TY - JOUR
T1 - Increase in negative charge of 68Ga/chelator complex reduces unspecific hepatic uptake but does not improve imaging properties of HER3-targeting affibody molecules
AU - Rinne, Sara S.
AU - Dahlsson Leitao, Charles
AU - Gentry, Joshua
AU - Mitran, Bogdan
AU - Abouzayed, Ayman
AU - Tolmachev, Vladimir
AU - Ståhl, Stefan
AU - Löfblom, John
AU - Orlova, Anna
N1 - Funding Information:
This study was supported by the Swedish Cancer Society (grants CAN 2017/425 (A.O.) and CAN 2018/436 (V.T.), CAN2017/649 (J.L.) and CAN2016/463 (S.S.)), the Swedish Research Council (grants 2015–02509 (A.O.), 2015– 02353 (V.T.)), the Swedish Agency for Innovation VINNOVA (grants 2016/04060 (A.O.), 2019/00104 (J.L.)) and the Wallenberg Center for Protein Technology (S.S. and J.L.) which are acknowledged for financial support.
Publisher Copyright:
© 2019, The Author(s).
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Upregulation of the human epidermal growth factor receptor type 3 (HER3) is a common mechanism to bypass HER-targeted cancer therapy. Affibody-based molecular imaging has the potential for detecting and monitoring HER3 expression during treatment. In this study, we compared the imaging properties of newly generated 68Ga-labeled anti-HER3 affibody molecules (HE)3-ZHER3-DOTA and (HE)3-ZHER3-DOTAGA with previously reported [68Ga]Ga-(HE)3-ZHER3-NODAGA. We hypothesized that increasing the negative charge of the gallium-68/chelator complex would reduce hepatic uptake, which could lead to improved contrast of anti-HER3 affibody-based PET-imaging of HER3 expression. (HE)3-ZHER3-X (X = DOTA, DOTAGA) were produced and labeled with gallium-68. Binding of the new conjugates was specific in HER3 expressing BxPC-3 and DU145 human cancer cells. Biodistribution and in vivo specificity was studied in BxPC-3 xenograft bearing Balb/c nu/nu mice 3 h pi. DOTA- and DOTAGA-containing conjugates had significantly higher concentration in blood than [68Ga]Ga-(HE)3-ZHER3-NODAGA. Presence of the negatively charged 68Ga-DOTAGA complex reduced the unspecific hepatic uptake, but did not improve overall biodistribution of the conjugate. [68Ga]Ga-(HE)3-ZHER3-DOTAGA and [68Ga]Ga-(HE)3-ZHER3-NODAGA had similar tumor-to-liver ratios, but [68Ga]Ga-(HE)3-ZHER3-NODAGA had the highest tumor uptake and tumor-to-blood ratio among the tested conjugates. In conclusion, [68Ga]Ga-(HE)3-ZHER3-NODAGA remains the favorable variant for PET imaging of HER3 expression.
AB - Upregulation of the human epidermal growth factor receptor type 3 (HER3) is a common mechanism to bypass HER-targeted cancer therapy. Affibody-based molecular imaging has the potential for detecting and monitoring HER3 expression during treatment. In this study, we compared the imaging properties of newly generated 68Ga-labeled anti-HER3 affibody molecules (HE)3-ZHER3-DOTA and (HE)3-ZHER3-DOTAGA with previously reported [68Ga]Ga-(HE)3-ZHER3-NODAGA. We hypothesized that increasing the negative charge of the gallium-68/chelator complex would reduce hepatic uptake, which could lead to improved contrast of anti-HER3 affibody-based PET-imaging of HER3 expression. (HE)3-ZHER3-X (X = DOTA, DOTAGA) were produced and labeled with gallium-68. Binding of the new conjugates was specific in HER3 expressing BxPC-3 and DU145 human cancer cells. Biodistribution and in vivo specificity was studied in BxPC-3 xenograft bearing Balb/c nu/nu mice 3 h pi. DOTA- and DOTAGA-containing conjugates had significantly higher concentration in blood than [68Ga]Ga-(HE)3-ZHER3-NODAGA. Presence of the negatively charged 68Ga-DOTAGA complex reduced the unspecific hepatic uptake, but did not improve overall biodistribution of the conjugate. [68Ga]Ga-(HE)3-ZHER3-DOTAGA and [68Ga]Ga-(HE)3-ZHER3-NODAGA had similar tumor-to-liver ratios, but [68Ga]Ga-(HE)3-ZHER3-NODAGA had the highest tumor uptake and tumor-to-blood ratio among the tested conjugates. In conclusion, [68Ga]Ga-(HE)3-ZHER3-NODAGA remains the favorable variant for PET imaging of HER3 expression.
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U2 - 10.1038/s41598-019-54149-3
DO - 10.1038/s41598-019-54149-3
M3 - Article
C2 - 31776413
AN - SCOPUS:85075755842
VL - 9
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 17710
ER -