Influence of macrocyclic chelators on the targeting properties of (68)Ga-labeled synthetic affibody molecules : comparison with (111)In-labeled counterparts
(2013) In PLoS ONE 8(8).- Abstract
Affibody molecules are a class of small (7 kDa) non-immunoglobulin scaffold-based affinity proteins, which have demonstrated substantial potential as probes for radionuclide molecular imaging. The use of positron emission tomography (PET) would further increase the resolution and quantification accuracy of Affibody-based imaging. The rapid in vivo kinetics of Affibody molecules permit the use of the generator-produced radionuclide (68)Ga (T1/2=67.6 min). Earlier studies have demonstrated that the chemical nature of chelators has a substantial influence on the biodistribution properties of Affibody molecules. To determine an optimal labeling approach, the macrocyclic chelators 1,4,7,10-tetraazacylododecane-1,4,7,10-tetraacetic acid... (More)
Affibody molecules are a class of small (7 kDa) non-immunoglobulin scaffold-based affinity proteins, which have demonstrated substantial potential as probes for radionuclide molecular imaging. The use of positron emission tomography (PET) would further increase the resolution and quantification accuracy of Affibody-based imaging. The rapid in vivo kinetics of Affibody molecules permit the use of the generator-produced radionuclide (68)Ga (T1/2=67.6 min). Earlier studies have demonstrated that the chemical nature of chelators has a substantial influence on the biodistribution properties of Affibody molecules. To determine an optimal labeling approach, the macrocyclic chelators 1,4,7,10-tetraazacylododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-N,N,N-triacetic acid (NOTA) and 1-(1,3-carboxypropyl)-1,4,7- triazacyclononane-4,7-diacetic acid (NODAGA) were conjugated to the N-terminus of the synthetic Affibody molecule ZHER2:S1 targeting HER2. Affibody molecules were labeled with (68)Ga, and their binding specificity and cellular processing were evaluated. The biodistribution of (68)Ga-DOTA-ZHER2:S1, (68)Ga-NOTA-ZHER2:S1 and (68)Ga-NODAGA-ZHER2:S1, as well as that of their (111)In-labeled counterparts, was evaluated in BALB/C nu/nu mice bearing HER2-expressing SKOV3 xenografts. The tumor uptake for (68)Ga-DOTA-ZHER2:S1 (17.9 ± 0.7%IA/g) was significantly higher than for both (68)Ga-NODAGA-ZHER2:S1 (16.13 ± 0.67%IA/g) and (68)Ga-NOTA-ZHER2:S1 (13 ± 3%IA/g) at 2 h after injection. (68)Ga-NODAGA-ZHER2:S1 had the highest tumor-to-blood ratio (60 ± 10) in comparison with both (68)Ga-DOTA-ZHER2:S1 (28 ± 4) and (68)Ga-NOTA-ZHER2:S1 (42 ± 11). The tumor-to-liver ratio was also higher for (68)Ga-NODAGA-ZHER2:S1 (7 ± 2) than the DOTA and NOTA conjugates (5.5 ± 0.6 vs.3.3 ± 0.6). The influence of chelator on the biodistribution and targeting properties was less pronounced for (68)Ga than for (111)In. The results of this study demonstrate that macrocyclic chelators conjugated to the N-terminus have a substantial influence on the biodistribution of HER2-targeting Affibody molecules labeled with (68)Ga.This can be utilized to enhance the imaging contrast of PET imaging using Affibody molecules and improve the sensitivity of molecular imaging. The study demonstrated an appreciable difference of chelator influence for (68)Ga and (111)In.
(Less)
- author
- Strand, Joanna LU ; Honarvar, Hadis ; Perols, Anna ; Orlova, Anna ; Selvaraju, Ram Kumar ; Karlström, Amelie Eriksson and Tolmachev, Vladimir
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Amides/chemistry, Amino Acid Sequence, Animals, Chelating Agents/chemistry, Drug Design, Female, Gallium Radioisotopes, Indium Radioisotopes, Macrocyclic Compounds/chemistry, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Recombinant Fusion Proteins/chemistry
- in
- PLoS ONE
- volume
- 8
- issue
- 8
- article number
- e70028
- pages
- 10 pages
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- scopus:84881020952
- pmid:23936372
- ISSN
- 1932-6203
- DOI
- 10.1371/journal.pone.0070028
- language
- English
- LU publication?
- no
- id
- 8fa0812e-fe40-4f75-b6f9-e0c209a30e10
- date added to LUP
- 2022-11-16 13:41:57
- date last changed
- 2024-04-04 06:20:04
@article{8fa0812e-fe40-4f75-b6f9-e0c209a30e10,
abstract = {{<p>Affibody molecules are a class of small (7 kDa) non-immunoglobulin scaffold-based affinity proteins, which have demonstrated substantial potential as probes for radionuclide molecular imaging. The use of positron emission tomography (PET) would further increase the resolution and quantification accuracy of Affibody-based imaging. The rapid in vivo kinetics of Affibody molecules permit the use of the generator-produced radionuclide (68)Ga (T1/2=67.6 min). Earlier studies have demonstrated that the chemical nature of chelators has a substantial influence on the biodistribution properties of Affibody molecules. To determine an optimal labeling approach, the macrocyclic chelators 1,4,7,10-tetraazacylododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-N,N,N-triacetic acid (NOTA) and 1-(1,3-carboxypropyl)-1,4,7- triazacyclononane-4,7-diacetic acid (NODAGA) were conjugated to the N-terminus of the synthetic Affibody molecule ZHER2:S1 targeting HER2. Affibody molecules were labeled with (68)Ga, and their binding specificity and cellular processing were evaluated. The biodistribution of (68)Ga-DOTA-ZHER2:S1, (68)Ga-NOTA-ZHER2:S1 and (68)Ga-NODAGA-ZHER2:S1, as well as that of their (111)In-labeled counterparts, was evaluated in BALB/C nu/nu mice bearing HER2-expressing SKOV3 xenografts. The tumor uptake for (68)Ga-DOTA-ZHER2:S1 (17.9 ± 0.7%IA/g) was significantly higher than for both (68)Ga-NODAGA-ZHER2:S1 (16.13 ± 0.67%IA/g) and (68)Ga-NOTA-ZHER2:S1 (13 ± 3%IA/g) at 2 h after injection. (68)Ga-NODAGA-ZHER2:S1 had the highest tumor-to-blood ratio (60 ± 10) in comparison with both (68)Ga-DOTA-ZHER2:S1 (28 ± 4) and (68)Ga-NOTA-ZHER2:S1 (42 ± 11). The tumor-to-liver ratio was also higher for (68)Ga-NODAGA-ZHER2:S1 (7 ± 2) than the DOTA and NOTA conjugates (5.5 ± 0.6 vs.3.3 ± 0.6). The influence of chelator on the biodistribution and targeting properties was less pronounced for (68)Ga than for (111)In. The results of this study demonstrate that macrocyclic chelators conjugated to the N-terminus have a substantial influence on the biodistribution of HER2-targeting Affibody molecules labeled with (68)Ga.This can be utilized to enhance the imaging contrast of PET imaging using Affibody molecules and improve the sensitivity of molecular imaging. The study demonstrated an appreciable difference of chelator influence for (68)Ga and (111)In.</p>}},
author = {{Strand, Joanna and Honarvar, Hadis and Perols, Anna and Orlova, Anna and Selvaraju, Ram Kumar and Karlström, Amelie Eriksson and Tolmachev, Vladimir}},
issn = {{1932-6203}},
keywords = {{Amides/chemistry; Amino Acid Sequence; Animals; Chelating Agents/chemistry; Drug Design; Female; Gallium Radioisotopes; Indium Radioisotopes; Macrocyclic Compounds/chemistry; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Recombinant Fusion Proteins/chemistry}},
language = {{eng}},
number = {{8}},
publisher = {{Public Library of Science (PLoS)}},
series = {{PLoS ONE}},
title = {{Influence of macrocyclic chelators on the targeting properties of (68)Ga-labeled synthetic affibody molecules : comparison with (111)In-labeled counterparts}},
url = {{http://dx.doi.org/10.1371/journal.pone.0070028}},
doi = {{10.1371/journal.pone.0070028}},
volume = {{8}},
year = {{2013}},
}