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Current Application of CRISPR/Cas9 Gene-Editing Technique to Eradication of HIV/AIDS
Published in Yashwant Pathak, Gene Delivery, 2022
Prachi Pandey, Jayvadan Patel, Samarth Kumar
The most popular approach for brain targeting using nanomaterials is receptor-mediated transcytosis. The endothelial cells that form the BBB are known to specific receptors, including the transferrin receptor and insulin receptor. Ligand functionalized nanoparticles can promote efficient brain delivery through the binding of ligands to the receptors on endothelial cells. Various nanoparticles are developed for brain targeting using this receptor-mediated transcytosis, like transferrin, lactoferrin, monoclonal antibody-conjugated liposomes, polymer nanoparticles, gold nanoparticles, and iron oxide nanoparticles. Magnetic targeting is another approach to boost BBB transmigration of nanoparticles.
Carriers for Nucleic Acid Delivery to the Brain
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
The increasing prevalence of central nervous system (CNS)-related diseases urgently requires the development of biological drugs such as proteins, antibodies, peptides or nucleic acids which can cross the blood-brain barrier (BBB) [1, 2]. The transfer of therapeutic genes and oligonucleotides offers great opportunities for the treatment of serious neurological diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis and Parkinson’s disease. Despite the enormous potential of therapeutic nucleic acids, minimal BBB transport is the main reason that only 1.8% of all gene therapy clinical trials worldwide address neurological disorders [3]. Efficient delivery of therapeutic agents to the brain is limited by the BBB consisting of endothelial cells along with astrocytes, pericytes and the basal lamina at the plasma membrane of the capillary of the brain parenchyma [4]. Large nucleic acids, either free or formulated as nanoparticles, lack the requirements for free diffusion into the brain (molecular weight <400 Da, <8 hydrogen bonds). Therefore, such therapeutics need to be designed to exploit carrier-mediated transport (CMT) or receptor-mediated transport (RMT) systems or need to undergo adsorptive-mediated transcytosis (AMT) [5, 6].
Drug Delivery
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Gudrun Fleischhack, Martin Garnett, Kévin Beccaria
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.
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.
There and back again: a dendrimer’s tale
Published in Drug and Chemical Toxicology, 2022
Barbara Ziemba, Maciej Borowiec, Ida Franiak-Pietryga
Zhang et al. (2020) showed that deep tumor penetration of PAMAM dendrimers modified with dimethyl maleic anhydride (DMA) occurred via caveolae-mediated transcytosis. Transcytosis is a process characterized by rapid endocytosis on one side of the cell and exocytosis on the opposite side. Since the use of appropriate inhibitors significantly reduced both endocytosis and exocytosis of tested nanoparticles, the authors assumed that tumor penetration occurred mainly through energy-dependent transcytosis rather than through passive movements. It is commonly accepted that for dendrimers endocytosis is the principal process of cellular uptake (J. Wang et al. 2015, Chowdhury et al. 2018, Manzanares and Ceña 2020). We distinguish several types of endocytosis, including phagocytosis (in immune response cells), fluid-phase endocytosis and pinocytosis (nonspecific), clathrin-mediated endocytosis (CME), and clathrin-independent caveolae-mediated endocytosis (CvME).
The challenges of oral drug delivery via nanocarriers
Published in Drug Delivery, 2018
Jonas Reinholz, Katharina Landfester, Volker Mailänder
The major obstacle after penetrating the mucus layer is, however, crossing the first line of epithelial cells. Once the nanocarrier reaches the apical side of the cells, there are two possibilities for the transport to the basal side. The first is a paracellular transport, which involves a loosening of tight junctions and a transport between epithelial cells without a cellular uptake. A promising material for achieving paracellular transport is chitosan, a polysaccharide, which is demonstrably able to reversibly open tight junctions (Rosenthal et al., 2012). Nevertheless, for most nanocarrier systems, a paracellular transport is either toxic when inevitably also other constituents of the feces are diffusing through the opened paracellular route or simply not feasible due to size restrictions. The second possibility is transcytosis, which is defined as the transport of a molecule through the interior of a cell. This process consists of an uptake, preferably endocytosis, a transport within the cell as well as a withdrawal from the interior of the cell, namely exocytosis.