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Position for site-specific attachment of a DOTA chelator to synthetic affibody molecules has a different influence on the targeting properties of 68Ga- compared to 111in-labeled conjugates

Honarvar, Hadis ; Strand, Joanna LU ; Perols, Anna ; Orlova, Anna ; Selvaraju, Ram Kumar ; Eriksson Karlström, Amelie and Tolmachev, Vladimir (2014) In Molecular Imaging 13.
Abstract

Affibody molecules, small (7 kDa) scaffold proteins, are a promising class of probes for radionuclide molecular imaging. Radiolabeling of Affibody molecules with the positron-emitting nuclide 68Ga would permit the use of positron emission tomography (PET), providing better resolution, sensitivity, and quantification accuracy than single-photon emission computed tomography (SPECT). The synthetic anti-HER2 ZHER2:S1 Affibody molecule was conjugated with DOTA at the N-terminus, in the middle of helix 3, or at the C-terminus. The biodistribution of 68Ga- and 111In-labeled Affibody molecules was directly compared in NMRI nu/nu mice bearing SKOV3 xenografts. The position of the chelator strongly influenced the biodistribution of the tracers,... (More)

Affibody molecules, small (7 kDa) scaffold proteins, are a promising class of probes for radionuclide molecular imaging. Radiolabeling of Affibody molecules with the positron-emitting nuclide 68Ga would permit the use of positron emission tomography (PET), providing better resolution, sensitivity, and quantification accuracy than single-photon emission computed tomography (SPECT). The synthetic anti-HER2 ZHER2:S1 Affibody molecule was conjugated with DOTA at the N-terminus, in the middle of helix 3, or at the C-terminus. The biodistribution of 68Ga- and 111In-labeled Affibody molecules was directly compared in NMRI nu/nu mice bearing SKOV3 xenografts. The position of the chelator strongly influenced the biodistribution of the tracers, and the influence was more pronounced for 68Ga-labeled Affibody molecules than for the 111In-labeled counterparts. The best 68Ga-labeled variant was 68Ga-[DOTA-A1]-ZHER2:S1, which provided a tumor uptake of 13 ± 1 %ID/g and a tumor to blood ratio of 39 ± 12 at 2 hours after injection. 111In-[DOTA-A1]-ZHER2:S1 and 111In-[DOTA-K58]-ZHER2:S1 were equally good at this time point, providing a tumor uptake of 15 to 16 %ID/g and a tumor to blood ratio in the range of 60 to 80. In conclusion, the selection of the best position for a chelator in Affibody molecules can be used for optimization of their imaging properties. This may be important for the development of Affibody-based and other protein-based imaging probes.

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author
; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Cell Line, Tumor, Chelating Agents/chemistry, Female, Gallium Radioisotopes/pharmacokinetics, Heterocyclic Compounds, 1-Ring/chemistry, Humans, Indium Radioisotopes/pharmacokinetics, Isotope Labeling, Mice, Neoplasm Transplantation, Ovarian Neoplasms/diagnostic imaging, Positron-Emission Tomography, Recombinant Fusion Proteins/chemical synthesis
in
Molecular Imaging
volume
13
publisher
BC Decker
external identifiers
  • scopus:84918563830
  • pmid:25249017
ISSN
1535-3508
DOI
10.2310/7290.2014.00034
language
English
LU publication?
no
id
c821c59b-5004-4688-ac29-0b7018a50172
date added to LUP
2022-11-16 13:39:28
date last changed
2024-01-03 11:15:50
@article{c821c59b-5004-4688-ac29-0b7018a50172,
  abstract     = {{<p>Affibody molecules, small (7 kDa) scaffold proteins, are a promising class of probes for radionuclide molecular imaging. Radiolabeling of Affibody molecules with the positron-emitting nuclide 68Ga would permit the use of positron emission tomography (PET), providing better resolution, sensitivity, and quantification accuracy than single-photon emission computed tomography (SPECT). The synthetic anti-HER2 ZHER2:S1 Affibody molecule was conjugated with DOTA at the N-terminus, in the middle of helix 3, or at the C-terminus. The biodistribution of 68Ga- and 111In-labeled Affibody molecules was directly compared in NMRI nu/nu mice bearing SKOV3 xenografts. The position of the chelator strongly influenced the biodistribution of the tracers, and the influence was more pronounced for 68Ga-labeled Affibody molecules than for the 111In-labeled counterparts. The best 68Ga-labeled variant was 68Ga-[DOTA-A1]-ZHER2:S1, which provided a tumor uptake of 13 ± 1 %ID/g and a tumor to blood ratio of 39 ± 12 at 2 hours after injection. 111In-[DOTA-A1]-ZHER2:S1 and 111In-[DOTA-K58]-ZHER2:S1 were equally good at this time point, providing a tumor uptake of 15 to 16 %ID/g and a tumor to blood ratio in the range of 60 to 80. In conclusion, the selection of the best position for a chelator in Affibody molecules can be used for optimization of their imaging properties. This may be important for the development of Affibody-based and other protein-based imaging probes.</p>}},
  author       = {{Honarvar, Hadis and Strand, Joanna and Perols, Anna and Orlova, Anna and Selvaraju, Ram Kumar and Eriksson Karlström, Amelie and Tolmachev, Vladimir}},
  issn         = {{1535-3508}},
  keywords     = {{Animals; Cell Line, Tumor; Chelating Agents/chemistry; Female; Gallium Radioisotopes/pharmacokinetics; Heterocyclic Compounds, 1-Ring/chemistry; Humans; Indium Radioisotopes/pharmacokinetics; Isotope Labeling; Mice; Neoplasm Transplantation; Ovarian Neoplasms/diagnostic imaging; Positron-Emission Tomography; Recombinant Fusion Proteins/chemical synthesis}},
  language     = {{eng}},
  publisher    = {{BC Decker}},
  series       = {{Molecular Imaging}},
  title        = {{Position for site-specific attachment of a DOTA chelator to synthetic affibody molecules has a different influence on the targeting properties of 68Ga- compared to 111in-labeled conjugates}},
  url          = {{http://dx.doi.org/10.2310/7290.2014.00034}},
  doi          = {{10.2310/7290.2014.00034}},
  volume       = {{13}},
  year         = {{2014}},
}