期刊
BIOCONJUGATE CHEMISTRY
卷 29, 期 4, 页码 1364-1372出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.bioconjchem.8b00081
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资金
- National Institutes of Health (NIH) [4R00CA178205-02, R01CA204167]
- TeamConnor Childhood Cancer Foundation
- National Institute on Minority Health and Health Disparities [G12MD007599]
- NIH [R24 CA83084, P30 CA08748]
Maleimide-bearing bifunctional chelators have been used extensively for the site-selective bioconjugation and radiolabeling of peptides and proteins. However, bioconjugates obtained using these constructs inevitably suffer from limited stability in vivo, a trait that translates into suboptimal activity concentrations in target tissues and higher uptake levels in healthy, nontarget tissues. To circumvent this issue, phenyloxadiazolyl methylsulfones have previously been reported as alternatives to maleimides for thiol-based ligations, but these constructs have scarcely been used in the field of radiochemistry. In this report, we describe the synthesis of two thiol-reactive bifunctional chelators for Zr-89 and Lu-177 based on a new, easy-to-make phenyloxadiazolyl methylsulfone reagent, PODS. Radioimmunoconjugates created using these novel bifunctional chelators displayed in vitro stability that was higher than that of their maleimide-derived cousins. More importantly, positron emission tomography imaging in murine models of cancer revealed that a Zr-89-labeled radioimmunoconjugate created using a PODS-bearing bifunctional chelator produced a rate of uptake in nontarget tissues that is significantly lower than that of its analogous maleimide-based counterpart.
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