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Overcoming the Blood–Brain Barrier. Challenges and Tricks for CNS Drug Delivery

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Overcoming the Blood–Brain Barrier. Challenges and Tricks for CNS Drug Delivery Scientia Pharmaceutica Review Overcoming the Blood–Brain Barrier. Challenges and Tricks for CNS Drug Delivery Luca Anna Bors and Franciska Erd˝o* Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, Práter u. 50a, H-1083 Budapest, Hungary; [email protected] * Correspondence: [email protected] Received: 26 January 2019; Accepted: 26 February 2019; Published: 28 February 2019 Abstract: Treatment of certain central nervous system disorders, including different types of cerebral malignancies, is limited by traditional oral or systemic administrations of therapeutic drugs due to possible serious side effects and/or lack of the brain penetration and, therefore, the efficacy of the drugs is diminished. During the last decade, several new technologies were developed to overcome barrier properties of cerebral capillaries. This review gives a short overview of the structural elements and anatomical features of the blood–brain barrier. The various in vitro (static and dynamic), in vivo (microdialysis), and in situ (brain perfusion) blood–brain barrier models are also presented. The drug formulations and administration options to deliver molecules effectively to the central nervous system (CNS) are presented. Nanocarriers, nanoparticles (lipid, polymeric, magnetic, gold, and carbon based nanoparticles, dendrimers, etc.), viral and peptid vectors and shuttles, sonoporation and microbubbles are briefly shown. The modulation of receptors and efflux transporters in the cell membrane can also be an effective approach to enhance brain exposure to therapeutic compounds. Intranasal administration is a noninvasive delivery route to bypass the blood–brain barrier, while direct brain administration is an invasive mode to target the brain region with therapeutic drug concentrations locally. Nowadays, both technological and mechanistic tools are available to assist in overcoming the blood–brain barrier. With these techniques more effective and even safer drugs can be developed for the treatment of devastating brain disorders. Keywords: structure of the blood–brain barrier; models of the blood–brain barrier; drug delivery across the blood–brain barrier; nanocarriers; nanoparticles; vectors; intranasal delivery; efflux transporter inhibition; ultrasound-microbubbles 1. Introduction The capillary microvessels of the brain have evolved to constrain the movement of molecules and cells between blood and brain, providing a natural defense against circulating toxic or infectious agents. The relative impermeability of the blood–brain barrier (BBB) results from tight junctions and adherens junctions between capillary endothelial cells formed by cell adhesion molecules. Brain endothelial cells also possess few alternate transport pathways (e.g., fenestra, transendothelial channels, pinocytotic vesicles), and express high levels of active efflux transport proteins, including P-glycoprotein (P-gp, MDR-1 or ABCB1) and breast cancer resistance protein (BCRP, ABCG2). The BBB maintains essential brain homeostasis but as a result, represents a significant impediment to the effective treatment of many brain diseases [1,2]. Current strategies to enhance drug delivery to the brain are either focused on locally circumventing the BBB through direct injections or nasal drug applications, for example, or globally through the bloodstream (using targeted delivery approaches or by opening the blood–brain barrier). Many approaches to enhance drug delivery across the BBB are under development, both by academic Sci. Pharm. 2019, 87, 6; doi:10.3390/scipharm87010006 www.mdpi.com/journal/scipharm Sci. Pharm. 2019, 87, 6 2 of 28 research groups as well as pharmaceutical and biotechnology companies. To translate basic (academic) research into safe and effective treatments for patients with devastating brain diseases, many steps in many different research areas are required. The pharmaceutical formulation (chemistry, manufacturing, Sci. Pharm. 2018, x, x FOR PEER REVIEW 2 of 28 control, analytics, and selection of proper nanocarriers), pharmacology and pharmacokinetics (drug delivery,research neuroscience, groups as and well crossing as pharmaceutical the blood–brain and biotechnology barrier), andcompanies. safety To (toxicology, translate basic behavioral, route of drug(academic) administration, research into safe and and chronic effective treatment) treatments concerns for patients should with devastating be harmonized brain diseases, and taken into many steps in many different research areas are required. The pharmaceutical formulation account. One of the major challenges in the area of brain delivery is first to find an efficient vector for (chemistry, manufacturing, control, analytics, and selection of proper nanocarriers), pharmacology brain deliveryand pharmacokinetics using a physiological (drug delivery, pathway neuroscience, mechanism and crossing tocross the blood–brain the BBB. barrier), These and vectors safety can be in the form(toxicology, of peptides, behavioral, proteins, route antibodies, of drug administration, or some other and specific chronic formulation,treatment) concerns such should as nanoparticles, be which targetharmonized a specific and receptortaken into ataccount. the BBB One and of the will major cross challenges the BBB in the by area transcytosis. of brain delivery is first In thisto find review, an efficient the authors vector for give brain an delivery overview using of a the physiological different pathway advanced mechanism technologies to cross and the tricks on BBB. These vectors can be in the form of peptides, proteins, antibodies, or some other specific how to crossformulation, the BBB, such and as nanoparticles, how to deliver which pharmacologically target a specific receptor active at the molecules BBB and will to cross the centralthe BBB nervous system (CNS)by transcytosis. target site. This article attempts to provide a synthesis of the existing knowledge of the observationsIn this and review, findings the authors from give the an last overview decades of the on different the structure advanced and technologies function and of tricks the BBB and classical technologicalon how to cross approachesthe BBB, and tohow overcome to deliver this phar physiologicalmacologically active barrier. molecules It also to includes the central the newest nervous system (CNS) target site. This article attempts to provide a synthesis of the existing developments and methods for modeling and crossing the blood–brain interfaces (e.g., dynamic chip knowledge of the observations and findings from the last decades on the structure and function of models ofthe the BBB BBB, and classical nanocarriers, technological vectors, approaches and efflux to overcome transporter this physiological modulation barrier. to helpIt also theincludes brain uptake of therapeuticthe newest drugs). developments and methods for modeling and crossing the blood–brain interfaces (e.g., dynamic chip models of the BBB, nanocarriers, vectors, and efflux transporter modulation to help the 2. Anatomy,brain Physiology uptake of therapeutic and Molecular drugs). Constituents of Blood–Brain Barrier The2. mature Anatomy, blood–brain Physiology and barrier Molecular (BBB) Constituents is composed of Blood–Brain of capillary Barrier endothelial cells (ECs) tightly connected withThe tight mature junctions blood–brain (TJs) barrier and adherens(BBB) is composed juntions of (AJs) capillary that endothelial prevent paracellularcells (ECs) tightly transport [3] and haveconnected a lowpinocytotic with tight junctions activity (TJs) [ 4and,5], adherens although juntions limited (AJs) transcellular that prevent paracellular transport transport does occur [6]. In addition,[3] and the have BBB a low is influenced pinocytotic activity by closely [4,5], althou associatedgh limited perivascular transcellular astrocytictransport does end-feet, occur [6]. pericytes, and microgliaIn addition, [7] (Figure the BBB1 is). influenced These different by closely cell associ typesated perivascular play essential astrocyt rolesic end-feet, in BBB pericytes, induction and and microglia [7] (Figure 1). These different cell types play essential roles in BBB induction and maintenancemaintenance by regulating by regulating the proliferation, the proliferation, migration, migration, and vascularand vascular branching branching of theof the brain brain endothelial cells. Additionally,endothelial cells. the basementAdditionally, membrane the basement provides membrane structural provides structural support support around around the pericytes the and endothelialpericytes cells. and The endothelial basal laminacells. The is basal contiguous lamina is contiguous with the with plasma the plasma membranes membranes of of the the astrocyte end-feet [astrocyte8]. The end-feet BBB provides [8]. The BBB strong provides resistance strong resist to movementance to movement of ions, of ions, with with transendothelial transendothelial electrical electrical resistance (TEER) around 1500 X cm2 [5], 100 times higher than that for peripheral resistance (TEER) around 1500 X cm2 [5], 100 times higher than that for peripheral microvessels [9,10]. microvessels [9,10]. Figure 1.FigureShematic 1. Shematic structure structure ofthe of the blood–brain blood–brain barrier (BBB). (BBB). The The brain brain capillary capillary endothelial endothelial cells cells (ECs) connected to each other by tight junctions (TJs) and adherens junctions (AJs). The endothelial (ECs) connected to each other by tight junctions (TJs)
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