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      Preliminary Study on the Therapeutic Effect of Doxorubicin-Loaded Targeting Nanoparticles on Glioma

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      1 , 2 , 3 ,
      Applied Bionics and Biomechanics
      Hindawi

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          Abstract

          Doxorubicin (DOX) is an anthracycline anticancer drug, which is often associated with drug resistance and cytotoxicity. More unfortunately, the biological barrier in the human environment can weaken the efficacy of DOX, such as the blood-brain barrier (BBB). This work attempts to make efforts to solve this problem. We used polyethylene glycol distearoylphosphatidylethanolamine (PEG-DSPE) as a nanocarrier and DOX as a model drug to construct a composite nanodrug (TF-PEG-DSPE/DOX NPs) by coupling transferrin (TF). The results of glioma experiments show that the nanodrug can effectively penetrate BBB to achieve an antitumor effect.

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          Most cited references31

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          Transferrin and transferrin receptor function in brain barrier systems.

          1. Iron (Fe) is an essential component of virtually all types of cells and organisms. In plasma and interstitial fluids, Fe is carried by transferrin. Iron-containing transferrin has a high affinity for the transferrin receptor, which is present on all cells with a requirement for Fe. The degree of expression of transferrin receptors on most types of cells is determined by the level of Fe supply and their rate of proliferation. 2. The brain, like other organs, requires Fe for metabolic processes and suffers from disturbed function when a Fe deficiency or excess occurs. Hence, the transport of Fe across brain barrier systems must be regulated. The interaction between transferrin and transferrin receptor appears to serve this function in the blood-brain, blood-CSF, and cellular-plasmalemma barriers. Transferrin is present in blood plasma and brain extracellular fluids, and the transferrin receptor is present on brain capillary endothelial cells, choroid plexus epithelial cells, neurons, and probably also glial cells. 3. The rate of Fe transport from plasma to brain is developmentally regulated, peaking in the first few weeks of postnatal life in the rat, after which it decreases rapidly to low values. Two mechanisms for Fe transport across the blood-brain barrier have been proposed. One is that the Fe-transferrin complex is transported intact across the capillary wall by receptor-mediated transcytosis. In the second, Fe transport is the result of receptor-mediated endocytosis of Fe-transferrin by capillary endothelial cells, followed by release of Fe from transferrin within the cell, recycling of transferrin to the blood, and transport of Fe into the brain. Current evidence indicates that although some transcytosis of transferrin does occur, the amount is quantitatively insufficient to account for the rate of Fe transport, and the majority of Fe transport probably occurs by the second of the above mechanisms. 4. An additional route of Fe and transferrin transport from the blood to the brain is via the blood-CSF barrier and from the CSF into the brain. Iron-containing transferrin is transported through the blood-CSF barrier by a mechanism that appears to be regulated by developmental stage and iron status. The transfer of transferrin from blood to CSF is higher than that of albumin, which may be due to the presence of transferrin receptors on choroid plexus epithelial cells so that transferrin can be transported across the cells by a receptor-mediated process as well as by nonselective mechanisms. 5. Transferrin receptors have been detected in neurons in vivo and in cultured glial cells. Transferrin is present in the brain interstitial fluid, and it is generally assumed that Fe which transverses the blood-brain barrier is rapidly bound by brain transferrin and can then be taken up by receptor-mediated endocytosis in brain cells. The uptake of transferrin-bound Fe by neurons and glial cells is probably regulated by the number of transferrin receptors present on cells, which changes during development and in conditions with an altered iron status. 6. This review focuses on the information available on the functions of transferrin and transferrin receptor with respect to Fe transport across the blood-brain and blood-CSF barriers and the cell membranes of neurons and glial cells.
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            Blood‐brain barrier transport using a high affinity, brain‐selective VNAR antibody targeting transferrin receptor 1

            Transfer across the blood-brain barrier (BBB) remains a significant hurdle for the development of biopharmaceuticals with therapeutic effects within the central nervous system. 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. A synthetic phage display library based on the variable domain of new antigen receptor (VNAR) was used for in vitro selection against recombinant human TfR1 ectodomain (rh-TfR1-ECD) followed by in vivo selection in mouse for brain parenchyma penetrating antibodies. TXB2 VNAR was identified as a high affinity, species cross-reactive VNAR antibody against TfR1-ECD that does not compete with transferrin or ferritin for receptor binding. IV dosing of TXB2 when fused to human Fc domain (TXB2-hFc) at 25 nmol/kg (1.875 mg/kg) in mice resulted in rapid binding to brain capillaries with subsequent transport into the brain parenchyma and specific uptake into TfR1-positive neurons. Likewise, IV dosing of TXB2-hFc fused with neurotensin (TXB2-hFc-NT) at 25 nmol/kg resulted in a rapid and reversible pharmacological response as measured by body temperature reduction. TXB2-hFc did not elicit any acute adverse reactions, bind, or deplete circulating reticulocytes or reduce BBB-expressed endogenous TfR1 in mice. There was no evidence of target-mediated clearance or accumulation in peripheral organs except lung. In conclusion, TXB2 is a high affinity, species cross-reactive, and brain-selective VNAR antibody to TfR1 that rapidly crosses the BBB and exhibits a favorable pharmacokinetic and safety profile and can be readily adapted to carry a wide variety of biotherapeutics from blood to brain.
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              Application of poly(ethylene glycol)–distearoylphosphatidylethanolamine (PEG-DSPE) block copolymers and their derivatives as nanomaterials in drug delivery

              Poly(ethylene glycol)–distearoylphosphatidylethanolamine (PEG-DSPE) block copolymers are biocompatible and amphiphilic polymers that can be widely utilized in the preparation of liposomes, polymeric nanoparticles, polymer hybrid nanoparticles, solid lipid nanoparticles, lipid–polymer hybrid nanoparticles, and microemulsions. Particularly, the terminal groups of PEG can be activated and linked to various targeting ligands, which can prolong the circulation time, improve the drug bioavailability, reduce undesirable side effects, and especially target specific cells, tissues, and even the intracellular localization in organelles. This review herein aims to describe recent developments in drug carriers exploiting PEG-DSPE block copolymers and their derivatives, and the incorporation of different ligands to the end groups of PEG-DSPE to target delivery, focusing on their modification approaches, advantages, applications, and the probable associated drawbacks.
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                Author and article information

                Contributors
                Journal
                Appl Bionics Biomech
                Appl Bionics Biomech
                ABB
                Applied Bionics and Biomechanics
                Hindawi
                1176-2322
                1754-2103
                2022
                28 March 2022
                : 2022
                : 6405400
                Affiliations
                1Department of Neurosurgery, Cangzhou People's Hospital, Cangzhou, 061000 Hebei, China
                2Department of Neurosurgery, Gaotang People's Hospital, Liaocheng, 252800 Shandong, China
                3Department of Neurosurgery, Zibo Central Hospital, Zibo, 255000 Shandong, China
                Author notes

                Academic Editor: Fahd Abd Algalil

                Author information
                https://orcid.org/0000-0002-9557-2161
                Article
                10.1155/2022/6405400
                8979730
                095a755d-0732-4b16-bb67-d460aefd7755
                Copyright © 2022 Weitu Lan et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 18 December 2021
                : 5 January 2022
                : 10 January 2022
                Categories
                Research Article

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