Transient and Local Increase in the Permeability of the Blood-Brain Barrier and the Blood-Retinal Barrier by Hyperthermia of Magnetic Nanoparticles in a Rat Model

RESUME Apres avoir reussi a propulser des agents therapeutiques encapsules dans des micro-transporteurs magnetiques a un endroit precis a l'interieur d'un modele animal en utilisant le gradient de champ magnetique dans un appareil de resonance magnetique (RM) modifie, nous visons maintenant a livrer une drogue localement dans le systeme nerveux central (SNC). Afin de reussir la livraison de la drogue de facon localisee et augmenter l'efficacite du traitement, ce projet met de l’avant que les agents therapeutiques doivent etre administres par des moyens pas plus envahissants qu’une injection intraveineuse, suivis par la propulsion a distance, controlee, et actionnee sur commande dans le SNC. La fonction exigeante du tissu neuronal dans le SNC (haute sensibilite/complexite du systeme) necessite un environnement extremement stable. Un changement minime dans la composition du liquide interstitiel dans le SNC peut jouer un role preponderant dans la regulation de son microenvironnement et de l'activite neuronale. Par consequent, le SNC est concu pour se proteger des fluctuations frequentes de la concentration extracellulaire d’hormones, d’acides amines, et des niveaux d'ions produits apres les repas, l'exercice ou le stress (ainsi que d'agents pathogenes toxiques qui peuvent etre en circulation dans le sang). Cette protection du SNC est permise grâce a la presence d’une barriere, nommee barriere hemato-encephalique (BHE). Cette barriere preventive se compose essentiellement de cellules endotheliales etroitement reliees entre elles qui tapissent la surface interieure de la plupart des vaisseaux sanguins dans le SNC. Bien que ceci offre un environnement neuronal stable, plus de 98% des molecules que constituent les drogues ne sont pas en mesure de franchir la BHE et leur penetration est uniquement determinee par les caracteristiques de permeabilite de la barriere. Ceci est alors un frein pour les traitements ciblant le SNC. Par consequent, la recherche pharmaceutique fait un reel effort pour maximiser la livraison des medicaments vers le SNC. Pour autant, la presence des barrieres physiologiques, bien qu’essentielles a la survie en conditions physiologiques, limitent les traitements qu’on a a notre disposition en conditions pathologiques. ----------ABSTRACT After successfully propelling therapeutic agents encapsulated in magnetic micro-carriers to a specific location inside an animal model by the gradient magnetic field of a modified clinical Magnetic Resonance (MR) scanner, we are now aiming to perform local drug delivery in the region of the central nervous system (CNS). To achieve localized drug delivery and increase efficacy, this project advances the theme that the therapeutic agents must be administered by means no more invasive than an intravenous injection followed by remote propulsion, controlled tracking, and on-command actuation in the CNS. The demanding function of the CNS 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 its microenvironment and neuronal activity. Therefore, the CNS is conceived to protect itself from frequent fluctuations of extracellular concentration of hormones, amino acids, and ion levels that occur after meals, exercise, or stress - as well as from toxic pathogens that may be circulating in the blood stream. This preventive barrier consists mainly of tightly interconnected endothelial cells that carpet the inner surface of most blood vessels in the CNS. While it provides a stable neuronal environment, more than 98% of all drug molecules are not able to cross this barrier and the extent to which a molecule enters is determined only by the permeability characteristics of the barrier. Therefore, while pharmaceutical research progresses for drug delivery to the CNS, it is limited by its pharmacokinetics through physiological barriers. Successful transient and local opening of the barrier for diffusion of therapeutics could strongly support the feasibility of treating a variety of neurological disorders. A recent effort presented in this dissertation provides evidence for the emergence of a novel approach to overcome this problem. This technique uses magnetic nanoparticles (MNPs) in conjunction with an alternating magnetic field to transiently increase barrier permeability for drug delivery. MNPs can act as miniaturized heat sources that, when under the influence of the alternating magnetic field, dissipate thermal energy directly and exclusively to the barrier (hyperthermia). In addition to its novelty, the findings confirm that the technique does not damage the neurovascular unit, i.e. neurons, astrocytes, etc.