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]. 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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