Targeting targeting Targeted delivery across the blood–brain barrier The delivery of therapeutics to target areas contin-ues to be a challenge for drug developers. Receptor-mediated endocytosis is one of the most important mechanisms of brain targeting drug delivery system. Transferrin and the transferrin receptor for the targeted delivery of therapeutic agents to the brain and cancer cells. Abstract. Such systems have been shown to be effective in animal models including primates, but no clinical trials have been performed so far. Brain Progress in Neurobiology 2019, 181 , 101665. @article{osti_1816315, title = {Transferrin receptor targeting by de novo sheet extension}, author = {Sahtoe, Danny D. and Coscia, Adrian and Mustafaoglu, Nur and Miller, Lauren M. and Olal, Daniel and Vulovic, Ivan and Yu, Ta-Yi and Goreshnik, Inna and Lin, Yu-Ru and Clark, Lars and Busch, Florian and Stewart, Lance and Wysocki, Vicki H. and Ingber, … Transferrin This efficient cellular uptake pathway has been exploited for the site-specific delivery not only of anticancer drugs and proteins, but also of therapeutic genes into proliferating malignant … ON THE USE OF THE TRANSFERRIN RECEPTOR AS A TARGET FOR BRAIN DRUG DELIVERY 6 Meanwhile, my work with Professor Torben Moos had progressed to include the use of liposomes for brain drug delivery, especially regarding how these (non-targeted) liposomes could accumulate in specific brain regions after experimental induction of Parkinson’s disease. The ability to target therapeutic agents to specific tissues is an important element in the development of new disease treatments. Pharmacol Rev 2002; 54 : 561–87. The IgG domain is a MAb against an endogenous BBB receptor such as the transferrin receptor (TfR). Targeting the transferrin receptor for brain drug delivery. Customized vectors for targeted drug delivery. Drug delivery to the brain: self-assembled phage mimetics for crossing the blood-brain-barrier ... to further initiate molecular stacking. Amongst the numerous potential targets at the BBB, the transferrin receptor (TfR) remains the most common target used to ensure sufficient drug delivery to the brain. Acid-Responsive Transferrin Dissociation and GLUT Mediated Exocytosis for Increased Blood–Brain Barrier Transcytosis and Programmed Glioma Targeting Delivery Shaobo Ruan , Key laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu, 610041 China Direct conjugation and immunotoxin studies using the transferrin peptide or anti-transferrin receptor antibodies as the targeting moiety have established the capacity to enhance cellular uptake, cross the blood brain barrier, limit systemic toxicity and reverse multi-drug resistance. Biologics are large molecule therapeutics that do not cross the blood-brain barrier (BBB). This review provides a full account on the use of the transferrin receptor as a target for brain drug delivery by describing the function of the TfR in the BBB, the historical background of its use in drug delivery, and the most recent evidence suggesting TFR-targeted medicines to be efficient for brainDrug delivery with a clear clinical potential. The in-vivo results indicated that transferrin receptor-targeted theranostic liposomes could be a promising carrier for brain theranostics due to nano-sized delivery and its permeability which provided an improved and prolonged brain targeting of docetaxel and QDs in comparison to the non- targeted preparations. It is certainly true that transferrin and the TfR are potentially important as targeting ligands to deliver a wide range of therapeutics, including anticancer drugs, peptides, proteins and even genes, into malignant cells that overexpress transferrin receptors. The Tf receptor is of particular interest because its expression in capillaries throughout the body is restricted to brain capillaries ( 10 ). The membrane transferrin receptor-mediated endocytosis or internalization of the complex of transferrin bound iron and the transferrin receptor is the major route of cellular iron uptake. In this study, transferrin (Tf) was employed as a brain targeting ligand … The OX26 monoclonal antibody against the rat transferrin receptor offers great promise in the delivery of therapeutic agents across the blood-brain barrier to the brain and serves as a potential alternative to viral vector for gene therapy. Abstract. Targeting of the transferrin receptor is one of the most efficient ways of obtaining brain drug delivery. optimal rates of MAb association with the targeted receptor. Transferrin receptors (TfR) as one of receptors, are of special interest for delivery therapeutic agents across BBB in order to enhance the targeting efficiency . Tumour-Targeted Drug Delivery Systems. Among the classical targets, we can cite the transferrin receptors (TfR) or nicotinic acetylcholine receptors that allow the reach the environment of brain tumours. tumors highly express certain receptors such as transferrin for iron transport into brain tumors respectively. TfR is expressed at a high level at the BBB ( 32 , 33 ) and mediates iron delivery to the brain via binding and intracellular trafficking of the iron-binding protein transferrin (Tf) ( 34 ). Transferrin receptor-mediated nanodrug delivery system was expected to target deliver chemotherapeutics to glioma cells across the BBB, and circumvent barriers to improve the antiglioma effect in vivo. The blood–brain barrier (BBB) restricts the delivery of many potentially important therapeutic agents for the treatment of brain disorders. Targeting the transferrin receptor for brain drug delivery. The transferrin receptor (TfR) is one potential target for drug delivery, as it expressed on many dividing cells and on brain endothelium, the key cellular component of the blood-brain barrier. This efficient cellular uptake pathway has been exploited for the site-specific delivery not only of anticancer drugs and proteins, but also of therapeutic genes into … In order to remediate this problem, the protein transferrin (Tf) has been extensively studied as a targeting molecule for the transport of drug and gene delivery … The idea is fairly simple: tether a therapy to an antibody or antibody fragment featuring a receptor, in this case for transferrin, that can carry a … In the present study a delivery system was developed for targeted drug delivery across the blood‑brain barrier (BBB) to the brain cancer cells. The potential use of many promising novel drugs is limited by their inability to specifically reach their site of action after intravenous administration, without secondary effects on healthy tissues. The liposomes were prepared by the lipid film hydration method. These are major limitations in the effective treatment of brain cancer. The optimized S. cerevisiae expression system is amenable to production of soluble and active brain targeting OX26 scFv, and the yeast-produced scFv has potential for the targeting and delivery of small molecules, proteins, or … Introduction While denoting the primary obstacle for delivering therapeutics to the brain 1,2, the blood-brain barrier Transferrin peptide (Tfpep) targeted gold nanoparticles (Tfpep-Au NPs) loaded with the photodynamic pro-drug, P @article{Dufs2013TransferrinAT, title={Transferrin and the transferrin receptor for the targeted delivery of therapeutic agents to the brain and cancer cells. Some nanodrugs are able to overcome the blood-brain barrier that is an obstacle to treatment of brain tumors. Targeting transferrin receptors at the blood-brain barrier improves the uptake of immunoliposomes and subsequent cargo transport into the brain parenchyma. Immunoliposomes conjugated with the OX26 monoclonal antibody to the rat transferrin receptor can be used for brain delivery of small molecules. In the present study the uptake of OX26-immunoliposomes by target cells as well as their transcytosis across the blood-brain barrier was investigated. The idea is fairly simple: tether a therapy to an antibody or antibody fragment featuring a receptor, in this case for transferrin, that can carry a … Direct conjugation and immunotoxin studies using the transferrin peptide or anti-transferrin receptor antibodies as the targeting moiety have established the capacity to enhance cellular uptake, cross the blood brain barrier, limit systemic toxicity and reverse multi-drug resistance. therapeutic genes/drugs to brain. The safest and most effective way of targeting drugs to the entire brain is via delivery systems directed at endogenous receptor-mediated uptake mechanisms present at the cerebral capillaries. Various RMT-targeting strategies have been developed over the past 20 years, and this review explores exciting recent advances, emphasizing studies that show brain targeting in vivo. Murine monoclonal antibodies to the rat transferrin receptor, such as the OX26 monoclonal antibody, are targeted through the BBB … CAS Article Google Scholar widely studied receptor for brain targeting. There are multiple receptors on the surface of BBB endothelial cells that have been targeted for the delivery of CNS-disorder medications, including the transferrin receptor (ischemic stroke, glioblastoma) and insulin receptor (Alzheimer’s disorder) [112,113,114,115,116]. Various RMT-targeting strategies have been developed over the past 20 years, and this review explores exciting recent advances, emphasizing studies that show brain targeting in vivo. Amongst the numerous potential targets at the BBB, the transferrin receptor (TfR) remains the most common target used to ensure sufficient drug delivery to the brain. The Tf receptor is of particular interest because its expression in capillaries throughout the body is restricted to brain capillaries ( 10 ). A brain-targeted drug delivery system targeting TfR, modified by polyamides dendrimer PAMAM, was developed for the treatment of gliomas using a … To overcome this obstacle, targeting strategies binding to nutrient receptors present at the luminal membrane of the BBB are frequently employed. Transferrin recep-tors have a specific function for brain, that is, regulation of uptake of iron via transferrin that is present as a plasma protein and transports iron in the circulation. DOI: 10.4155/tde.13.21 Corpus ID: 3319017. Exploration of the potential of site-specific and target-oriented drug delivery systems has gained interest recently. The OX26 monoclonal antibody against the rat transferrin receptor offers great promise in the delivery of therapeutic agents across the blood-brain barrier to the brain and serves as a potential alternative to viral vector for gene therapy. Herein, we designed a stable peptide modified PM to overcome BBB/BBTBs and target glioma cells. In particular, the TfR plays a significant role in brain drug and gene delivery. We describe a design which binds hTfR with a 20 nM K d,is hyperstable, and crosses an in vitro microfluidic organ-on-a-chip monoclonal antibody and indicates that targeted delivery using the transferrin receptor should aim for increased mobilization of already available transferrin receptor molecules to improve tracking through the BBB. Malignant glioma is the second leading cause of death from diseases of the central nervous system, threatening human health for fast development and poor prognosis.1–4 The standard clinical treatments for glioma include surgical resection, radiotherapy, chemotherapy, gene therapy, and immunotherapy.5,6 However, clinical outcome is very limited, the survival rate of p… It worked. We targeted transferrin and nicotinic acetylcholine receptors by conjugating transferrin (Tf) and rabies virus glycoprotein (RVG) peptide to surface of liposomes. In spite of the rapid growth in recent years in drug development, there is still a low success rate of effective therapies focused in diseases of the central nervous system. To overcome this obstacle, targeting strategies binding to nutrient receptors present at the luminal membrane of the BBB are frequently employed. through receptors present in the brain capillary endothelium. These findings suggest that transferrin receptor-targeting is a relevant strategy of increasing drug exposure to the brain. The safest and most effective way of targeting drugs to the entire brain is via delivery systems directed at endogenous receptor-mediated uptake mechanisms present at the cerebral capillaries. Neurons are fragile cells with a high dependency on the homeostatic mechanisms that regulate their microenvironment. Transferrin and the transferrin receptor system have shown great potential in the delivery of a wide variety of therapeutics (e.g. Targeting the transferrin receptor (TfR) on the surface of brain capillaries has been a popular strategy to Submitted: 29 June 2015 Accepted: 10 August 2015 Published online: 10 September 2015 Keywords: α-synuclein • blood–brain barrier • drug delivery • dual targeting • immunoliposomes • peptidomimetic monoclonal antibodies • transferrin receptor We established a functional selection method to identify high-affinity single domain antibodies to the transferrin receptor 1 (TfR1) with efficient biotherapeutic delivery across the BBB. Thus, the nanoparticle targeting transferrin receptors is not an effective system to deliver drugs to the brain in this specific disease condition. A main issue hindering therapeutic success is the tightly regulated extrac… Progress in Neurobiology 2019, 181 , 101665. Therapeutic drug delivery across the blood-brain barrier (BBB) is not only inefficient, but also nonspecific to brain stroma. The transferrin receptor is responsible for the transport of iron into the brain parenchyma to maintain iron homeostasis that is of great importance for metabolism, neural conductivity, and hence, proper brain function. }, author={C. Duf{\`e}s and Majed … therapeutic genes/drugs to brain. To overcome this obstacle, targeting strategies binding to nutrient receptors present at the luminal membrane of the BBB are frequently employed. An important role of the endogenous ligand, transferrin (Tf) or insulin, in receptor-mediated-transport (RMT) of the associated MAb was found and was attributed to the five order magnitude difference between plasma concentrations of Tf (25,000 nM) and insulin (0.3 nM). Increased brain uptake of targeted nanoparticles by adding an acid-cleavable linkage between transferrin and the nanoparticle core Andrew J. Clark and Mark E. Davis1 Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 Contributed by Mark E. Davis, August 27, 2015 (sent for review August 13, 2015) The in-vivo results indicated that transferrin receptor-targeted theranostic liposomes could be a promising carrier for brain theranostics due to nano-sized delivery and its permeability which provided an improved and prolonged brain targeting of docetaxel and QDs in comparison to the non-targeted preparations. To overcome this obstacle, targeting strategies binding to nutrient receptors present at the luminal membrane of the BBB are frequently employed. The transferrin receptor (TfR) was one of the first RMT systems studied for BBB drug delivery applications . To explore the potential of this tumor induced expression of transferrin receptors for targeting drug carriers, in this study, I have developed and characterized liposome carriers containing paclitaxel, for targeted delivery to the glioma Nonfenestrated Keywords Introduction: Biologic drugs are large molecules that do not cross the blood– brain barrier (BBB). The aim of this study was to compare a set … teins that bind to an exposed beta sheet on the human transferrin receptor (hTfR), which shuttles interacting proteins across the blood – brain barrier (BBB), opening up avenues for drug delivery into the brain. The delivery of therapeutics to brain tissues is one of the main challenges in neuropathology. Keywords blood-brain barrier , biologics , receptor-mediated transport , antibody , transferrin receptor , insulin receptor , low density lipoprotein receptor Brain penetration is possible following the re-engineering of the biologic drug as an IgG fusion protein. Specifically, this research work was focused on designing PEGylated liposomes surface modified with the receptor targeting protein, transferrin and cell penetrating peptides (CPPs) for targeting and improving the delivery of desired therapeutic agent to brain. The membrane transferrin receptor-mediated endocytosis or internalization of the complex of transferrin bound iron and … Brain diseases are among the less understood and poorly treated conditions. BBB drug delivery is the limiting factor in the future development of new therapeutics for the brain. the transferrin receptor (TfR) remains the most common target used to ensure sufficient drug delivery to the brain. Transfer across the blood-brain barrier (BBB) remains a significant hurdle for the development of biopharmaceuticals with therapeutic effects within the central nervous system. For the past two decades, a variety of drug delivery systems has been designed to target components of the blood-brain barrier, including the transferrin receptor, a transmembrane glycoprotein highly expressed in the brain endothelium. Drug targeting through the brain capillary endothelium, which forms the blood-brain barrier (BBB) in vivo, may be achieved with peptidomimetic monoclonal antibodies that target peptide transcytosis systems on the BBB in vivo. Abstract. An efficient strategy for brain targeted delivery is the utilization of the targeting ligand conjugated nanoparticles to trigger the receptor-mediated transcytosis. drugs and genes) across biological barriers. Such systems have been shown to be effective in animal models including primates, but no clinical trials have been performed so far. Moreover, the influence of disease conditions on the expression of receptors is very specific and should be evaluated case-by-case. Keywords blood-brain barrier , biologics , receptor-mediated transport , antibody , transferrin receptor , insulin receptor , low density lipoprotein receptor The transferrin receptor is of special interest since its expression is limited to the endothelium of the brain as opposed to peripheral endothelium. Here, we investigate the possibility of delivering immunoliposomes and their encapsulated cargo to the brain via targeting of the transferrin receptor. In this review, we provide a full account on the use of the TfR as a target for brain drug delivery by describing the function of the TfR in the BBB, the historical background of its use in drug delivery, and the The membrane transferrin receptor-mediated endocytosis or internalization of the complex of transferrin bound iron … Alzheimer’s disease (AD) and treatment of the brain in aging require the development of new biologic drugs, such as recombinant proteins or gene therapies. To explore the potential of this tumor induced expression of transferrin receptors for targeting drug carriers, in this study, I have developed and characterized liposome carriers containing paclitaxel, for targeted delivery to the glioma Receptors expressed on the BBB, including transferrin (Tf) receptor and insulin receptor, have been used for brain-targeting drug delivery research . Amongst the numerous potential targets at the BBB, the transferrin receptor (TfR) remains the most common target used to ensure sufficient drug delivery to the brain. An antibody-avidin fusion protein specific for the transferrin receptor serves as a delivery vehicle for effective brain targeting: Initial applications in anti-HIV antisense drug delivery to the brain. tumors highly express certain receptors such as transferrin for iron transport into brain tumors respectively. The role of the transferrin–transferrin-receptor system in drug delivery and targeting: Trends in Pharmacological Sciences 45 Transferrin receptor- Transferrin, a serum glycoprotein, transports iron through the blood and into cells by binding to the transferring receptor and subsequently being internalized via receptor-mediated endocytosis. AuNPs conjugated with peptides against both the epidermal growth factor and transferrin receptors and loaded with the … Materials & methods: PEGylated immunoliposomes were prepared with anti-transferrin receptor OX26 and anti-alpha-synuclein LB509 antibodies to overcome the BBB in … The delivery of recombinant protein or gene medicines to the brain is a binary process: either the brain drug developer re-engineers the biologic with BBB drug delivery technology, or goes forward with brain drug development in the absence of a BBB delivery platform. The in-vivo results indicated that transferrin receptor-targeted theranostic liposomes could be a promising carrier for brain theranostics due to nano-sized delivery and its permeability which provided an improved and prolonged brain targeting of docetaxel and QDs in comparison to the non-targeted preparations. Amongst the numerous potential targets at … Despite decades of development, very little clinical progression has been made, although clinical trials are emerging. Targeting gold nanoparticles (AuNPs) with two or more receptor binding peptides has been proposed to address intratumoral heterogeneity of glioblastomas that overexpress multiple cell surface receptors to ultimately improve therapeutic efficacy. Specifically, this research work was focused on designing PEGylated liposomes surface modified with the receptor targeting protein, transferrin and cell penetrating peptides (CPPs) for targeting and improving the delivery of desired therapeutic agent to brain. 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