Self-assembling polycations for gene delivery: Effects of polymer structure and environmental pH

SUMMARY In this thesis, novel polycationic vectors for therapeutic gene delivery were introduced with the focus on structure-function relationship in both physicochemical and biological aspects. First the transfection related differences of classical vectors with high and low branching grade and charge density: PEI and PLL, were examined under pH-alternating tumor tissue conditions. Further structural design for siRNA delivery was proposed on base of PEG-PCL-PEI multifunctional self-assembly ABC-construct, showing the importance of total hydrophilic-lipophilic balance for efficient gene silencing performance. For DNA delivery a new low molecular weight di-block pDMAEMA derivative was synthesized and characterized, proving it to be a low toxic and efficient vector. The relationship between pHEMA-content and polymer chain flexibility was assessed via molecular dynamics simulation (MD). The thermodynamic polymer-DNA binding characteristics, monitored via ITC, appeared to depend on glass transition temperatue (Tg). The use of both MD and ITC methodologies provided new information on the cargo-carrier self-assembly process in solution, relevant to transfection performance of diblock-copolymers.