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Molecular Design of HER3-Targeting Affibody Molecules: Influence of Chelator and Presence of HEHEHE-Tag on Biodistribution of 68 Ga-Labeled Tracers
KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap.
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2019 (Engelska)Ingår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, nr 5Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Affibody-based imaging of HER3 is a promising approach for patient stratification. We investigated the influence of a hydrophilic HEHEHE-tag ((HE)₃-tag) and two different gallium-68/chelator-complexes on the biodistribution of Z08698 with the aim to improve the tracer for PET imaging. Affibody molecules (HE)₃-Z08698-X and Z08698-X (X = NOTA, NODAGA) were produced and labeled with gallium-68. Binding specificity and cellular processing were studied in HER3-expressing human cancer cell lines BxPC-3 and DU145. Biodistribution was studied 3 h p.i. in Balb/c nu/nu mice bearing BxPC-3 xenografts. Mice were imaged 3 h p.i. using microPET/CT. Conjugates were stably labeled with gallium-68 and bound specifically to HER3 in vitro and in vivo. Association to cells was rapid but internalization was slow. Uptake in tissues, including tumors, was lower for (HE)₃-Z08698-X than for non-tagged variants. The neutral [68Ga]Ga-NODAGA complex reduced the hepatic uptake of Z08698 compared to positively charged [68Ga]Ga-NOTA-conjugated variants. The influence of the chelator was more pronounced in variants without (HE)3-tag. In conclusion, hydrophilic (HE)₃-tag and neutral charge of the [68Ga]Ga-NODAGA complex promoted blood clearance and lowered hepatic uptake of Z08698. [68Ga]Ga-(HE)₃-Z08698-NODAGA was considered most promising, providing the lowest blood and hepatic uptake and the best imaging contrast among the tested variants.

Ort, förlag, år, upplaga, sidor
NLM (Medline) , 2019. Vol. 20, nr 5
Nyckelord [en]
affibody, gallium-68, HER3, molecular imaging, NODAGA, NOTA, PET
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
URN: urn:nbn:se:kth:diva-246490DOI: 10.3390/ijms20051080ISI: 000462542300079PubMedID: 30832342Scopus ID: 2-s2.0-85062394960OAI: oai:DiVA.org:kth-246490DiVA, id: diva2:1299217
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QC 20190326

Tillgänglig från: 2019-03-26 Skapad: 2019-03-26 Senast uppdaterad: 2019-04-23Bibliografiskt granskad

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Dahlsson Leitao, CharlesStåhl, StefanLöfblom, John

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Dahlsson Leitao, CharlesAndersson, Ken GöstaStåhl, StefanLöfblom, John
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Proteinvetenskap
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International Journal of Molecular Sciences
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

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