Highly reactive trans-cyclooctene tags with improved stability for diels-alder chemistry in living systems
| Autor: | Sandra M. van den Bosch, M Marco Carvelli, Wolter ten Hoeve, Marc S. Robillard, Johan Lub, Ron M. Versteegen, Raffaella Rossin |
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| Přispěvatelé: | Macromolecular and Organic Chemistry, Stimuli-responsive Funct. Materials & Dev. |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Steric effects
Transplantation Heterologous Biomedical Engineering Pharmaceutical Science Bioengineering chemistry.chemical_compound Tetrazine Cyclooctanes Mice Cyclooctene Organic chemistry Animals Pretargeted Radioimmunotherapy Reactivity (chemistry) Pharmacology Tomography Emission-Computed Single-Photon Mice Inbred BALB C Organic Chemistry Combinatorial chemistry chemistry Reagent Molecular Probes Female Bioorthogonal chemistry Tomography X-Ray Computed Isomerization Biotechnology |
| Zdroj: | Bioconjugate Chemistry, 24(7), 1210-1217. American Chemical Society |
| ISSN: | 1043-1802 |
| Popis: | One of the challenges of pretargeted radioimmunotherapy, which centers on the capture of a radiolabeled probe by a preinjected tumor-bound antibody, is the potential immunogenicity of biological capturing systems. A bioorthogonal chemical approach may circumvent this drawback, but effective in vivo chemistry in mice, larger animals, and eventually humans, requires very high reagent reactivity, sufficient stability, and retained selectivity. We report here that the reactivity of the fastest bioorthogonal reaction, the inverse-electron- demand-Diels-Alder cycloaddition between a tetrazine probe and a trans-cyclooctene-tagged antibody, can be increased 10-fold (k2 = 2.7 × 105 M-1 s-1) via the trans-cyclooctene, approaching the speed of biological interactions, while also increasing its stability. This was enabled by the finding that the trans-cyclooctene tag is probably deactivated through isomerization to the unreactive cis-cyclooctene isomer by interactions with copper-containing proteins, and that increasing the steric hindrance on the tag can impede this process. Next, we found that the higher reactivity of axial vs equatorial linked TCO can be augmented by the choice of linker. The new, stabilized, and more reactive tag allowed for improved tumor-to-nontumor ratios in pretargeted tumor-bearing mice. |
| Databáze: | OpenAIRE |
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