Gene therapy is expected to have a major impact on medicine over the next decades. Viral vector posses high transfection efficiency but often poor biosafety. In contrast, non-viral delivery systems may overcome those limitations. These systems commonly involve polycations or block ionomers (polyplexes) or cationic lipids (lipoplexes). Although they can be designed to display lower immunogenicity and enable scale-up preparation, poor gene transfer efficiencies have often precluded their therapeutic application. Thus, there is a strong need to improve efficacy of synthetic vectors. In polyplexes the interactions of pDNA and the block ionomer (block copolymer combining a hydrophilic non-ionic and polycationic block) are essential for the performance as non-viral gene vector, since size and stability of polyplexes determine transfection efficiency. In general, DNA can be considered as a negatively charged semi-flexible polymer. Due to the electrostatic attraction, polycations can interact with DNA, to form polyplexes with a more compact structure (pDNA compactation/collapse). We use coarse-grained computer simulations to study the complex formation between the DNA and polycations of different architectures, and systematically investigate the effect of charge distribution of the polycations. The simulations indicate that block sequence (block polymer microstructure) in multiblock copolymers critically determines polyplex formation, size, morphology and stability. The results of the simulations are in line with polyplex characterization by static and dynamic light scattering (DLS&SLS) and electron microscopy. Furthermore, we demonstrate that these parameters determine transfection efficiency underlining the potential of simulation-guided design of block copolymers in gene therapy.

Simulation-guided design of block ionomer microstructure: Enhancing the performance of peptoplexes as non-viral transfection agents

251st National Meeting (2016)

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