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The 'most widely studied' receptor for targeted nano brain delivery is a target of Spike
‘The most widely studied’ target for ligands designed to direct nanocarriers across the protective BBB, the iron transferrin (TfR) receptor, is a target of Spike protein
‘Utilising … receptor ligands for active targeting is the most promising strategy… by employing ligands that preferentially bind the iron transferrin… [for] predictable pathways of internalisation to the brain’
TfR is a viral target for infection, including HIV and Adenoviruses
TfR is highly expressed on brain epithelium, with ‘bone marrow, splenic and hepatocellular accumulation also a concern’
Non-invasive /// BBB crossing
Advances in Non-Animal Testing Approaches towards Accelerated Clinical Translation of Novel Nanotheranostic Therapeutics for Central Nervous System Disorders
Lynch MJ, Gobbo OL. Review. Nanomaterials (Basel). 2021 Oct 7;11(10):2632. DOI: 10.3390/nano11102632
… This review aims to identify the most contemporary non-invasive approaches for BBB crossing using nanotheranostics as a novel drug delivery strategy…
Image: NTP platform design possibilities for targeted multifunctional imaging and treatment of CNS related disorders.
…The most promising and readily tested NTP platforms are those that make use of surface functionalisation with either known ligands of the receptors highly expressed on BBB endothelial cell surface, or indeed by using inherent cellular components such as macrophages [35] and fatty acids to enhance penetrance….
3.1. Adsorptive Endocytosis-Mediated NTP Delivery
Adsorptive-mediated delivery to the brain involves the functionalisation of the NTP surface with cationic components to selectively target the net anionic surface charge of luminal surface of endothelial cells of brain capillary [70]. This charge is a consequence of clathrin vesicles that function to regulate ionic trafficking of molecules, and to specifically repel anionic species. ...
They can also be used to condense and bind nucleic acid, and thus have been demonstrated to successfully deliver DNA plasmid across the BBB to brain tissues. A number of candidate neuropharmaceuticals, including gene therapies, neuroprotective agents and chemotherapeutics, with enhanced permeability, were confirmed by images to have increased accumulation, and in some cases sustained release profiles [73,74]. The most viable materials for such platforms are pegylated chitosan, lipid and polymeric nanoparticles such as polylactic acid (PLA), poly-Ɛ-caprolactone (PCL), cholesterol, poly(butyl cyanoacrylate) (PBCA) gelatin siloxane and mesoporous silica magnetic nanoparticles incorporating iron oxide (SiO2-Fe3O4) [75,76]. …
However, the primary issue with this class of NTPs is that despite their potential they are notably more toxic than non-ionic or anionic counterparts, which must be appraised before recommending their scale-up and clinical testing….
3.2. Receptor-Mediated Transcytosis
…Perhaps active targeting utilising functionalised receptor ligands for active targeting is the most promising strategy for the novel nanotherapy driven drug delivery systems. This is unsurprising given the exquisite regulatory function of the BBB and associated biochemical barriers to entry of exogenous compounds. As a direct consequence, by employing ligands that preferentially bind the iron transferrin, folate, insulin, and LDL cholesterol receptors, among others that have been studied, and predictable pathways of internalisation to the brain, it can be appreciated that these are the most probable candidates, particularly when exploited synergistically [64].
3.2.1. Transferrin (TfR) Receptor-Mediated Transcytosis
The most widely studied of the foregoing is arguably the iron transferrin (TfR) receptor, as they are very highly expressed in the brain endothelium in comparison to the periphery, although the bone marrow, splenic and hepatocellular accumulation is always a concern [81]. The lactoferrin receptor is also a notable member of this family and has been targeted to varying success in some instances, such as that achieved by Kumari and colleagues for temozolomide delivery, which was demonstrated both in vitro and in vivo to improve its pharmacokinetics and intratumoral accumulation by a pH-dependent responsive mechanism [82].
… A number of immunoliposomes have been developed using antibodies such as OX26, which recognise alternative epitopes on the transferrin receptor … achieving an 8-fold increased uptake compared to naked dopamine and 3-fold compared to pegylated liposome alone [83]. …
… The prototypical example in this class would be JR-141 (Pabinafusp Alfa), which was recently approved in Japan [88]. … JCR pharmaceuticals have patented a proprietary BBB permeating technology “J-Brain Cargo”, which utilises a fusion protein comprising an anti-TfR antibody and iduronate-2-sulfatase as an intravenous enzyme replacement therapy…
Transferrin receptor is another receptor for SARS-CoV-2 entry
Xiaopeng Tang, Mengli Yang, Zilei Duan, Zhiyi Liao, Lei Liu, Ruomei Cheng, Mingqian Fang, Gan Wang, Hongqi Liu, Jingwen Xu, Peter M Kamau, Zhiye Zhang, Lian Yang, Xudong Zhao, Xiaozhong Peng, Ren Lai
Preprint. doi: https://doi.org/10.1101/2020.10.23.350348
Angiotensin-converting enzyme 2 (ACE2) has been suggested as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry to cause coronavirus disease 2019 (COVID-19). However, no ACE2 inhibitors have shown definite beneficiaries for COVID-19 patients, applying the presence of another receptor for SARS-CoV-2 entry. Here we show that ACE2 knockout dose not completely block virus entry, while TfR directly interacts with virus Spike protein to mediate virus entry and SARS-CoV-2 can infect mice with over-expressed humanized transferrin receptor (TfR) and without humanized ACE2. TfR-virus co-localization is found both on the membranes and in the cytoplasma, suggesting SARS-CoV-2 transporting by TfR, the iron-transporting receptor shuttling between cell membranes and cytoplasma. Interfering TfR-Spike interaction blocks virus entry to exert significant anti-viral effects. Anti-TfR antibody (EC50 ~16.6 nM) shows promising anti-viral effects in mouse model. Collectively, this report indicates that TfR is another receptor for SARS-CoV-2 entry and a promising anti-COVID-19 target.
… We identified the ubiquitously expressed transferrin receptor (TfR), which is co-localized with ACE2 on cell membranes, as an entry factor of SARS-CoV-2 by directly binding to virus spike protein and ACE2 with high affinities…
Results
Elevated expression of TfR in respiratory tract and lung tissue of monkey and mouse infected by SARS-CoV-2
Direct interactions among virus spike protein, ACE2 and TfR
Interferences of TfR-Spike interaction inhibit SARS-CoV-2 infection
SARS-CoV-2 infects ACE2 knockout cells
Anti-TfR antibody shows promising anti-SARS-CoV-2 effects
…An emerging enigma is that many viruses use the host gate of iron, TfR, as a means to enter into the cells and TfR is a viral target for infection (23,29-31). The entry and infection of a number different types of viruses including canine parvovirus32, mink enteritis virus (33), feline panleukopenia virus (32,34,35), New World hemorrhagic fever arenaviruses (36,37), mouse mammary tumor virus38,39, human and simian immunodeficiency viruses (40-42), hepatitis C virus43, human adenoviruses (44) and alphaviruses (45) depends on TfR trafficking pathway. Given that TfR is one of the most highly expressed plasma membrane components, different reports suggest that TfR an attractive target for the virus to initiate host cell infection.
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