Journal
BIOCONJUGATE CHEMISTRY
Volume 27, Issue 8, Pages 1789-1795Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.bioconjchem.6b00235
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Funding
- NIH [R24 CA83084, P30 CA08748]
- National Institutes of Health [4R00CA178205-02]
- TeamConnor Childhood Cancer Foundation
- National Institute on Minority Health and Health Disparities [G12MD007599]
- Tow Foundation Fellowship Program in Molecular Imaging and Nanotechnology
- Commonwealth Foundation for Cancer Research
- Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center
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In recent years, both site-specific bioconjugation techniques and bioorthogonal pretargeting strategies have emerged as exciting technologies with the potential to improve the safety and efficacy of antibody-based nuclear imaging. In the work at hand, we have combined these two approaches to create a pretargeted PET imaging strategy based on the rapid and bioorthogonal inverse electron demand :Diels-Alder reaction between a Cu-64-labeled tetrazine radioligand (Cu-64-Tz-SarAr) and a site-specifically modified huA33-trans-cyclooctene immunoconjugate ((ss)huA33-PEG(12)-TCO). A bioconjugation strategy that harnesses enzymatic transformations and strain-promoted azide-alkyne click chemistry was used to site-specifically append PEGylated TCO moieties to the heavy chain glycans of the colorectal cancer-targeting huA33 antibody. Preclinical in vivo validation studies were performed in athymic nude mice bearing A33 antigen-expressing SW1222 human colorectal carcinoma xenografts. To this end, mice were administered (ss)huA33-PEG(12)-TCO via tail vein injection and following accumulation intervals of 24 or 48 h-Cu-64-Tz-SarAr. PET imaging and biodistribution studies reveal that this strategy clearly delineates tumor tissue as early as 1 h post-injection (6.7 +/- 1.7%ID/g at 1 h p.i.), producing images with excellent contrast and high tumor-to-background activity concentration ratios (tumor:muscle = 21.5 +/- 5.6 at 24 h p.i.). Furthermore, dosimetric calculations illustrate that this pretargeting approach produces only a fraction of the overall effective dose (0.0214 mSv/MBq; 0.079 rem/mCi) of directly labeled radioimmunoconjugates. Ultimately, this method effectively facilitates the high contrast pretargeted PET imaging of colorectal carcinoma using a site-specifically modified immunoconjugate.
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