Lipophilic prodrugs of oligonucleotides: synthesis, properties and conjugates for cellular targeting

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Oligonucleotides (ON) represent attractive drug candidates as they display the potential to bind endogenous nucleic acids in a sequence-specific manner. Thus, single-stranded ON can inhibit protein biosynthesis via the antisense mechanism (i.e. via sequence-specific binding to mRNA), resulting in the selective modulation of a gene product. However, potential therapeutic applications of ON are hampered by significant hurdles. In particular, their pharmacokinetic properties (cellular uptake and stability) are insufficient, hence requiring the chemical modification of the backbone structure of ON. This has resulted in a significant number of such backbone modifications which have already been described. In spite of some remarkable success in this field, none of these modifications has become a universally applicable tool for a pharmacologically useful alteration of ON structures. For these reasons, the design of prodrug concepts for ON has been discussed in order to improve their pharmacokinetic properties. Thus, the polar polyanionic backbone of ON is envisioned to be 'masked' with lipophilic units, which are supposed to be cleaved after cellular uptake to provide the ON ('chemical Trojan horse' principle). In this project, we aim to develop and investigate novel prodrugs of single-stranded ON with potential antisense activity. Thereby, it is envisioned to fundamentally contribute to the development of modified ON with therapeutic potential. The synthesis of new ON prodrugs will be established, and the according products will be tested in detail for their pharmacokinetic properties. Furthermore, it is our goal to establish the cellular targeting of such ON prodrugs in order to develop them into therapeutically useful antisense agents. We will therefore study a novel approach for a cell-specific targeting of estrogen-dependent breast cancer cells, which is based on the conjugation of low-molecular targeting units with the ON prodrugs. The overall goal will be to obtain an ON prodrug as a potential drug candidate with activity against breast cancer cells.