Non-Biased fluorescent dyes as markers of drugs for optical in cellulo and in vivo imaging
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).