Increase in negative charge of 68 Ga/chelator complex reduces unspecific hepatic uptake but does not improve imaging properties of HER3-targeting affibody molecules

• Published in: Scientific reports 2019-11, Vol.9 (1), p.17710
• Main Authors: Rinne, Sara S, Dahlsson Leitao, Charles, Gentry, Joshua, Mitran, Bogdan, Abouzayed, Ayman, Tolmachev, Vladimir, Ståhl, Stefan, Löfblom, John, Orlova, Anna
• Format: Article
• Language: English
• Subjects: Acetates - chemistry; Animals; Cell Line, Tumor; Chelating Agents - chemistry; Female; Gallium Radioisotopes - chemistry; Heterocyclic Compounds, 1-Ring - chemistry; Humans; Liver - metabolism; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Experimental - diagnostic imaging; Octreotide - analogs & derivatives; Positron-Emission Tomography; Protein Binding; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Receptor, ErbB-3 - metabolism; Static Electricity; Tissue Distribution
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-54149-3

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 Ga-labeled anti-HER3 affibody molecules (HE) -Z -DOTA and (HE) -Z -DOTAGA with previously reported [ Ga]Ga-(HE) -Z -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) -Z -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 [ Ga]Ga-(HE) -Z -NODAGA. Presence of the negatively charged Ga-DOTAGA complex reduced the unspecific hepatic uptake, but did not improve overall biodistribution of the conjugate. [ Ga]Ga-(HE) -Z -DOTAGA and [ Ga]Ga-(HE) -Z -NODAGA had similar tumor-to-liver ratios, but [ Ga]Ga-(HE) -Z -NODAGA had the highest tumor uptake and tumor-to-blood ratio among the tested conjugates. In conclusion, [ Ga]Ga-(HE) -Z -NODAGA remains the favorable variant for PET imaging of HER3 expression.