Drug Delivery Strategies to Overcome the Blood–Brain Barrier (BBB)

Helms, Hans Christian Cederberg; Kristensen, M; Saaby, Lasse; Fricker, Gert; Brodin, Birger

doi:10.1007/164_2020_403

Cited by 14 publications

(11 citation statements)

References 167 publications

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“…Targeting nutrient receptors and transporters which are highly expressed at the BBB is of interest for delivery of large therapeutics to the brain. These transporting molecules follow Michaelis-Menten type kinetics with the maximum transport capacity being re ected in their surface availability 30 , which led to the question if it would be possible to increase the expression of TfR1, GLUT1 or CD98hc on the BCECs by epigenetic mechanisms leading to increases at the surface availability and transport of targeted molecules.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic upregulation by valproic acid of transferrin receptor 1, and not glucose transporter 1 or CD98hc, at the blood-brain barrier

Helgudottir

Johnsen²,

Routhe

et al. 2022

Preprint

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BackgroundThe objectives of the present study were to investigate whether the expression of transferrin receptor 1 (TfR1), glucose transporter 1 (Glut1), or Cluster of Differentiation 98 Heavy Chain (CD98hc) is epigenetically regulated in brain capillary endothelial cells (BCECs) denoting the blood-brain barrier (BBB).MethodsThe expression of these targets was investigated both in vitro and in vivo following treatment with the histone deacetylase inhibitor (HDACi) valproic acid (VPA). Mice were injected intraperitoneally with VPA followed by analysis of isolated brain capillaries, and the capillary depleted brain samples. Brain tissue, isolated brain capillaries, and cultured primary endothelial cells were analyzed by RT-qPCR, immunolabeling and ELISA for expression of TfR1, Glut1 and CD98hc. We also studied the vascular targeting in VPA-treated mice injected with monoclonal anti-transferrin receptor (Ri7) conjugated with 1.4 nm gold nanoparticles. ResultsValidating the effects of VPA on gene transcription in BCECs, transcriptomic analysis identified 24,371 expressed genes, of which 305 were differentially expressed with 192 upregulated and 113 downregulated genes. In vitro using BCECs co-cultured with glial cells, the mRNA expression of Tfrc was significantly higher after VPA treatment for 6 h with its expression returning to baseline after 24 h. Conversely, the mRNA expression of Glut1 and Cd98hc was unaffected by VPA treatment. In vivo, the TfR1 protein expression in brain capillaries increased significantly after treatment with both 100 mg/kg and 400 mg/kg VPA. Conversely, VPA treatment did not increase GLUT1 or CD98hc. Using ICP-MS-based quantification, the brain uptake of nanogold conjugated anti-TfR1 antibodies was non-significant in spite of increased expression of TfR1. ConclusionsWe report that VPA treatment upregulates TfR1 at the BBB both in vivo and in vitro in isolated primary endothelial cells. In contrast, VPA treatment does not influence the expression of GLUT1 and CD98hc. The increase in the overall TfR1 protein expression however does not increase transport of TfR-targeted monoclonal antibody and indicates that targeted delivery using the transferrin receptor should aim for increased mobilization of already available transferrin receptor molecules to improve trafficking through the BBB.

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Section: Discussionmentioning

confidence: 99%

Epigenetic upregulation by valproic acid of transferrin receptor 1, and not glucose transporter 1 or CD98hc, at the blood-brain barrier

Helgudottir

Johnsen²,

Routhe

et al. 2022

Preprint

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“…Indiscriminate destruction of the BBB may lead to the development of unpredictable brain diseases. [ 19 ]…”

Section: Blood‐brain Barriermentioning

confidence: 99%

“…Indiscriminate destruction of the BBB may lead to the development of unpredictable brain diseases. [19] In addition to osmosis, it is possible to use chemicals to destroy the BBB. Chemical disruption of the BBB often involves vasoactive substances in the arteries that produce a temporary inflammatory response in the endothelium.…”

Section: Enhanced Paracellular Transport Patternsmentioning

confidence: 99%

Micro‐Nanocarriers Based Drug Delivery Technology for Blood‐Brain Barrier Crossing and Brain Tumor Targeting Therapy

Wang

Shi

Jiang

et al. 2022

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His research interests include translational studies in the development of new therapies and biomarkers for prognosis and prediction of therapy, and mechanism investigation of treatment resistance in lymphoma. Yinyan Wang is a neurosurgeon and doctoral supervisor at Beijing Tiantan Hospital, and he is a principal investigator for the National Research Center of Neurological Diseases, a principal investigator for China Institute for Brain Research, Beijing. He focused on the individualized precise treatment of gliomas, and he published 72 papers in this field. Lin Feng is an associate professor/doctoral supervisor of Beihang University, "Beijing New Star of Science and Technology." He is a member of the IEEE International Technical Committee on Micro and Nano Robotics, a member of the SCI-indexed journal "Bio-Design and Manufacturing," "Frontiers in Robotics and AI," Science cooperative journal "Cyborg and Bionic Systems." He has published more than 115 academic papers and one textbook on "Introduction to Micro and Nano Robotics." His research interests include precision technology and medical fundamental research on targeted drug delivery field-controlled micro-nanorobots, which is supported by the National Key R&D Program for Intelligent Robotics.

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“…In addition, the transport of substances across the BBB also includes absorptive-mediated transport (AMT), carrier-mediated transport (CMT), receptor-mediated transport (RMT), active efflux transport, and cell-mediated transport [54,55]. Among them, AMT has poor selectivity and cationic protein can bind to any negatively charged cell membrane component.…”

Section: Active Targetingmentioning

confidence: 99%

Regulation of Pathological Blood Brain Barrier for Intracranial Enhanced Drug Delivery and Anti-glioblastoma Therapeutics

Wang¹,

Zhang²,

Wen³

et al. 2022

Preprint

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The blood brain barrier (BBB) is an essential component in regulating and maintaining the homeostatic microenvironment of the central nervous system (CNS). During the occurrence and development of glioblastoma (GBM), BBB is pathologically disrupted with markedly increased permeability. Due to the obstruction imposed by the BBB, strategies currently employed for GBM therapeutics still obtain a very low success rate and lead to systemic toxicity. Moreover, chemotherapy could promote pathological BBB functional restoration, accompanied with a prominent decrease of intracerebral therapeutics transportion during GBM multiple administration, resulting in chemotherapy failure for GBM treatment. The effective delivery of therapeutics into the brain still faces with severe challenges. Regulation of pathological BBB for enhanced transporting of therapeutics across the barrier may provide new opportunities for effective and safe treatment of GBM. This article reviews the structure and function of BBB in physiological state, the mechanisms underlying BBB pathological fenestration during the development of GBM, and the therapeutic strategies of GBM based on BBB intervention and therapeutic drugs transporting across the BBB.

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Drug Delivery Strategies to Overcome the Blood–Brain Barrier (BBB)

Cited by 14 publications

References 167 publications

Epigenetic upregulation by valproic acid of transferrin receptor 1, and not glucose transporter 1 or CD98hc, at the blood-brain barrier

Epigenetic upregulation by valproic acid of transferrin receptor 1, and not glucose transporter 1 or CD98hc, at the blood-brain barrier

Micro‐Nanocarriers Based Drug Delivery Technology for Blood‐Brain Barrier Crossing and Brain Tumor Targeting Therapy

Regulation of Pathological Blood Brain Barrier for Intracranial Enhanced Drug Delivery and Anti-glioblastoma Therapeutics

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