Thiol-Reactive Bifunctional Chelators for the Creation of Site-Selectively Modified Radioimmunoconjugates with Improved Stability
| Autor: | Maria Davydova, Brian M. Zeglis, Pierre Adumeau |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Immunoconjugates Biomedical Engineering Mice Nude Pharmaceutical Science Bioengineering Lutetium Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Neoplasms Animals Humans Sulfhydryl Compounds Bifunctional Chelating Agents Mesylates Radioisotopes Pharmacology chemistry.chemical_classification Bioconjugation Extramural Chemistry Organic Chemistry Combinatorial chemistry In vitro 030104 developmental biology Positron-Emission Tomography 030220 oncology & carcinogenesis Reagent Thiol Zirconium Biotechnology |
| Zdroj: | Bioconjugate Chemistry. 29:1364-1372 |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/acs.bioconjchem.8b00081 |
| Popis: | 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 which translates into suboptimal activity concentrations in target tissue and higher uptake levels in healthy, non-target 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 (89)Zr and (177)Lu based on a new, easy-to-make phenyloxadiazolyl methylsulfone reagent: PODS. Radioimmunoconjugates created using these novel bifunctional chelators displayed higher in vitro stability than their maleimide-derived cousins. More importantly, PET imaging in murine models of cancer revealed that a (89)Zr-labeled radioimmunoconjugate created using a PODS-bearing bifunctional chelator produced significantly lower uptake in non-target tissues than its analogous maleimide-based counterpart. |
| Databáze: | OpenAIRE |
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