Descripción del proyecto
Nuevos marcadores farmacológicos fluorescentes para la imagenología «in vivo»
Las fases preclínicas y clínicas del descubrimiento de fármacos se beneficiarían en gran medida de contar con una información precisa sobre la distribución de fármacos. En términos de seguridad, la imagenología con fluorescencia es mucho mejor que los marcadores radiactivos empleados en la tomografía por emisión de positrones. Sin embargo, los marcadores fluorescentes actuales son grandes entidades con carga positiva o negativa que podrían cambiar las propiedades del fármaco. Este proyecto financiado con fondos europeos incluye cuatro equipos académicos y dos equipos industriales pluridisciplinarios que tienen como finalidad desarrollar tintes fluorescentes infrarrojos cercanos y rojos no sesgados para la imagenología «in vivo» que no afecten a las propiedades de los fármacos marcados. Los tintes desarrollados se evaluarán mediante fármacos conocidos y representativos para monitorizar y analizar su distribución «in vitro» e «in vivo».
Objetivo
Imaging of distribution of drugs in mice delivers accurate information for confirmation that the mechanism of action elaborated in cell-based assays is also operative in vivo. These data are critical for the transfer of drug discovery process from pre-clinical to clinical phase. To enable the imaging, drugs should be labeled with easily detectable moieties, e.g. radioactive markers and fluorescent dyes. Ideally, the markers should not affect in vivo properties of the drugs that can be better achieved with radioactive markers, since they can be selected to be small: e.g. a single atom marker 18F applied in positron emission tomography. Despite this intrinsic advantage, PET suffers from safety issues, since radioactivity is harmful to humans and environment. In terms of safety optical imaging is much better and, therefore, in future can replace PET. However, fluorescent dyes compatible with the optical imaging are usually extended pi-systems carrying overall positive or negative charge. Their conjugation strongly affects properties of the majority of medium sized and low molecular weight drugs that limits the applicability of this method in drug discovery. The interdisciplinary and intersectoral consortium NoBiasFluors consisting of 4 academic and 2 industrial teams aims at achieving a breakthrough solution of this problem. We will develop non-biased red and near infrared fluorescent dyes, which are compatible with in vivo optical imaging and do not affect properties of drugs upon their conjugation. This goal will be achieved by the careful optimization of dye structure, polarity and charge. We will confirm the functionality of the developed dyes for labeling of representative drugs (anticancer N-alkylaminoferrocene-based prodrugs, D-peptides targeting Alzheimer’s disease) and binders of biomolecules (nucleopeptides and lectins) and monitoring their distribution both in cellulo and in vivo (for a selected labeled drug).
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MSCA-RISE - Marie Skłodowska-Curie Research and Innovation Staff Exchange (RISE)Coordinador
91054 Erlangen
Alemania