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Shortcut Approaches to Substance Delivery Into the Brain Based on Intranasal Administration Using Nanodelivery Strategies for Insulin

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Shortcut Approaches to Substance Delivery Into the Brain Based on Intranasal Administration Using Nanodelivery Strategies for Insulin molecules Review Shortcut Approaches to Substance Delivery into the Brain Based on Intranasal Administration Using Nanodelivery Strategies for Insulin Toshihiko Tashima Tashima Laboratories of Arts and Sciences, 1239-5 Toriyama-cho, Kohoku-ku, Yokohama, Kanagawa 222-0035, Japan; [email protected] Academic Editor: Alexandru Mihai Grumezescu Received: 4 October 2020; Accepted: 5 November 2020; Published: 7 November 2020 Abstract: The direct delivery of central nervous system (CNS) drugs into the brain after administration is an ideal concept due to its effectiveness and non-toxicity. However, the blood–brain barrier (BBB) prevents drugs from penetrating the capillary endothelial cells, blocking their entry into the brain. Thus, alternative approaches must be developed. The nasal cavity directly leads from the olfactory epithelium to the brain through the cribriform plate of the skull bone. Nose-to-brain drug delivery could solve the BBB-related repulsion problem. Recently, it has been revealed that insulin improved Alzheimer’s disease (AD)-related dementia. Several ongoing AD clinical trials investigate the use of intranasal insulin delivery. Related to the real trajectory, intranasal labeled-insulins demonstrated distribution into the brain not only along the olfactory nerve but also the trigeminal nerve. Nonetheless, intranasally administered insulin was delivered into the brain. Therefore, insulin conjugates with covalent or non-covalent cargos, such as AD or other CNS drugs, could potentially contribute to a promising strategy to cure CNS-related diseases. In this review, I will introduce the CNS drug delivery approach into the brain using nanodelivery strategies for insulin through transcellular routes based on receptor-mediated transcytosis or through paracellular routes based on escaping the tight junction at the olfactory epithelium. Keywords: intranasal drug administration; nose-to-brain drug delivery; drug delivery system; insulin delivery to brain; olfactory nerve route; nanodelivery 1. Introduction The blood–brain barrier (BBB) pharmacokinetically blocks the entry of therapeutic agents into the brain. This impermeability represents a serious problem in drug discovery or the development of efficient treatments for central nervous system (CNS)-related diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [1]. Therefore, it is essential to develop approaches that enable substances to cross directly or indirectly the BBB for better brain-targeted drug delivery. The BBB is virtually composed of (i) a physical barrier based on the tight junctions of the capillary endothelial cells supported by adjacent glial cells and (ii) excreted components from endothelial cells by ATP-binding cassette (ABC) transporters such as multiple drug resistance 1 (MDR1, P-glycoprotein). However, the brain needs nutritional materials such as glucose and has to be able to eliminate waste materials. Solute carrier (SLC) transporters [2] expressed at the BBB allow the entry of low-molecular-weight hydrophilic nutrients. Furthermore, receptor-mediated transcytosis (RMT) distributes the corresponding middle- or high-molecular-weight ligands, such as insulin and transferrin, across the capillary endothelium to the brain. Therefore, carrier-mediated transport using arbitrary substrates with cargos could be a direct approach to bypass MDR1 and the tight junction-based physical boundary at the BBB [3]. Similarly, RMT using arbitrary ligands with cargos could be a direct approach to bypass tight junction-based Molecules 2020, 25, 5188; doi:10.3390/molecules25215188 www.mdpi.com/journal/molecules Molecules 2020, 25, x 2 of 22 Moleculesboundary2020 at, 25 the, 5188 BBB [3]. Similarly, RMT using arbitrary ligands with cargos could be a direct2 of 22 approach to bypass tight junction-based physical boundaries at the BBB [4]. In general, substances could be classified as low-molecular-weight compounds (< approximately 500 Da), high-molecular- physicalweight boundariescompounds at (> the BBBapproximately [4]. In general, 3000 substances Da), and could middle-molecular-weight be classified as low-molecular-weight compounds compounds(approximately (<approximately 500–3000 Da). 500 Drug Da), delivery high-molecular-weight strategies depend compounds on features (>approximately such as molecular 3000 size, Da), andphysicochemical middle-molecular-weight properties, such compounds as hydrophobici (approximatelyty or hydrophilicity, 500–3000 Da). enzymatic Drug delivery stability, strategies and dependaffinity to on intermedium features such molecules, as molecular such size, as transporters physicochemical and receptors, properties, or suchtarget as molecules. hydrophobicity It is true or hydrophilicity,that direct methods enzymatic to cross stability, the BBB and using affinity carrier-mediated to intermedium transport molecules, and such RMT as transporterscould indeed and be receptors,promising orsolutions, target molecules. but the off-target It is true side that effects direct should methods also to be cross considered the BBB that using might carrier-mediated occur due to transportincorrect andmolecular RMT could collisions indeed through be promising the systemic solutions, circulation, but the oalthoughff-target side a certain effects level should of alsotissue- be consideredspecific SLC that transporter might occur and due receptor to incorrect expression molecular could collisions be observed. through Thus, the an systemic alternative circulation, bypass althoughapproach afor certain a brain-targeted level of tissue-specific substance SLC delivery transporter should and be receptor developed. expression It is couldwell-known be observed. that Thus,intranasal an alternative molecules bypass enter the approach brain. forAccordingly, a brain-targeted intranasally substance administered delivery should substances be developed. could be Itdelivered is well-known into the that brain intranasal through moleculesa nose-to-brain enter route the brain. 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I have based already on nanodelivery described carrier-mediated strategies have beentransport extraordinarily methods based used on for tissue-specifically membrane permeation. expressed I have transporters alreadydescribed using arbitrary carrier-mediated substrate– transportcargo conjugates methods [3], based molecular on tissue-specifically cross-membrane expressed internalization transporters into usingthe cells arbitrary using substrate–cargocell-penetrating conjugatespeptides (CPPs) [3], molecular [7], specific cross-membrane delivery into internalization cancer cells based into theon cellsreceptor-mediated using cell-penetrating endocytosis peptides [8], (CPPs)and RMT-based [7], specific brain-targeted delivery into cancer delivery cells across based the on receptor-mediatedBBB using arbitrary endocytosis ligand–cargo [8], and conjugates RMT-based [4]. brain-targetedA constantly growing delivery number across of the new BBB results using allows arbitrary us to ligand–cargo gain a broader conjugates view and [4 a]. more A constantly in-depth growingunderstanding number of of the new cross-membrane results allows us drug to gain delive a broaderry. Inview this andperspective a more in-depth review, understandingI introduce a ofshortcut the cross-membrane approach to deliver drug pharmaceutical delivery. In this agents perspective into the review, brain Ithrough introduce intranasal a shortcut administration, approach to deliverparticularly pharmaceutical focusing on agents insulin, into with the or brain without through nanoparticles intranasal using administration, nano drug particularly delivery systems, focusing as onshown insulin, in Figure with or 1. without nanoparticles using nano drug delivery systems, as shown in Figure1. Molecules para- CSF cellular Conduit Olfactory Nasal cavity Olfactory Olfactory Brain epithelium sensory bulb trans- neuron trans- cellular cellular para- Conduit CSF cellular BBB Respiratory Trigeminal epithelium trans- nerve cellular Mucociliary clearance Blood Nasopharynx FigureFigure 1.1. Schematic overview of several molecular pathwayspathways after intranasal drug administration. CSFCSF standsstands forfor cerebrospinalcerebrospinal fluid.fluid. BBBBBB standsstands forfor blood–brainblood–brain barrier.barrier. 2.2. Discussions 2.1. Anatomical Features of the Nasal Cavity 2.1. Anatomical Features of the Nasal Cavity The proper development of the olfactory system is essential for animals, particularly nocturnal and The proper development of the olfactory system is essential for animals, particularly nocturnal forest animals, to survive difficult circumstances by quickly smelling scents in the air. Humans could and forest animals, to survive difficult circumstances by quickly smelling scents in the air. Humans feel spring in the air due to the volatile organic compounds emitted by plants. Vapored molecules of could feel spring in the air due to the volatile organic compounds emitted by plants. Vapored geraniol, a scent ingredient in roses, drift into
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