Transcytosis of payloads that are non-covalently complexed to bispecific antibodies across the hCMEC/D3 blood-brain barrier model

Schmid, Daniela; Buntz, Annette; Phan, Thi Ngoc Hanh; Mayer, Klaus; Hoffmann, Eike; Thorey, Irmgard S.; Niewöhner, Jens; Vasters, Katrin; Sircar, Ranjan; Mundigl, Olaf; Kontermann, Roland E.; Brinkmann, Ulrich

doi:10.1515/hsz-2017-0311

Cited by 7 publications

(4 citation statements)

References 23 publications

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“…For example, it is not yet known whether FcRn, an endosome-resident receptor expressed in BECs which specializes in recycling antibodies back to the circulation [122], impacts transcytosis of TfR-antibody-based shuttles. Furthermore, the development of new antibody formats using, for example, pH-sensitive linkers [123] or sequential targeting to promote binding at the cell surface followed by intracellular redirection [29], clearly require a detailed understanding of sorting pathways and protein interactions within endosomes. Through the impact on these three areas, we consider that investigating the mechanisms of intracellular pathways at the BBB will help to accelerate the clinical development of new brain delivery platforms for biologics.…”

Section: Open Questions and Challengesmentioning

confidence: 99%

Intracellular transport and regulation of transcytosis across the blood–brain barrier

Villaseñor

Lampe

Schwaninger

et al. 2018

Cell. Mol. Life Sci.

152

107

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The blood–brain barrier is a dynamic multicellular interface that regulates the transport of molecules between the blood circulation and the brain parenchyma. Proteins and peptides required for brain homeostasis cross the blood–brain barrier via transcellular transport, but the mechanisms that control this pathway are not well characterized. Here, we highlight recent studies on intracellular transport and transcytosis across the blood–brain barrier. Endothelial cells at the blood–brain barrier possess an intricate endosomal network that allows sorting to diverse cellular destinations. Internalization from the plasma membrane, endosomal sorting, and exocytosis all contribute to the regulation of transcytosis. Transmembrane receptors and blood-borne proteins utilize different pathways and mechanisms for transport across brain endothelial cells. Alterations to intracellular transport in brain endothelial cells during diseases of the central nervous system contribute to blood–brain barrier disruption and disease progression. Harnessing the intracellular sorting mechanisms at the blood–brain barrier can help improve delivery of biotherapeutics to the brain.

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Section: Open Questions and Challengesmentioning

confidence: 99%

Intracellular transport and regulation of transcytosis across the blood–brain barrier

Villaseñor

Lampe

Schwaninger

et al. 2018

Cell. Mol. Life Sci.

152

107

View full text Add to dashboard Cite

show abstract

“…Despite ample literature describing small molecule and biologic transport in BBB models, 23 , 24 there has been limited study of and little standardization in methodology for assessing BBB transport of nanomaterials. 20 , 25 Three commonly used assays include NP association via flow cytometry, 26 , 27 monolayer association of NPs, 25 , 28 and transport of NPs across transwell‐grown cell monolayers 26 , 28 (Figure 1b ).…”

Section: Introductionmentioning

confidence: 99%

Trafficking through the blood–brain barrier is directed by core and outer surface components of layer‐by‐layer nanoparticles

Lamson,

Pickering,

Wyckoff

et al. 2023

Bioengineering & Transla Med

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Drug‐carrying nanoparticles are a promising strategy to deliver therapeutics into the brain, but their translation requires better characterization of interactions between nanomaterials and endothelial cells of the blood–brain barrier (BBB). Here, we use a library of 18 layer‐by‐layer electrostatically assembled nanoparticles (NPs) to independently assess the impact of NP core and surface materials on in vitro uptake, transport, and intracellular trafficking in brain endothelial cells. We demonstrate that NP core stiffness determines the magnitude of transport, while surface chemistry directs intracellular trafficking. Finally, we demonstrate that these factors similarly dictate in vivo BBB transport using intravital imaging through cranial windows in mice. We identify that hyaluronic acid surface chemistry increases transport across the BBB in vivo, and flow conditions are necessary to replicate this finding in vitro. Taken together, these findings highlight the importance of assay geometry, cell biology, and fluid flow in developing nanocarriers for delivery to the brain.

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“…In addition to varying cell line and model geometry, and despite ample literature describing small molecule and biologic transport in BBB models 20,21 , there has been limited study of and little standardization in methodology for assessing BBB transport of nanomaterials 17,22 . Three commonly used assays include nanoparticle (NP) association via flow cytometry 23,24 , monolayer association of NPs 22,25 , and transport of NPs across transwell-grown cell monolayers 23,25 ( Figure 1b ).…”

Section: Introductionmentioning

confidence: 99%

Core material and surface chemistry of Layer-by-Layer (LbL) nanoparticles independently direct uptake, transport, and trafficking in preclinical blood-brain barrier (BBB) models

Lamson

Pickering

Wyckoff

et al. 2022

Preprint

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Development of new treatments for neurological disorders, especially brain tumors and neurodegenerative diseases, is hampered by poor accumulation of new therapeutic candidates in the brain. Drug carrying nanoparticles are a promising strategy to deliver therapeutics, but there is a major need to understand interactions between nanomaterials and the cells of the blood-brain barrier (BBB), and to what degree these interactions can be predicted by preclinical models. Here, we use a library of eighteen layer-by-layer electrostatically assembled nanoparticles (LbL-NPs) to independently assess the impact of nanoparticle core stiffness and surface chemistry on in vitro uptake and transport in three common assays, as well as intracellular trafficking in hCMEC/D3 endothelial cells. We demonstrate that nanoparticle core stiffness impacts the magnitude of material transported, while surface chemistry influences how the nanoparticles are trafficked within the cell. Finally, we demonstrate that these factors similarly dictate in vivo BBB transport using intravital imaging through cranial windows in mice, and we discover that a hyaluronic acid surface chemistry provides an unpredicted boost to transport. Taken together, these findings highlight the importance of considering factors such as assay geometry, nanomaterial labelling strategies, and fluid flow in designing preclinical assays to improve nanoparticle screening throughput for drug delivery to the brain.

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Transcytosis of payloads that are non-covalently complexed to bispecific antibodies across the hCMEC/D3 blood-brain barrier model

Cited by 7 publications

References 23 publications

Intracellular transport and regulation of transcytosis across the blood–brain barrier

Intracellular transport and regulation of transcytosis across the blood–brain barrier

Trafficking through the blood–brain barrier is directed by core and outer surface components of layer‐by‐layer nanoparticles

Core material and surface chemistry of Layer-by-Layer (LbL) nanoparticles independently direct uptake, transport, and trafficking in preclinical blood-brain barrier (BBB) models

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