Design and optimization of cationic hydrophobic polymer-based delivery systems for nucleic acids

There is high interest in the therapeutic delivery of nucleic acids, as it offers considerable potential for the treatment of genetic diseases, cancer therapy and vaccination. Due to their degradable and highly charged nature, suitable carriers are required for delivery of nucleic acids into targeted cells. The carrier should protect the nucleic acids from degradation, possess high stability, facilitate crossing of cell membranes, release the nucleic acids inside the cell and show high biocompatibility. There is a growing interest in polymeric carriers, due to their versatile synthesis, offering numerous possibilities of fine-tuning and their high stability. Typically, cationic polymers are used, electrostatically complexing the negatively charged genetic material. However, the cationic charge is often associated with cytotoxicity, low serum stability, changed biodistribution and thus reduced transfection efficiency. A promising approach to address these challenges of cationic polymers is their hydrophobic modification to increase stability and interaction with cell membranes. This thesis deals with different hydrophobically modified cationic polymers and strategies to optimize their performance in vitro and in vivo. Overall, hydrophobic modification results in highly efficient carriers for various kinds of genetic material (e.g., pDNA, siRNA and mRNA). Thereby, a novel pH-dependent formulation method enables to exploit poorly water-soluble but highly efficient cationic/hydrophobic polymers for gene delivery. By pH-responsive shielding concepts, biocompatibility and in vivo applicability of these polymers was enhanced, without substantially diminishing transfection efficiency. These polymeric gene delivery systems can find a wide range of applications in future gene therapy, for example for delivery to tumor and inflamed tissue due to their pH- responsive nature, immune therapies or vaccination and form the basis for further optimization for cell specific delivery.