problem [3]. This technique uses magnetic nanoparticles in conjunction with an alternating magnetic field to tran-siently increase BBB permeability for drug

delivery. In addition to novelty, the findings confirm that the technique does not dam-age the neurovascular unit, in other words neurons, astrocytes, etc.

Current popular strategies may be clas-sified as being either neurosurgical-based (invasive) or noninvasive approaches that enhance BBB permeability in response to various physical, chemical or biological stimuli. Neurosurgical-based strategies often require either a craniotomy, which includes intracerebroventricular infusion of drugs, or intracerebral implants. Chemical stimuli such as endogenous peptides (insulin) are able to transport certain drug molecules across the BBB by endocytosis [2]. Biological stimuli such as viruses or microphages may be used as trojan horse to deceive and dis-rupt BBB integrity in order to deliver specific therapeutics to the brain tissue [4]. Physical stimuli such as microwave or electromagnetic fields are also able to facilitate the infiltration of therapeutics across the BBB via hyperther-mia. These techniques use the electromag-netic radiation energy to elevate the homeo-static temperature of the cerebrovascular unit. While elevation of temperature may create risks to the surrounding biological structures, hyperthermia offers an increase in BBB permeability through a mechanism that widens the tight junctions [5,6]. In spite of the fact that many of the aforementioned techniques are promising, and despite the remarkable progress in the synthesis of phar-maceutical compounds, the clinical transla-

Toward nonsystemic delivery of therapeutics across the blood–brain barrier

“It is evident that linking hyperthermia of magnetic nanoparticles with the magnetic resonance navigation could provide drug delivery

to the brain with higher spatial precision, advanced control and lower immune reaction.”

Seyed Nasrollah Tabatabaei Author for correspondence: 

Institute of Biomedical Engineering, 

Polytechnique de Montréal, Montréal, 

QC, Canada

nasr.tabatabaei@polymtl.ca

Hélène GirouardDepartment of Pharmacology, Faculty 

of Medicine, Université de Montréal, 

Montréal, QC, Canada

Anne-Sophie CarretPediatric Hematologist-Oncologistat 

CHU Sainte-Justine, Montréal, QC, 

Canada

and

Department of Pediatrics, Faculty of 

Medicine, Université de Montréal, 

Montréal, QC, Canada

Sylvain MartelDepartment of Computer & Software 

Engineering, Institute of Biomedical 

Engineering, Polytechnique de 

Montréal, Montréal, QC, Canada

For reprint orders, please contact: reprints@futuremedicine.com

2130 Nanomedicine (Lond.) (2015) 10(14) future science group

Editorial Tabatabaei, Girouard, Carret & Martel

tion of drug delivery to the brain remains a challenge. In addition, systemic administration of drugs causes the active principles to distribute throughout the body and consequently increases cytotoxic effects on healthy tissues while reducing significantly the thera-peutic index. These facts reinforce the need for a new approach capable of providing nonsystemic controlled delivery of therapeutics to the brain tissue.

Among recent and prominent techniques, high-intensity focused ultrasound promises increase in BBB permeability as well as localized control for drug deliv-ery to the brain tissue [7]. Nevertheless, this strategy pro-vides low spatial and temporal resolution. High-inten-sity focused ultrasound propagates nonlinearly over a broad region of biological structures before converging into its relatively large focal point (1 × 1 × 7 mm3 [8]). In addition, the difference of acoustic impedance of skull from that of the adjacent soft tissue can promote intolerable change of temperature in the brain and on the surface of the skull [9]. Magnetic targeting or trapping is another attractive technique that uses a mobile external magnet to maneuver magnetic carriers inside superficial vasculature and drags them across the BBB [10]. This technique, however, could potentially harm the cerebrovascular unit (i.e., neurons, glia and vascular cells). Due to rapid decay of the magnetic field strength and the lack of volumetric targeting capabil-ity, magnetic targeting is not suitable for targets deep within the brain.

Magnetic nanoparticles (MNPs) offer many advan-tages; nonsystemic delivery to spatially determined regions of the brain could potentially be achieved with these particles using an approach known as magnetic resonance navigation (MRN) [11]. This approach pro-vides physicians with a platform that allows targeting and delivery of medications to any specific location in the human body. In this design, MRN relies on a clinical MRI scanner to navigate magnetic therapeutic agents along a predetermined suitable vascular route on their journey toward the target. The MNPs func-tion as MRI contrast agents and provide the capabil-ity to assess the targeting efficacy through imaging sequences. Biocompatible iron-oxide superparamag-netic nanoparticles used in MRN have already proved to be effective to orchestrate monitoring and steering in the MRI to deliver therapeutic agents through a suit-able vascular route. Once at the target, various release

mechanisms can be envisioned from the simple biodeg-radation of a polymer matrix [12] to the use of thermally triggered releases from hydrogel-based carriers [13].

While this technique has shown to be effective to tar-get deep physiological regions such as the liver in ani-mal models [12], it requires a proper BBB opening strat-egy to become clinically viable for nonsystemic target delivery to the brain. A recent published study [3] shows that the same superparamagnetic nanoparticles used to enable MRN could also temporary open the BBB. The results of this study show that when exposed to a low radiofrequency field, these MNPs release energy in the form of heat to their surroundings. Such eleva-tion of the local temperature increases the BBB perme-ability between adjacent endothelial cells (tight junc-tions) [14,15]. In this configuration, the radiofrequency parameters (field strength and frequency) are set to be just as effective in deep structures as they would be at the surface of the human brain. More interesting is the fact that the MNPs lead to an enhanced BBB specificity where the therapeutics are delivered while providing such targeting ability without perturbing surrounding structures of the cerebrovascular unit. In addition, MNPs can be chemically engineered to specifically target the surface of the vascular endothe-lium by means of adhesion antibodies. For instance, transferrin has receptors specifically localized on the surface of the endothelium and at higher concentra-tion around certain brain disorders [16]. This strategy could optimize the required MNPs concentration at the target site and lower side effects. In addition, the BBB leakage appears to be entirely reversible and not associated with an increase in brain immune response.

It is evident that linking hyperthermia of MNPs with the MRN could provide drug delivery to the brain with higher spatial precision, advanced control and lower immune reaction. MRN minimizes the risk of systemic distribution of toxic therapeutic agents. Engineering the MNPs to couple with adhesion anti-bodies will most likely intensify their ability to target the BBB. Finally, hyperthermia of the MNPs increases BBB permeability and provides an opportunity for the medications to reach the desired location. The BBB should then be able to fully recover spontaneously. Fur-thermore, the process appears to lack primary immune response. Although more efforts are required such as linking MRN with hyperthermia of MNPs before this approach becomes clinically viable, it opens a new win-dow in search for a local drug delivery mechanism to treat various neurological disorders.

Financial & competing interests disclosureThis project is supported in part by the Chaire de Recherche 

de l’École Polytechnique de Montréal, the Canada Founda-

“Magnetic nanoparticles offer many advantages; nonsystemic delivery to spatially determined

regions of the brain could potentially be achieved with these particles using an approach known as

magnetic resonance navigation.”

www.futuremedicine.com 2131future science group

Toward nonsystemic delivery of therapeutics across the blood–brain barrier Editorial

tion for Innovation (CFI) and the Natural Sciences and Engi-

neering  Research Council  of Canada  (NSERC)  from S Mar-

tel’s  laboratory, as well as  Fonds de Recherche du Québec 

–  Santé  (FRQS)  and  the  Heart  and  Stroke  Foundation  of 

Canada (HSFC) New Investigator Awards from H Girouard’s 

laboratory. The authors have no other relevant affiliations or 

financial  involvement with  any  organization  or  entity with 

a  financial  interest  in  or  financial  conflict with  the  subject 

matter or materials discussed in the manuscript apart from 

those disclosed.

No writing assistance was utilized in the production of this 

manuscript.

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