P12 - Aptamer-targeted delivery of nucleoside drugs
The systemic application of nucleoside-based epigenetic modulators such as Decitabine has become routine therapy in severe cases of leukaemia. The treatment is, despite its effectiveness, associated with strong side effects and resistance formation. The Carell group has developed a stabilized derivative of Decitabine, which shows very promising effects in a mouse xenograft model for AML with strongly reduced toxicity. The substance further proved effective in lung cancer cell lines, which may open up new therapeutic opportunities. Two goals are pursued in this project: the compound is to be specifically delivered as integral building block of aptamers, which are oligonucleotides with strong binding affinity to specific target proteins, e.g. cancer specific surface proteins. Once internalized, these aptamers are degraded and release their payload directly in the cancerous cells, which further reduces the toxicity compared to systemic application. The second goal is to apply the strategy to lung cancer models. The methodology involves chemical synthesis of triphosphates, their enzymatic incorporation into oligonucleotides as well as mass spectrometric quantification of nucleosides and cell culture techniques.