Novel VHH-Based Tracers with Variable Plasma Half-Lives for Imaging of CAIX-Expressing Hypoxic Tumor Cells
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| Název: | Novel VHH-Based Tracers with Variable Plasma Half-Lives for Imaging of CAIX-Expressing Hypoxic Tumor Cells |
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| Autoři: | Sanne A.M. van Lith, Fokko J. Huizing, Gerben M. Franssen, Bianca A.W. Hoeben, Jasper Lok, Sofia Doulkeridou, Otto C. Boerman, Martin Gotthardt, Paul M.P. van Bergen en Henegouwen, Johan Bussink, Sandra Heskamp |
| Přispěvatelé: | MS Radiotherapie, Cancer, Sub Cell Biology, Cell Biology, Neurobiology and Biophysics |
| Zdroj: | Mol Pharm Molecular Pharmaceutics, 19, 10, pp. 3511-3520 |
| Informace o vydavateli: | American Chemical Society (ACS), 2022. |
| Rok vydání: | 2022 |
| Témata: | 0301 basic medicine, Pharmaceutical Science, Antibodies, Monoclonal/chemistry, variable domain of heavy chain only antibody (VHH), Mice, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Antigens, Neoplasm, Albumins, Cell Line, Tumor, Medical Imaging - Radboud University Medical Center, Drug Discovery, Journal Article, Animals, Humans, Tissue Distribution, Carbonic Anhydrase IX, Hypoxia, carbonic anhydrase IX (CAIX), tumor hypoxia, Tomography, Emission-Computed, Single-Photon, Antigens, Neoplasm/metabolism, Carbonic Anhydrase IX/metabolism, Radboudumc 19: Nanomedicine RIMLS: Radboud Institute for Molecular Life Sciences, Antibodies, Monoclonal, Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health Sciences, albumin-binding domain (ABD), Pentetic Acid, Radboudumc 9: Rare cancers RIMLS: Radboud Institute for Molecular Life Sciences, 3. Good health, Radboudumc 14: Tumours of the digestive tract RIMLS: Radboud Institute for Molecular Life Sciences, Head and Neck Neoplasms, Head and Neck Neoplasms/diagnostic imaging, Radiation Oncology - Radboud University Medical Center, Molecular Medicine, Albumins/metabolism, Half-Life |
| Popis: | Hypoxic areas are present in the majority of solid tumors, and hypoxia is associated with resistance to therapies and poor outcomes. A transmembrane protein that is upregulated by tumor cells that have adapted to hypoxic conditions is carbonic anhydrase IX (CAIX). Therefore, noninvasive imaging of CAIX could be of prognostic value, and it could steer treatment strategies. The aim of this study was to compare variants of CAIX-binding VHH B9, with and without a C-terminal albumin-binding domain with varying affinity (ABDlow and ABDhigh), for SPECT imaging of CAIX expression. The binding affinity and internalization of the various B9-variants were analyzed using SK-RC-52 cells. Biodistribution studies were performed in mice with subcutaneous SCCNij153 human head and neck cancer xenografts. Tracer uptake was determined by ex vivo radioactivity counting and visualized by SPECT/CT imaging. Furthermore, autoradiography images of tumor sections were spatially correlated with CAIX immunohistochemistry. B9-variants demonstrated a similar moderate affinity for CAIX in vitro. Maximal tumor uptake and acceptable tumor-to-blood ratios were found in the SCCNij153 model at 4 h post injection for [111In]In-DTPA-B9 (0.51 ± 0.08%ID/g and 8.1 ± 0.85, respectively), 24 h post injection for [111In]In-DTPA-B9-ABDlow (2.39 ± 0.44%ID/g and 3.66 ± 0.81, respectively) and at 72 h post injection for [111In]In-DTPA-B9-ABDhigh (8.7 ± 1.34%ID/g and 2.43 ± 0.15, respectively). An excess of unlabeled monoclonal anti-CAIX antibody efficiently inhibited tumor uptake of [111In]In-DTPA-B9, while only a partial reduction of [111In]In-DTPA-B9-ABDlow and [111In]In-DTPA-B9-ABDhigh uptake was found. Immunohistochemistry and autoradiography images showed colocalization of all B9-variants with CAIX expression; however, [111In]In-DTPA-B9-ABDlow and [111In]In-DTPA-B9-ABDhigh also accumulated in non-CAIX expressing regions. Tumor uptake of [111In]In-DTPA-B9-ABDlow and [111In]In-DTPA-B9-ABDhigh, but not of [111In]In-DTPA-B9, could be visualized with SPECT/CT imaging. In conclusion, [111In]In-DTPA-B9 has a high affinity to CAIX and shows specific targeting to CAIX in head and neck cancer xenografts. The addition of ABD prolonged plasma half-life, increased tumor uptake, and enabled SPECT/CT imaging. This uptake was, however, partly CAIX- independent, precluding the ABD-tracers for use in hypoxia quantification in this tumor type. |
| Druh dokumentu: | Article Other literature type |
| Popis souboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/acs.molpharmaceut.1c00841 |
| Přístupová URL adresa: | https://pubs.acs.org/doi/pdf/10.1021/acs.molpharmaceut.1c00841 https://pubmed.ncbi.nlm.nih.gov/35044182 https://hdl.handle.net/https://repository.ubn.ru.nl/handle/2066/283433 https://doi.org/10.1021/acs.molpharmaceut.1c00841 https://research-portal.uu.nl/en/publications/d1129659-d8ca-43a1-af97-6f91d8aadde7 https://doi.org/10.1021/acs.molpharmaceut.1c00841 https://dspace.library.uu.nl/handle/1874/447666 https://hdl.handle.net/2066/283433 https://repository.ubn.ru.nl//bitstream/handle/2066/283433/283433.pdf https://dspace.library.uu.nl/handle/1874/423208 |
| Rights: | CC BY URL: http://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (http://creativecommons.org/licenses/by/4.0/). |
| Přístupové číslo: | edsair.doi.dedup.....862189908a8129b2deaa66bc7d6af3a4 |
| Databáze: | OpenAIRE |
Nájsť tento článok vo Web of Science | Abstrakt: | Hypoxic areas are present in the majority of solid tumors, and hypoxia is associated with resistance to therapies and poor outcomes. A transmembrane protein that is upregulated by tumor cells that have adapted to hypoxic conditions is carbonic anhydrase IX (CAIX). Therefore, noninvasive imaging of CAIX could be of prognostic value, and it could steer treatment strategies. The aim of this study was to compare variants of CAIX-binding VHH B9, with and without a C-terminal albumin-binding domain with varying affinity (ABDlow and ABDhigh), for SPECT imaging of CAIX expression. The binding affinity and internalization of the various B9-variants were analyzed using SK-RC-52 cells. Biodistribution studies were performed in mice with subcutaneous SCCNij153 human head and neck cancer xenografts. Tracer uptake was determined by ex vivo radioactivity counting and visualized by SPECT/CT imaging. Furthermore, autoradiography images of tumor sections were spatially correlated with CAIX immunohistochemistry. B9-variants demonstrated a similar moderate affinity for CAIX in vitro. Maximal tumor uptake and acceptable tumor-to-blood ratios were found in the SCCNij153 model at 4 h post injection for [111In]In-DTPA-B9 (0.51 ± 0.08%ID/g and 8.1 ± 0.85, respectively), 24 h post injection for [111In]In-DTPA-B9-ABDlow (2.39 ± 0.44%ID/g and 3.66 ± 0.81, respectively) and at 72 h post injection for [111In]In-DTPA-B9-ABDhigh (8.7 ± 1.34%ID/g and 2.43 ± 0.15, respectively). An excess of unlabeled monoclonal anti-CAIX antibody efficiently inhibited tumor uptake of [111In]In-DTPA-B9, while only a partial reduction of [111In]In-DTPA-B9-ABDlow and [111In]In-DTPA-B9-ABDhigh uptake was found. Immunohistochemistry and autoradiography images showed colocalization of all B9-variants with CAIX expression; however, [111In]In-DTPA-B9-ABDlow and [111In]In-DTPA-B9-ABDhigh also accumulated in non-CAIX expressing regions. Tumor uptake of [111In]In-DTPA-B9-ABDlow and [111In]In-DTPA-B9-ABDhigh, but not of [111In]In-DTPA-B9, could be visualized with SPECT/CT imaging. In conclusion, [111In]In-DTPA-B9 has a high affinity to CAIX and shows specific targeting to CAIX in head and neck cancer xenografts. The addition of ABD prolonged plasma half-life, increased tumor uptake, and enabled SPECT/CT imaging. This uptake was, however, partly CAIX- independent, precluding the ABD-tracers for use in hypoxia quantification in this tumor type. |
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| ISSN: | 15438392 15438384 |
| DOI: | 10.1021/acs.molpharmaceut.1c00841 |