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Evaluation of backb...
Evaluation of backbone-cyclized HER2-binding 2-helix Affibody molecule for In Vivo molecular imaging
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- Honarvar, Hadis (författare)
- Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap,Tolmachev
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- Jokilaakso, Nima (författare)
- KTH,Molekylär Bioteknologi
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- Andersson, Karl (författare)
- Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap
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- Malmberg, Jennie (författare)
- Uppsala universitet,Plattformen för preklinisk PET
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- Rosik, Daniel (författare)
- KTH,Molekylär Bioteknologi
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- Orlova, Anna (författare)
- Uppsala universitet,Plattformen för preklinisk PET
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- Eriksson Karlström, Amelie (författare)
- KTH,Molekylär Bioteknologi
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- Tolmachev, Vladimir (författare)
- Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap,Tolmachev
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- Järver, Peter (författare)
- KTH,Molekylär Bioteknologi
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(creator_code:org_t)
- Elsevier BV, 2013
- 2013
- Engelska.
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 40:3, s. 378-386
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https://uu.diva-port... (primary) (Raw object)
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Introduction: Affibody molecules, small scaffold proteins, have demonstrated an appreciable potential as imaging probes. Affibody molecules are composed of three alpha-helices. Helices 1 and 2 are involved in molecular recognition, while helix 3 provides stability. The size of Affibody molecules can be reduced by omitting the third alpha-helix and cross-linking the two remaining, providing a smaller molecule with better extravasation and quicker clearance of unbound tracer. The goal of this study was to develop a novel 2-helix Affibody molecule based on backbone cyclization by native chemical ligation (NCL). Methods: The HER2-targeting NCL-cyclized Affibody molecule Z(HER2:342min) has been designed, synthesized and site-specifically conjugated with a DOTA chelator. DOTA-Z(HER2:342min) was labeled with In-111 and (68) Ga. The binding affinity of DOTA-Z(HER2:342min) was evaluated in vitro. The targeting properties of In-111- and (68) Ga-DOTA-Z(HER2:342min) were evaluated in mice bearing SKOV-3 xenografts and compared with the properties of In-111- and (68) Ga-labeled PEP09239, a DOTA-conjugated 2-helix Affibody analogue cyclized by a homocysteine disulfide bridge. Results: The dissociation constant (K-D) for DOTA-Z(HER2:342min) binding to HER2 was 18 nM according to SPR measurements. DOTA-Z(HER2:342min) was labeled with In-111 and (68) Ga. Both conjugates demonstrated bi-phasic binding kinetics to HER2-expressing cells, with K-D1 in low nanbmolar range. Both variants demonstrated specific uptake in HER2-expressing xenografts. Tumor-to-blood ratios at 2 h p.i. were 6.1 +/- 1.3 for In-111-DOTA-Z(HER2:342min) and 4.6 +/- 0.7 for (68) Ga-DOTA-Z(HER2:342min). However, the uptake of DOTA-Z(HER2:342min) in lung, liver and spleen was appreciably higher than the uptake of PEP09239-based counterparts. Conclusions: Native chemical ligation enables production of a backbone-cyclized HER2-binding 2-helix Affibody molecule (Z(HER2:342min)) with low nanomolar target affinity and specific tumor uptake.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
Nyckelord
- Affibody
- HER2
- 2-helix protein
- SPPS
- Native chemical ligation
- biodistribution
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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