Enhanced glutathione PEGylated liposomal brain delivery of an anti-amyloid single domain antibody fragment in a mouse model for Alzheimer's disease
Copyright © 2015 Elsevier B.V. All rights reserved..
Treatment of neurodegenerative disorders such as Alzheimer's disease is hampered by the blood-brain barrier (BBB). This tight cerebral vascular endothelium regulates selective diffusion and active transport of endogenous molecules and xenobiotics into and out of the brain parenchyma. In this study, glutathione targeted PEGylated (GSH-PEG) liposomes were designed to deliver amyloid-targeting antibody fragments across the BBB into the brain. Two different formulations of GSH-PEG liposomes based on 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and egg-yolk phosphatidylcholine (EYPC) were produced. Both formulations encapsulate 15kDa amyloid beta binding llama single domain antibody fragments (VHH-pa2H). To follow the biodistribution of VHH-pa2H rather than the liposome, the antibody fragment was labeled with the radioisotope indium-111. To prolong the shelf life of the construct beyond the limit of radioactive decay, an active-loading method was developed to efficiently radiolabel the antibody fragments after encapsulation into the liposomes, with radiolabeling efficiencies of up to 68% after purification. The radiolabeled liposomes were administered via a single intravenous bolus injection to APPswe/PS1dE9 double transgenic mice, a mouse model of Alzheimer's disease, and their wildtype littermates. Both GSH-PEG DMPC and GSH-PEG EYPC liposomes significantly increased the standard uptake values (SUV) of VHH-pa2H in the blood of the animals compared to free VHH-pa2H. Encapsulation in GSH-PEG EYPC liposomes resulted in the highest increase in SUV in the brains of transgenic animals. Overall, these data provide evidence that GSH-PEG liposomes may be suitable for specific delivery of single domain antibody fragments over the BBB into the brain.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:203 |
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| Enthalten in: |
Journal of controlled release : official journal of the Controlled Release Society - 203(2015) vom: 10. Apr., Seite 40-50 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rotman, Maarten [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 09.03.2016 Date Revised 02.12.2018 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jconrel.2015.02.012 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM246114010 |
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| 245 | 1 | 0 | |a Enhanced glutathione PEGylated liposomal brain delivery of an anti-amyloid single domain antibody fragment in a mouse model for Alzheimer's disease |
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| 500 | |a Date Revised 02.12.2018 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2015 Elsevier B.V. All rights reserved. | ||
| 520 | |a Treatment of neurodegenerative disorders such as Alzheimer's disease is hampered by the blood-brain barrier (BBB). This tight cerebral vascular endothelium regulates selective diffusion and active transport of endogenous molecules and xenobiotics into and out of the brain parenchyma. In this study, glutathione targeted PEGylated (GSH-PEG) liposomes were designed to deliver amyloid-targeting antibody fragments across the BBB into the brain. Two different formulations of GSH-PEG liposomes based on 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and egg-yolk phosphatidylcholine (EYPC) were produced. Both formulations encapsulate 15kDa amyloid beta binding llama single domain antibody fragments (VHH-pa2H). To follow the biodistribution of VHH-pa2H rather than the liposome, the antibody fragment was labeled with the radioisotope indium-111. To prolong the shelf life of the construct beyond the limit of radioactive decay, an active-loading method was developed to efficiently radiolabel the antibody fragments after encapsulation into the liposomes, with radiolabeling efficiencies of up to 68% after purification. The radiolabeled liposomes were administered via a single intravenous bolus injection to APPswe/PS1dE9 double transgenic mice, a mouse model of Alzheimer's disease, and their wildtype littermates. Both GSH-PEG DMPC and GSH-PEG EYPC liposomes significantly increased the standard uptake values (SUV) of VHH-pa2H in the blood of the animals compared to free VHH-pa2H. Encapsulation in GSH-PEG EYPC liposomes resulted in the highest increase in SUV in the brains of transgenic animals. Overall, these data provide evidence that GSH-PEG liposomes may be suitable for specific delivery of single domain antibody fragments over the BBB into the brain | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a (111)In labeling | |
| 650 | 4 | |a APP(swe)/PS1dE9 mice | |
| 650 | 4 | |a G-Technology | |
| 650 | 4 | |a Glutathione PEGylated liposomes | |
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| 650 | 7 | |a Immunoglobulin Heavy Chains |2 NLM | |
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| 650 | 7 | |a Single-Chain Antibodies |2 NLM | |
| 650 | 7 | |a Polyethylene Glycols |2 NLM | |
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| 650 | 7 | |a Glutathione |2 NLM | |
| 650 | 7 | |a GAN16C9B8O |2 NLM | |
| 700 | 1 | |a Welling, Mick M |e verfasserin |4 aut | |
| 700 | 1 | |a Bunschoten, Anton |e verfasserin |4 aut | |
| 700 | 1 | |a de Backer, Maaike E |e verfasserin |4 aut | |
| 700 | 1 | |a Rip, Jaap |e verfasserin |4 aut | |
| 700 | 1 | |a Nabuurs, Rob J A |e verfasserin |4 aut | |
| 700 | 1 | |a Gaillard, Pieter J |e verfasserin |4 aut | |
| 700 | 1 | |a van Buchem, Mark A |e verfasserin |4 aut | |
| 700 | 1 | |a van der Maarel, Silvère M |e verfasserin |4 aut | |
| 700 | 1 | |a van der Weerd, Louise |e verfasserin |4 aut | |
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