Drug Delivery
David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack in Brain and Spinal Tumors of Childhood, 2020
Substances necessary for brain nutrition and survival are distributed thanks to specific transporters and internalizing receptors localized on the luminal and basolateral side of the endothelial cells that constitute the BBB. These specific transport systems can be used to deliver drugs to the CNS. Some drugs are able to target such transporters, whereas other drugs need to be chemically modified in order to induce and/or increase their transport through the BBB. Targeting may be obtained thanks to specific ligands or antibodies attached to the drug. This approach is based on receptor-mediated transcytosis. Insulin, transferrin, and low-density lipoprotein receptors are commonly used.219 CRM197, a non-toxic mutant of diphtheria toxin, was also used as a possible vector.223 Limitations to this approach are: (1) the necessity to obtain drugs that bind to a specific receptor and easily dissociate once they have crossed the endothelial interface to be delivered to the CNS; and (2) systemic effects due to the presence of such receptors in peripheral organs.
Exploration of Nanonutraceuticals in Neurodegenerative Diseases
Raj K. Keservani, Anil K. Sharma, Rajesh K. Kesharwani in Nutraceuticals and Dietary Supplements, 2020
Lipophilic molecules cross BBB via transcelluar route while the proteins, peptides, and polysaccharides cross BBB via receptor-mediated transcytosis and through paracellular route. Remarkably receptor-mediated transcytosis, predominantly bi-directional, is also involved in the transportation of nanoparticles as well as biopharmaceuticals (De Boer and Gaillard, 2007). On the other hand, efflux transporters, namely, ABC transporter family, multidrug resistance proteins and brain multidrug resistance proteins, regulate the homeostasis of excitatory transmitters, like glutamate and entry of drugs to the brain. This in turn becomes a major limitation for the drug delivery to the brain for treating central nervous system (CNS) aliments (Löscher and Potschka, 2005). CNS albumin levels are controlled by adsorptive transcytosis depending upon the disease condition (Joó, 1996). Thus, a strong cohesive endothelial system protects the brain allowing a selective access to certain requisite molecules only.
M cells and the follicle-associated epithelium
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
Epithelial cells move macromolecules and microbes from the apical cell surface to the basolateral surface by a process called transcytosis (Figure 15.4). Transcytosis is mediated by a complex series of events, including formation and fusion of endosomes and polarized recycling of membrane vesicles, with directional information provided by G proteins and adaptors and the highly polarized cytoskeleton. The first step in the transcytotic process is invagination of apical membrane microdomains to form intracellular compartments called early endosomes. The mechanisms by which M cells take up cargo are diverse. Adherent macromolecules, small particles, and viruses are taken up via clathrin-coated or noncoated pits and vesicles (see Figure 15.4); soluble macromolecules are captured in the fluid phase. Large adherent particles are internalized in a process resembling phagocytosis that involves the assembly of organized submembrane actin networks. Electron-micrographic and immunocytochemical data suggest that certain proteases are delivered into M cell endosomes, and that the endosomal lumen is acidified to pH 6–6.2, perhaps allowing some ligands to be released from their receptors.
Aluminum neurotoxicity and autophagy: a mechanistic view
Published in Neurological Research, 2023
Sajjad Makhdoomi, Saba Ariafar, Fatemeh Mirzaei, Mojdeh Mohammadi
Nowadays, nano-drug delivery systems have shown appropriate prospective in increasing drug delivery [117–120]. Several studies have discussed aluminum neurotoxicity treatment using novel drug delivery systems to cross medication through the blood–brain barrier (BBB) [121–123]. Brain microvascular endothelial cells (BMVECs) control the molecular and cellular flux between the blood and the brain. Receptor-mediated transcytosis is highly associated with drug delivery of large molecules into the brain. Recently, novel methods have been developed for drug screening purposes, such as a novel model of the human BBB in a high-throughput microfluidic device to evaluate the crossing of the bioactive compounds across the BBB [124]. To clarify the molecular mechanisms and perform translatable real-time quantitative assessments of drug transport across brain microvessels, in vitro models are used to analyze the inherent in vivo BBB and brain microvessels. For this purpose, Salman et al. developed and designed an in vitro human brain microvessel-on-a-chip consisting of a 3D microfluidic model [125]. It is suggested that these methods can be used in the future studies for real-time monitoring of changes in cellular dynamics such as autophagy process.
Anti-ageing peptides and proteins for topical applications: a review
Published in Pharmaceutical Development and Technology, 2022
Mengyang Liu, Shuo Chen, Zhiwen Zhang, Hongyu Li, Guiju Sun, Naibo Yin, Jingyuan Wen
The transcellular pathway refers to the transportation of solutes through a cell, including transcellular passive diffusion, transcellular active transport, and transcytosis (Kasting et al. 2019). Diffusion is the movement of chemicals from a region of higher concentration to a region of lower concentration. Active transport, also known as carrier-mediated transport, involves using energy to help specific molecules move across the barrier and against the concentration gradient (Fung et al. 2018). Since the cell membrane is lipophilic, it might resist the passive diffusion of hydrophilic or charged compounds. Transcytosis is another type of transcellular route, where macromolecules are carried across the cell membranes (Liu et al. 2019). These macromolecules are captured in vesicles on the side of the cell, drawn across the cell, and then ejected on the other side (Liu et al. 2019). However, most experimental studies suggest that the primary pathway across SC is the intercellular pathway, as described below.
Blood-brain barrier receptors and transporters: an insight on their function and how to exploit them through nanotechnology
Published in Expert Opinion on Drug Delivery, 2019
Rui Pedro Moura, Cláudia Martins, Soraia Pinto, Flávia Sousa, Bruno Sarmento
Considering all the previously mentioned features it is of no wonder that the BBB is extremely selective on the therapeutic compounds that can adequately cross its structure, and it is clear that the BBB only allows the translocation of specific compounds, through specific pathways. These include 1) direct paracellular pathway, in which the compound directly transverses the TJs (only applicable to polar solutes); 2) diffusion transcellular pathway, in which the compound directly crosses the cell (only applicable to small lipophilic and gaseous molecules); 3) adsorptive transcytosis, when a compound is internalized through a direct electrostatic interaction with the endothelial cell surface, triggering an endocytic process; and 4) carrier-mediated transcytosis, in which a receptor interacts with a specific ligand, triggering internalization and transport towards the abluminal side of endothelial cells [32,33]. Due to this, it is clear that conventional delivery routes are not the most adequate methodology to exploit considering brain drug delivery, giving room to alternative drug delivery options.
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