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Transferrin Recepto...
Transferrin Receptor Binding BBB-Shuttle Facilitates Brain Delivery of Anti-Aβ-Affibodies
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- Faresjö, Rebecca (författare)
- Uppsala universitet,Geriatrik
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- Lindberg, Hanna (författare)
- KTH,Proteinvetenskap,KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, S-10691 Stockholm, Sweden.
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- Ståhl, Stefan, 1961- (författare)
- KTH,Proteinvetenskap,KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, S-10691 Stockholm, Sweden.
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- Löfblom, John (författare)
- KTH,Proteinvetenskap,KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, S-10691 Stockholm, Sweden.
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- Syvänen, Stina (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Geriatrik
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- Sehlin, Dag, 1976- (författare)
- Uppsala universitet,Geriatrik
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(creator_code:org_t)
- 2022-05-10
- 2022
- Engelska.
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Ingår i: Pharmaceutical research. - : Springer Nature. - 0724-8741 .- 1573-904X. ; 39:7, s. 1509-1521
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- Affibodies targeting amyloid-beta (Aβ) could potentially be used as therapeutic and diagnostic agents in Alzheimer’s disease (AD). Affibodies display suitable characteristics for imaging applications such as high stability and a short biological half-life. The aim of this study was to explore brain delivery and retention of Aβ protofibril-targeted affibodies in wild-type (WT) and AD transgenic mice and to evaluate their potential as imaging agents. Two affibodies, Z5 and Z1, were fused with the blood–brain barrier (BBB) shuttle single-chain variable fragment scFv8D3. In vitro binding of 125I-labeled affibodies with and without scFv8D3 was evaluated by ELISA and autoradiography. Brain uptake and retention of the affibodies at 2 h and 24 h post injection was studied ex vivo in WT and transgenic (tg-Swe and tg-ArcSwe) mice. At 2 h post injection, [125I]I-Z5 and [125I]I-Z1 displayed brain concentrations of 0.37 ± 0.09% and 0.46 ± 0.08% ID/g brain, respectively. [125I]I-scFv8D3-Z5 and [125I]I-scFv8D3-Z1 showed increased brain concentrations of 0.53 ± 0.16% and 1.20 ± 0.35%ID/g brain. At 24 h post injection, brain retention of [125I]I-Z1 and [125I]I-Z5 was low, while [125I]I-scFv8D3-Z1 and [125I]I-scFv8D3-Z5 showed moderate brain retention, with a tendency towards higher retention of [125I]I-scFv8D3-Z5 in AD transgenic mice. Nuclear track emulsion autoradiography showed greater parenchymal distribution of [125I]I-scFv8D3-Z5 and [125I]I-scFv8D3-Z1 compared with the affibodies without scFv8D3, but could not confirm specific affibody accumulation around Aβ deposits. Affibody-scFv8D3 fusions displayed increased brain and parenchymal delivery compared with the non-fused affibodies. However, fast brain washout and a suboptimal balance between Aβ and mTfR1 affinity resulted in low intrabrain retention around Aβ deposits.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- affibody
- protein brain delivery
- transferrin receptor
- transferrin receptor mediated transcytosis (RMT)
- amyloid beta protein
- amyloid beta protein antibody
- CD71 antigen
- diagnostic agent
- iodine 125
- monoclonal antibody
- single chain fragment variable antibody
- single chain fragment variable antibody z1
- single chain fragment variable antibody z5
- unclassified drug
- z1 affibody
- z5 affibody
- Alzheimer disease
- animal experiment
- animal model
- animal tissue
- Article
- autoradiography
- blood brain barrier
- clinical evaluation
- concentration process
- controlled study
- drug retention
- drug uptake
- enzyme linked immunosorbent assay
- gene targeting
- in vitro study
- male
- mouse
- nonhuman
- nuclear medicine
- pharmacokinetic parameters
- radioactivity
- radiochemistry
- radiolabeling
- receptor binding
- transcytosis
- animal
- brain
- disease model
- metabolism
- positron emission tomography
- procedures
- transgenic mouse
- Amyloid beta-Peptides
- Animals
- Blood-Brain Barrier
- Disease Models
- Animal
- Mice
- Mice
- Transgenic
- Positron-Emission Tomography
- Receptors
- Transferrin
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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