A pretargeted PET imaging strategy based on bioorthogonal diels-alder click chemistry Journal Article
| Authors: | Zeglis, B. M.; Sevak, K. K.; Reiner, T.; Mohindra, P.; Carlin, S. D.; Zanzonico, P.; Weissleder, R.; Lewis, J. S. |
| Article Title: | A pretargeted PET imaging strategy based on bioorthogonal diels-alder click chemistry |
| Abstract: | The specificity of antibodies have made immunoconjugates promising vectors for the delivery of radioisotopes to cancer cells; however, their long pharmacologic half-lives necessitate the use of radioisotopes with long physical half-lives, a combination that leads to high radiation doses to patients. Therefore, the development of targeting modalities that harness the advantages of antibodies without their pharmacokinetic limitations is desirable. To this end, we report the development of a methodology for pretargeted PET imaging based on the bioorthogonal Diels-Alder click reaction between tetrazine and transcyclooctene. Methods: A proof-ofconcept system based on the A33 antibody, SW1222 colorectal cancer cells, and 64Cu was used. The huA33 antibody was covalently modified with transcyclooctene, and a NOTA-modified tetrazine was synthesized and radiolabeled with 64Cu. Pretargeted in vivo biodistribution and PET imaging experiments were performed with athymic nude mice bearing A33 antigen-expressing, SW1222 colorectal cancer xenografts. Results: The huA33 antibody was modified with transcyclooctene to produce a conjugate with high immunoreactivity, and the 64Cu-NOTA-labeled tetrazine ligand was synthesized with greater than 99% purity and a specific activity of 9-10 MBq/mg. For in vivo experiments, mice bearing SW1222 xenografts were injected with transcyclooctene-modified A33; after allowing 24 h for accumulation of the antibody in the tumor, the mice were injected with 64Cu-NOTA-labeled tetrazine for PET imaging and biodistribution experiments. At 12 h after injection, the retention of uptake in the tumor (4.1 6 0.3 percent injected dose per gram), coupled with the fecal excretion of excess radioligand, produced images with high tumor-to-background ratios. PET imaging and biodistribution experiments performed using A33 directly labeled with either 64Cu or 89Zr revealed that although absolute tumor uptake was higher with the directly radiolabeled antibodies, the pretargeted system yielded comparable images and tumor-to-muscle ratios at 12 and 24 h after injection. Further, dosimetry calculations revealed that the 64Cu pretargeting system resulted in only a fraction of the absorbed background dose of A33 directly labeled with 89Zr (0.0124 mSv/MBq vs. 0.4162 mSv/MBq, respectively). Conclusion: The high quality of the images produced by this pretargeting approach, combined with the ability of the methodology to dramatically reduce nontarget radiation doses to patients, marks this system as a strong candidate for clinical translation. COPYRIGHT © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc. |
| Keywords: | unclassified drug; pyridines; radiation dose; positron emission tomography; radiopharmaceuticals; colorectal cancer; antigen expression; animals; mice; in vivo study; cell line, tumor; immunoreactivity; xenograft; nude mouse; dosimetry; cancer cell; positron-emission tomography; antibody specificity; antibodies; radioisotope; heterocyclic compounds; feces; antibody; diels alder reaction; positron emission tomography (pet); click chemistry; copper radioisotopes; cycloaddition; radioligand; pretargeting; tetrazine derivative; transcyclooctene; cyclooctanes |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 54 |
| Issue: | 8 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2013-08-01 |
| Start Page: | 1389 |
| End Page: | 1396 |
| Language: | English |
| DOI: | 10.2967/jnumed.112.115840 |
| PROVIDER: | scopus |
| PUBMED: | 23708196 |
| PMCID: | PMC4151562 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 September 2013" - "CODEN: JNMEA" - "Source: Scopus" |
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