Targeted transport of biotherapeutics at the blood-brain barrier

Moos, Torben; Thomsen, Maj Schneider; Burkhart, Annette; Hede, Eva; Laczek, Bartosz

doi:10.1080/17425247.2023.2292697

Cited by 3 publications

(3 citation statements)

References 117 publications

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“…CD98hc has been verified as a strong candidate for pharmacological targeting to the BBB [52] where various delivery platforms utilizing its high and selective expression are being investigated. CD98hc is an intracellular amino acid transporter and integrin signaling enhancer [14] and among the most highly expressed transcripts in human and mouse brain capillaries [25,32,53], which is in agreement with the high CD98hc protein detected in the ELISA of the present study.…”

Section: Discussionsupporting

confidence: 91%

“…Targeting nutrient receptors and transporters, which are highly expressed at the BBB is of interest for delivery of large therapeutics to the brain [25]. The intriguing possibility of pharmacologically increasing the expression of TfR1, GLUT1, or CD98hc on BCECs in a manner that could increase the availability of targetable molecules inspired this study.…”

Section: Discussionmentioning

confidence: 99%

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Upregulation of Transferrin Receptor 1 (TfR1) at the Blood‐Brain Barrier by Valproic Acid, but Not of Glucose Transporter 1 (GLUT1) or CD98hc

Helgudottir,

Johnsen,

Routhe

et al. 2024

Preprint

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Background. Transferrin receptor 1 (TfR1), glucose transporter 1 (GLUT1), and CD98hc are candidates for targeted therapy at the blood-brain barrier (BBB). Our objective was to challenge the expression of TfR1, GLUT1, and CD98hc in brain capillaries by the histone deacetylase inhibitor (HDACi) valproic acid (VPA). Methods. Primary mouse brain capillary endothelial cells (BCECs) and brain capillaries isolated from mice injected intraperitoneally with VPA were examined using RT-qPCR and ELISA. Targeting to the BBB was performed by injecting monoclonal anti-TfR1 (Ri7217)-conjugated gold nanoparticles measured using ICP-MS. Results. In BCECs co-cultured with glial cells, Tfrc mRNA expression was significantly higher after 6 h VPA returning to baseline after 24 h. In vivo Glut1 mRNA expression was significantly higher in males, but not females', receiving VPA, whereas Cd98hc mRNA expression was unaffected by VPA. TfR1 increased significantly in vivo after VPA, whereas GLUT1 and CD98hc were unchanged. Uptake of anti-TfR1-conjugated nanoparticles was unaltered by VPA in spite upregulated TfR expression. Conclusions. VPA upregulates TfR1 in brain endothelium in vivo and in vitro. VPA does not increase GLUT1 and CD98hc proteins. The increase in TfR1 does not result in higher anti-TfR1 antibody targetability, suggesting targeting sufficiently occurs with available transferrin receptors without further contribution from accessory VPA-induced TfR1.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Upregulation of Transferrin Receptor 1 (TfR1) at the Blood‐Brain Barrier by Valproic Acid, but Not of Glucose Transporter 1 (GLUT1) or CD98hc

Helgudottir,

Johnsen,

Routhe

et al. 2024

Preprint

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show abstract

“…This minimalistic design endows nanobodies with several advantages, such as the ability to bind to cryptic epitopes inaccessible to conventional antibodies, high thermal stability, and ease of nanobody production in microbial systems. These features are particularly beneficial in targeting complex molecular structures including enzymes and toxins [ 75 , 76 , 77 ]. They offer advantages over traditional monoclonal antibodies, such as improved tissue penetration and the ability to be easily modified for therapeutic or diagnostic purposes due to their low immunogenicity and specificity for complex targets [ 78 ].…”

Section: Multi-target Drugsmentioning

confidence: 99%

Innovative Therapeutic Strategies in Alzheimer’s Disease: A Synergistic Approach to Neurodegenerative Disorders

Niazi,

Magoola,

Mariam

2024

Pharmaceuticals

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Alzheimer’s disease (AD) remains a significant challenge in the field of neurodegenerative disorders, even nearly a century after its discovery, due to the elusive nature of its causes. The development of drugs that target multiple aspects of the disease has emerged as a promising strategy to address the complexities of AD and related conditions. The immune system’s role, particularly in AD, has gained considerable interest, with nanobodies representing a new frontier in biomedical research. Advances in targeting antibodies against amyloid-β (Aβ) and using messenger RNA for genetic translation have revolutionized the production of antibodies and drug development, opening new possibilities for treatment. Despite these advancements, conventional therapies for AD, such as Cognex, Exelon, Razadyne, and Aricept, often have limited long-term effectiveness, underscoring the need for innovative solutions. This necessity has led to the incorporation advanced technologies like artificial intelligence and machine learning into the drug discovery process for neurodegenerative diseases. These technologies help identify therapeutic targets and optimize lead compounds, offering a more effective approach to addressing the challenges of AD and similar conditions.

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Upregulation of Transferrin Receptor 1 (TfR1) but Not Glucose Transporter 1 (GLUT1) or CD98hc at the Blood–Brain Barrier in Response to Valproic Acid

Helgudóttir,

Johnsen,

Routhe

et al. 2024

Cells

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Background: Transferrin receptor 1 (TfR1), glucose transporter 1 (GLUT1), and CD98hc are candidates for targeted therapy at the blood–brain barrier (BBB). Our objective was to challenge the expression of TfR1, GLUT1, and CD98hc in brain capillaries using the histone deacetylase inhibitor (HDACi) valproic acid (VPA). Methods: Primary mouse brain capillary endothelial cells (BCECs) and brain capillaries isolated from mice injected intraperitoneally with VPA were examined using RT-qPCR and ELISA. Targeting to the BBB was performed by injecting monoclonal anti-TfR1 (Ri7217)-conjugated gold nanoparticles measured using ICP-MS. Results: In BCECs co-cultured with glial cells, Tfrc mRNA expression was significantly higher after 6 h VPA, returning to baseline after 24 h. In vivo Glut1 mRNA expression was significantly higher in males, but not females, receiving VPA, whereas Cd98hc mRNA expression was unaffected by VPA. TfR1 increased significantly in vivo after VPA, whereas GLUT1 and CD98hc were unchanged. The uptake of anti-TfR1-conjugated nanoparticles was unaltered by VPA despite upregulated TfR expression. Conclusions: VPA upregulates TfR1 in brain endothelium in vivo and in vitro. VPA does not increase GLUT1 and CD98hc proteins. The increase in TfR1 does not result in higher anti-TfR1 antibody targetability, suggesting targeting sufficiently occurs with available transferrin receptors without further contribution from accessory VPA-induced TfR1.

show abstract

Targeted transport of biotherapeutics at the blood-brain barrier

Cited by 3 publications

References 117 publications

Upregulation of Transferrin Receptor 1 (TfR1) at the Blood‐Brain Barrier by Valproic Acid, but Not of Glucose Transporter 1 (GLUT1) or CD98hc

Upregulation of Transferrin Receptor 1 (TfR1) at the Blood‐Brain Barrier by Valproic Acid, but Not of Glucose Transporter 1 (GLUT1) or CD98hc

Innovative Therapeutic Strategies in Alzheimer’s Disease: A Synergistic Approach to Neurodegenerative Disorders

Upregulation of Transferrin Receptor 1 (TfR1) but Not Glucose Transporter 1 (GLUT1) or CD98hc at the Blood–Brain Barrier in Response to Valproic Acid

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