Focused Ultrasound and Microbubble Treatment Increases Delivery of Transferrin Receptor-Targeting Liposomes to the Brain

Marieke Olsman; Viktoria Sereti; Melina Mühlenpfordt; Kasper Bendix Johnsen; Thomas Lars Andresen; Andrew James Urquhart; Catharina de Lange Davies

doi:10.1016/j.ultrasmedbio.2021.01.014

Focused Ultrasound and Microbubble Treatment Increases Delivery of Transferrin Receptor-Targeting Liposomes to the Brain

Marieke Olsman^*, Viktoria Sereti, Melina Mühlenpfordt, Kasper Bendix Johnsen, Thomas Lars Andresen, Andrew James Urquhart, Catharina de Lange Davies

^*Corresponding author for this work

Department of Health Technology

Norwegian University of Science and Technology

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

The blood-brain barrier (BBB) is a major obstacle to treating several brain disorders. Focused ultrasound (FUS) in combination with intravascular microbubbles increases BBB permeability by opening tight junctions, creating endothelial cell openings, improving endocytosis and increasing transcytosis. Here we investigated whether combining FUS and microbubbles with transferrin receptor-targeting liposomes would result in enhanced delivery to the brain of post-natal rats compared with liposomes lacking the BBB-targeting moiety. For all animals, increased BBB permeability was observed after FUS treatment. A 40% increase in accumulation of transferrin receptor-targeting liposomes was observed in the FUS-treated hemisphere, whereas the isotype immunoglobulin G liposomes showed no increased accumulation. Confocal laser scanning microscopy of brain sections revealed that both types of liposomes were mainly observed in endothelial cells in the FUS-treated hemisphere. The results demonstrate that FUS and microbubble treatment combined with BBB-targeting liposomes could be a promising approach to enhance drug delivery to the brain.

Original language	English
Journal	Ultrasound in Medicine and Biology
Volume	47
Issue number	5
Pages (from-to)	1343-1355
ISSN	0301-5629
DOIs	https://doi.org/10.1016/j.ultrasmedbio.2021.01.014
Publication status	Published - 2021

Bibliographical note

Funding Information:
We thank Torben Moos, Aalborg University, for providing the OX26 antibody and Sofie Snipstad and Sigrid Berg for their technical support with the FUS instrumentation. MRI was performed at the MR Core Facility, Norwegian University of Science and Technology (NTNU). We acknowledge Deborah Hill for her technical assistance with the MRI. Housing of the animals was provided by the Comparative Medicine Core Facility (NTNU). Tissue sections were prepared by the Cellular and Molecular Imaging Core Facility (NTNU). We thank Astrid Bj?rk?y and the Centre for Advanced Microscopy at the Faculty of Natural Sciences (NTNU) for technical assistance with CLSM. Illustrations were created with BioRender.com. The project was internally funded by the Norwegian University of Science and Technology and the Technical University of Denmark. Thomas Lars Andresen acknowledges generous support from the Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery ( www.ribbdd.dk; grant R155-2013-14113). The authors declare no competing interest.

Keywords

Blood–brain barrier disruption
Liposomes
Microbubbles
Transferrin receptor-targeting
Ultrasound

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title = "Focused Ultrasound and Microbubble Treatment Increases Delivery of Transferrin Receptor-Targeting Liposomes to the Brain",

abstract = "The blood-brain barrier (BBB) is a major obstacle to treating several brain disorders. Focused ultrasound (FUS) in combination with intravascular microbubbles increases BBB permeability by opening tight junctions, creating endothelial cell openings, improving endocytosis and increasing transcytosis. Here we investigated whether combining FUS and microbubbles with transferrin receptor-targeting liposomes would result in enhanced delivery to the brain of post-natal rats compared with liposomes lacking the BBB-targeting moiety. For all animals, increased BBB permeability was observed after FUS treatment. A 40% increase in accumulation of transferrin receptor-targeting liposomes was observed in the FUS-treated hemisphere, whereas the isotype immunoglobulin G liposomes showed no increased accumulation. Confocal laser scanning microscopy of brain sections revealed that both types of liposomes were mainly observed in endothelial cells in the FUS-treated hemisphere. The results demonstrate that FUS and microbubble treatment combined with BBB-targeting liposomes could be a promising approach to enhance drug delivery to the brain.",

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author = "Marieke Olsman and Viktoria Sereti and Melina M{\"u}hlenpfordt and Johnsen, {Kasper Bendix} and Andresen, {Thomas Lars} and Urquhart, {Andrew James} and Davies, {Catharina de Lange}",

note = "Funding Information: We thank Torben Moos, Aalborg University, for providing the OX26 antibody and Sofie Snipstad and Sigrid Berg for their technical support with the FUS instrumentation. MRI was performed at the MR Core Facility, Norwegian University of Science and Technology (NTNU). We acknowledge Deborah Hill for her technical assistance with the MRI. Housing of the animals was provided by the Comparative Medicine Core Facility (NTNU). Tissue sections were prepared by the Cellular and Molecular Imaging Core Facility (NTNU). We thank Astrid Bj?rk?y and the Centre for Advanced Microscopy at the Faculty of Natural Sciences (NTNU) for technical assistance with CLSM. Illustrations were created with BioRender.com. The project was internally funded by the Norwegian University of Science and Technology and the Technical University of Denmark. Thomas Lars Andresen acknowledges generous support from the Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery ( www.ribbdd.dk; grant R155-2013-14113). The authors declare no competing interest. ",

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AU - Johnsen, Kasper Bendix

AU - Andresen, Thomas Lars

AU - Urquhart, Andrew James

AU - Davies, Catharina de Lange

N1 - Funding Information: We thank Torben Moos, Aalborg University, for providing the OX26 antibody and Sofie Snipstad and Sigrid Berg for their technical support with the FUS instrumentation. MRI was performed at the MR Core Facility, Norwegian University of Science and Technology (NTNU). We acknowledge Deborah Hill for her technical assistance with the MRI. Housing of the animals was provided by the Comparative Medicine Core Facility (NTNU). Tissue sections were prepared by the Cellular and Molecular Imaging Core Facility (NTNU). We thank Astrid Bj?rk?y and the Centre for Advanced Microscopy at the Faculty of Natural Sciences (NTNU) for technical assistance with CLSM. Illustrations were created with BioRender.com. The project was internally funded by the Norwegian University of Science and Technology and the Technical University of Denmark. Thomas Lars Andresen acknowledges generous support from the Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery ( www.ribbdd.dk; grant R155-2013-14113). The authors declare no competing interest.

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N2 - The blood-brain barrier (BBB) is a major obstacle to treating several brain disorders. Focused ultrasound (FUS) in combination with intravascular microbubbles increases BBB permeability by opening tight junctions, creating endothelial cell openings, improving endocytosis and increasing transcytosis. Here we investigated whether combining FUS and microbubbles with transferrin receptor-targeting liposomes would result in enhanced delivery to the brain of post-natal rats compared with liposomes lacking the BBB-targeting moiety. For all animals, increased BBB permeability was observed after FUS treatment. A 40% increase in accumulation of transferrin receptor-targeting liposomes was observed in the FUS-treated hemisphere, whereas the isotype immunoglobulin G liposomes showed no increased accumulation. Confocal laser scanning microscopy of brain sections revealed that both types of liposomes were mainly observed in endothelial cells in the FUS-treated hemisphere. The results demonstrate that FUS and microbubble treatment combined with BBB-targeting liposomes could be a promising approach to enhance drug delivery to the brain.

AB - The blood-brain barrier (BBB) is a major obstacle to treating several brain disorders. Focused ultrasound (FUS) in combination with intravascular microbubbles increases BBB permeability by opening tight junctions, creating endothelial cell openings, improving endocytosis and increasing transcytosis. Here we investigated whether combining FUS and microbubbles with transferrin receptor-targeting liposomes would result in enhanced delivery to the brain of post-natal rats compared with liposomes lacking the BBB-targeting moiety. For all animals, increased BBB permeability was observed after FUS treatment. A 40% increase in accumulation of transferrin receptor-targeting liposomes was observed in the FUS-treated hemisphere, whereas the isotype immunoglobulin G liposomes showed no increased accumulation. Confocal laser scanning microscopy of brain sections revealed that both types of liposomes were mainly observed in endothelial cells in the FUS-treated hemisphere. The results demonstrate that FUS and microbubble treatment combined with BBB-targeting liposomes could be a promising approach to enhance drug delivery to the brain.

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KW - Microbubbles

KW - Transferrin receptor-targeting

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DO - 10.1016/j.ultrasmedbio.2021.01.014

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C2 - 33608142

AN - SCOPUS:85101358010

SN - 0301-5629

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SP - 1343

EP - 1355

JO - Ultrasound in Medicine and Biology

JF - Ultrasound in Medicine and Biology

IS - 5

ER -

Focused Ultrasound and Microbubble Treatment Increases Delivery of Transferrin Receptor-Targeting Liposomes to the Brain

Abstract

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Keywords

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