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In vivo evaluation ...
In vivo evaluation of cysteine-based chelators for attachment of Tc-99m to tumor-targeting affibody molecules
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- Tran, Thuy (författare)
- Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap
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Engfeldt, Torun (författare)
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- Orlova, Anna (författare)
- Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap
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- Widstrom, Charles (författare)
- Uppsala universitet,Avdelningen för sjukhusfysik
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Bruskin, Alexander (författare)
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- Tolmachev, Vladimir (författare)
- Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap
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- Eriksson Karlström, Amelie (författare)
- KTH,Molekylär Bioteknologi
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(creator_code:org_t)
- 2007-03-02
- 2007
- Engelska.
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Ingår i: Bioconjugate chemistry. - : American Chemical Society (ACS). - 1043-1802 .- 1520-4812. ; 18:2, s. 549-558
- Relaterad länk:
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http://uu.diva-porta...
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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
- Affibody molecules present a new class of affinity proteins, which utilizes a scaffold based on a 58-amino acid domain derived from protein A. The small (7 kDa) Affibody molecule can be selected to bind to cell-surface targets with high affinity. An Affibody molecule (Z(HER2:342)) with a dissociation constant (K-d) of 22 pM for binding to the HER2 receptor has been reported earlier. Preclinical and pilot clinical studies have demonstrated the utility of radiolabeled Z(HER2:342) in imaging of HER2-expressing tumors. The small size and cysteine-free structure of Affibody molecules enable complete peptide synthesis and direct incorporation of radionuclide chelators. The goal of this study was to evaluate if incorporation of the natural peptide sequences cysteine-diglycine (CGG) and cysteine-triglycine (CGGG) sequences would enable labeling of Affibody molecules with Tc-99m. In a model monomeric form, the chelating sequences were incorporated by peptide synthesis. The HER2-binding affinity was 280 and 250 pM for CGG-Z(HER2:342) and CGGG-Z(HER2:342,) respectively. Conjugates were directly labeled with Tc-99m with 90% efficiency and preserved the capacity to bind specifically to HER2-expressing cells. The biodistribution in normal mice showed a rapid clearance from the blood and the majority of organs (except kidneys). In the mice bearing SKOV-3 xenografts, tumor uptake of Tc-99m-CGG-Z(HER2:342) was HER2-specific and a tumor-to-blood ratio of 9.2 was obtained at 6 h postinjection. Gamma-camera imaging with Tc-99m-CGG-Z(HER2:342) clearly visualized tumors at 6 h postinjection. The results show that the use of a cysteine-based chelator enables Tc-99m-labeling of Affibody molecules for imaging.
Nyckelord
- human-breast-cancer
- single-chain fv
- somatostatin analogs
- binding-proteins
- therapy
- peptide
- mice
- antibody
- recommendations
- localization
- MEDICINE
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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