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Site-Specific Radioiodination of HER2-Targeting Affibody Molecules using 4-Iodophenethylmaleimide Decreases Renal Uptake of Radioactivity
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
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2015 (engelsk)Inngår i: ChemistryOpen, ISSN 2191-1363, Vol. 4, nr 2, s. 174-182Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Affibody molecules are small scaffold-based affinity proteins with promising properties as probes for radionuclide-based molecular imaging. However, a high reabsorption of radiolabeled Affibody molecules in kidneys is an issue. We have shown that the use of I-125-3-iodo-((4-hydroxyphenyl)ethyl)maleimide (IHPEM) for site-specific labeling of cysteine-containing Affibody molecules provides high tumor uptake but low radioactivity retention in kidneys. We hypothesized that the use of 4-iodophenethylmaleimide (IPEM) would further reduce renal retention of radioactivity because of higher lipophilicity of radiometabolites. An anti-human epidermal growth factor receptor type2 (HER2) Affibody molecule (Z(HER2:2395)) was labeled using I-125-IPEM with an overall yield of 45 +/- 3%. I-125-IPEM-Z(HER2:2395) bound specifically to HER2-expressing human ovarian carcinoma cells (SKOV-3 cell line). In NMRI mice, the renal uptake of I-125-IPEM-Z(HER2:2395) (24 +/- 2 and 5.7 +/- 0.3%IAg(-1)at 1 and 4 h after injection, respectively) was significantly lower than uptake of I-125-IHPEM-Z(HER2:2395) (50 +/- 8 and 12 +/- 2%IAg(-1)at 1 and 4 h after injection, respectively). In conclusion, the use of a more lipophilic linker for the radioiodination of Affibody molecules reduces renal radioactivity.

sted, utgiver, år, opplag, sider
2015. Vol. 4, nr 2, s. 174-182
Emneord [en]
affibody molecules, drug design, iodophenethylmaleimide, radiolabeling, radiopharmaceuticals
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-253262DOI: 10.1002/open.201402097ISI: 000353653800014PubMedID: 25969816OAI: oai:DiVA.org:uu-253262DiVA, id: diva2:814329
Tilgjengelig fra: 2015-05-26 Laget: 2015-05-25 Sist oppdatert: 2017-12-04bibliografisk kontrollert
Inngår i avhandling
1. Affibody Molecules for PET Imaging
Åpne denne publikasjonen i ny fane eller vindu >>Affibody Molecules for PET Imaging
2015 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Optimization of Affibody molecules would allow for high contrast imaging of cancer associated surface receptors using molecular imaging. The primary aim of the thesis was to develop Affibody-based PET imaging agents to provide the highest possible sensitivity of RTK detection in vivo. The thesis evaluates the effect of radiolabelling chemistry on biodistribution and targeting properties of Affibody molecules directed against HER2 and PDGFRβ. The thesis is based on five published papers (I-V).

Paper I. The targeting properties of maleimido derivatives of DOTA and NODAGA for site-specific labelling of a recombinant HER2-binding Affibody molecule radiolabelled with 68Ga were compared in vivo. Favourable in vivo properties were seen for the Affibody molecule with the combination of 68Ga with NODAGA.

Paper II. The aim was to compare the biodistribution of 68Ga- and 111In-labelled HER2-targeting Affibody molecules containing DOTA, NOTA and NODAGA at the N-terminus. This paper also demonstrated favourable in vivo properties for Affibody molecules in combination with 68Ga and NODAGA placed on the N-terminus.

Paper III.  The influence of chelator positioning on the synthetic anti-HER2 affibody molecule labelled with 68Ga was investigated. The chelator DOTA was conjugated either at the N-terminus, the middle of helix-3 or at the C-terminus of the Affibody molecules. The N-terminus placement provided the highest tumour uptake and tumour-to-organ ratios.

Paper IV. The aim of this study was to evaluate if the 68Ga labelled PDGFRβ-targeting Affibody would provide an imaging agent suitable for PDGFRβ visualization using PET. The 68Ga labelled conjugate provided high-contrast imaging of PDGFRβ-expressing tumours in vivo using microPET as early as 2h after injection.

Paper V. This paper investigated if the replacement of IHPEM with IPEM as a linker molecule for radioiodination of Affibody molecules would reduce renal retention of radioactivity. Results showed that the use of the more lipophilic linker IPEM reduced the renal radioactivity retention for radioiodinated Affibody molecules.

In conclusion, this thesis clearly demonstrates that the labelling strategy is of great importance with a substantial influence on the targeting properties of Affibody molecules and should be taken under serious considerations when developing new imaging agents.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2015. s. 70
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1125
Emneord
Affibody molecules, Molecular imaging, PET, Radiolabelling, HER2, PDGFRβ
HSV kategori
Forskningsprogram
Biomedicinsk strålningsvetenskap
Identifikatorer
urn:nbn:se:uu:diva-259410 (URN)978-91-554-9299-1 (ISBN)
Disputas
2015-10-03, Fåhraeussalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, 751 85, Uppsala, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2015-09-03 Laget: 2015-08-03 Sist oppdatert: 2015-10-01

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