Influence of macrocyclic chelators on the targeting properties of (68)Ga-labeled synthetic affibody molecules: comparison with (111)In-labeled counterparts.
Identifieur interne : 000588 ( Main/Exploration ); précédent : 000587; suivant : 000589Influence of macrocyclic chelators on the targeting properties of (68)Ga-labeled synthetic affibody molecules: comparison with (111)In-labeled counterparts.
Auteurs : RBID : pubmed:23936372English descriptors
- KwdEn :
- Amides (chemistry), Amino Acid Sequence, Animals, Chelating Agents (chemistry), Drug Design, Female, Gallium Radioisotopes (diagnostic use), Indium Radioisotopes (diagnostic use), Macrocyclic Compounds (chemistry), Mice, Mice, Inbred BALB C, Molecular Sequence Data, Recombinant Fusion Proteins (chemistry), Recombinant Fusion Proteins (diagnostic use).
- MESH :
- chemical , chemistry : Amides, Chelating Agents, Macrocyclic Compounds, Recombinant Fusion Proteins.
- chemical , diagnostic use : Gallium Radioisotopes, Indium Radioisotopes, Recombinant Fusion Proteins.
- Amino Acid Sequence, Animals, Drug Design, Female, Mice, Mice, Inbred BALB C, Molecular Sequence Data.
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 (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.
DOI: 10.1371/journal.pone.0070028
PubMed: 23936372
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Influence of macrocyclic chelators on the targeting properties of (68)Ga-labeled synthetic affibody molecules: comparison with (111)In-labeled counterparts.</title><author><name sortKey="Strand, Joanna" uniqKey="Strand J">Joanna Strand</name><affiliation wicri:level="1"><nlm:affiliation>Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, Uppsala</wicri:regionArea></affiliation></author><author><name sortKey="Honarvar, Hadis" uniqKey="Honarvar H">Hadis Honarvar</name></author><author><name sortKey="Perols, Anna" uniqKey="Perols A">Anna Perols</name></author><author><name sortKey="Orlova, Anna" uniqKey="Orlova A">Anna Orlova</name></author><author><name sortKey="Selvaraju, Ram Kumar" uniqKey="Selvaraju R">Ram Kumar Selvaraju</name></author><author><name sortKey="Karlstr M, Amelie Eriksson" uniqKey="Karlstr M A">Amelie Eriksson Karlström</name></author><author><name sortKey="Tolmachev, Vladimir" uniqKey="Tolmachev V">Vladimir Tolmachev</name></author></titleStmt><publicationStmt><date when="2013">2013</date><idno type="doi">10.1371/journal.pone.0070028</idno><idno type="RBID">pubmed:23936372</idno><idno type="pmid">23936372</idno><idno type="wicri:Area/Main/Corpus">000472</idno><idno type="wicri:Area/Main/Curation">000472</idno><idno type="wicri:Area/Main/Exploration">000588</idno></publicationStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amides (chemistry)</term><term>Amino Acid Sequence</term><term>Animals</term><term>Chelating Agents (chemistry)</term><term>Drug Design</term><term>Female</term><term>Gallium Radioisotopes (diagnostic use)</term><term>Indium Radioisotopes (diagnostic use)</term><term>Macrocyclic Compounds (chemistry)</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Molecular Sequence Data</term><term>Recombinant Fusion Proteins (chemistry)</term><term>Recombinant Fusion Proteins (diagnostic use)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Amides</term><term>Chelating Agents</term><term>Macrocyclic Compounds</term><term>Recombinant Fusion Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="diagnostic use" xml:lang="en"><term>Gallium Radioisotopes</term><term>Indium Radioisotopes</term><term>Recombinant Fusion Proteins</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Drug Design</term><term>Female</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Molecular Sequence Data</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Owner="NLM" Status="MEDLINE"><PMID Version="1">23936372</PMID><DateCreated><Year>2013</Year><Month>08</Month><Day>12</Day></DateCreated><DateCompleted><Year>2014</Year><Month>03</Month><Day>18</Day></DateCompleted><Article PubModel="Electronic-Print"><Journal><ISSN IssnType="Electronic">1932-6203</ISSN><JournalIssue CitedMedium="Internet"><Volume>8</Volume><Issue>8</Issue><PubDate><Year>2013</Year></PubDate></JournalIssue><Title>PloS one</Title><ISOAbbreviation>PLoS ONE</ISOAbbreviation></Journal><ArticleTitle>Influence of macrocyclic chelators on the targeting properties of (68)Ga-labeled synthetic affibody molecules: comparison with (111)In-labeled counterparts.</ArticleTitle><Pagination><MedlinePgn>e70028</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1371/journal.pone.0070028</ELocationID><Abstract><AbstractText>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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Strand</LastName><ForeName>Joanna</ForeName><Initials>J</Initials><Affiliation>Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.</Affiliation></Author><Author ValidYN="Y"><LastName>Honarvar</LastName><ForeName>Hadis</ForeName><Initials>H</Initials></Author><Author ValidYN="Y"><LastName>Perols</LastName><ForeName>Anna</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Orlova</LastName><ForeName>Anna</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Selvaraju</LastName><ForeName>Ram Kumar</ForeName><Initials>RK</Initials></Author><Author ValidYN="Y"><LastName>Karlström</LastName><ForeName>Amelie Eriksson</ForeName><Initials>AE</Initials></Author><Author ValidYN="Y"><LastName>Tolmachev</LastName><ForeName>Vladimir</ForeName><Initials>V</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType>Comparative Study</PublicationType><PublicationType>Journal Article</PublicationType><PublicationType>Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2013</Year><Month>08</Month><Day>01</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>PLoS One</MedlineTA><NlmUniqueID>101285081</NlmUniqueID><ISSNLinking>1932-6203</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Amides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Chelating Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Gallium Radioisotopes</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Indium Radioisotopes</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Macrocyclic Compounds</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Recombinant Fusion Proteins</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="Cites"><RefSource>Curr Pharm Biotechnol. 2010 Sep 1;11(6):581-9</RefSource><PMID Version="1">20497119</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Eur J Nucl Med Mol Imaging. 2010 Jul;37(7):1356-67</RefSource><PMID Version="1">20130858</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Oncologist. 2010;15(11):1164-8</RefSource><PMID Version="1">21041379</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>J Mol Biol. 2011 Mar 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MajorTopicYN="N">Gallium Radioisotopes</DescriptorName><QualifierName MajorTopicYN="N">diagnostic use</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Indium Radioisotopes</DescriptorName><QualifierName MajorTopicYN="Y">diagnostic use</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Macrocyclic Compounds</DescriptorName><QualifierName MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Mice, Inbred BALB C</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Molecular Sequence Data</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N">Recombinant Fusion Proteins</DescriptorName><QualifierName MajorTopicYN="Y">chemistry</QualifierName><QualifierName MajorTopicYN="Y">diagnostic use</QualifierName></MeshHeading></MeshHeadingList><OtherID Source="NLM">PMC3731330</OtherID></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="ppublish"><Year>2013</Year><Month></Month><Day></Day></PubMedPubDate><PubMedPubDate PubStatus="received"><Year>2013</Year><Month>4</Month><Day>28</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2013</Year><Month>6</Month><Day>19</Day></PubMedPubDate><PubMedPubDate PubStatus="epublish"><Year>2013</Year><Month>8</Month><Day>1</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2013</Year><Month>8</Month><Day>13</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2013</Year><Month>8</Month><Day>13</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2014</Year><Month>3</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="doi">10.1371/journal.pone.0070028</ArticleId><ArticleId 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