Poly(ethylene imine) (PEI) has widely been used as synthetic material for the delivery of nucleic acids to cells. A common approach to suppress non-specific interactions of polyplexes (complexes of PEI and nucleic acids) with non-target cells and components of the extracellular matrix (ECM) is to shield their positive surface charge by the attachment of poly(ethylene glycol) (PEG). However, PEG-PEI copolymers that allow for a highly effective shielding, and consequently a favorable distribution of the polyplexes in the ECM of the target tissue have not been developed. To overcome existing limitations, our first goal will be to synthesize a library of strictly linear, redox-sensitive PEG-PEI copolymers. We hypothesize that this strategy leads to a better shielding of polyplexes because the PEG moiety is sterically isolated from PEI, and hence, does not interfere with the interaction between PEI and the nucleic acid. In addition, in comparison to graft copolymers, the synthesis of linear PEG-PEI copolymers does not lead to a mixture of products which would complicate the interpretation of the experimental readout. Our second goal will be to focus on the distribution of polyplexes within the target tissue, which is a prerequisite for successful the nucleic acid delivery, but has nearly been neglected in the past. We will determine which of the PEG-PEI copolymers allow for the diffusion of the polyplexes through the ECM while maintaining their stability at the same time.
