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Molecular Design of HER3-Targeting Affibody Molecules: Influence of Chelator and Presence of HEHEHE-Tag on Biodistribution of 68Ga-Labeled Tracers
KTH Royal Inst Technol, Dept Prot Sci, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.ORCID-id: 0000-0001-7921-3268
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.ORCID-id: 0000-0002-4778-3909
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2019 (engelsk)Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, nr 5, artikkel-id 1080Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2019. Vol. 20, nr 5, artikkel-id 1080
Emneord [en]
HER3, affibody, NOTA, NODAGA, molecular imaging, gallium-68, PET
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-381825DOI: 10.3390/ijms20051080ISI: 000462542300079PubMedID: 30832342OAI: oai:DiVA.org:uu-381825DiVA, id: diva2:1305854
Forskningsfinansiär
Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353Swedish Research Council, 2012-05236Vinnova, 2016/04060Swedish Cancer Society, CAN2014/474Swedish Cancer Society, CAN 2017/425Swedish Cancer Society, CAN2015/350Swedish Cancer Society, CAN 2018/436Swedish Cancer Society, CAN2017/649Swedish Cancer Society, CAN2016/463
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Tilgjengelig fra: 2019-04-18 Laget: 2019-04-18 Sist oppdatert: 2019-04-18bibliografisk kontrollert

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