Optimization of Labile Esters for Esterase-Assisted Accumulation of Nitroxides into Cells: A Model for In Vivo EPR Imaging
| Autor: | Scott R. Burks, Andrew Coop, Gerald M. Rosen, Jiahong Ni, Sukumaran Muralidharan, Joseph P. Y. Kao |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Nitroxide mediated radical polymerization
Stereochemistry Kinetics Intracellular Space Biomedical Engineering Pharmaceutical Science Bioengineering Esterase Article law.invention Jurkat Cells In vivo law Humans Moiety Electron paramagnetic resonance Pharmacology Chemistry Organic Chemistry Electron Spin Resonance Spectroscopy Esterases Esters Biocatalysis Biophysics Nitrogen Oxides Oxidation-Reduction Intracellular Biotechnology |
| Zdroj: | Bioconjugate Chemistry. 19:2068-2071 |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/bc8001562 |
| Popis: | Nitroxide–based electron paramagnetic resonance (EPR) imaging agents are useful quantitative probes of O2 concentration in vivo in real time. Lipophilic, labile alkanoyloxymethyl esters of nitroxides can cross the blood-brain barrier, and after hydrolysis, the corresponding anionic nitroxide is intracellularly entrapped at levels sufficient to permit O2 measurements. The utility of nitroxides as EPR imaging agents depends critically on their ability to accumulate in the brain to high levels. In this study, we systematically investigated the relationship between the structure of the alkanoyl moiety and the ability of the corresponding labile ester to deliver nitroxide intracellularly. We demonstrate, in a cultured cell model, that for nitroxide labile esters with unbranched alkanoyl chains, increasing the chain length improves intracellular loading. Moreover, by studying an isomeric series of labile esters, we conclude that branching of the alkanoyl chain drastically reduces intracellular loading. These structural insights improve our general ability to use labile esters to deliver carboxylates intracellularly, and suggest a strategy for how to enhance delivery of nitroxide imaging agents across the blood-brain barrier in a living animal. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|