In this project, a novel strategy considers polymeric vesicles for DNA delivery into the nucleus for gene therapy are preferred over virus-based vesicles, because they avoid the well known problems of severe immunogenic side effects. For a successful therapy, a sufficient drug condensation/incorporation and transfection into cells and nuclei with a non viral-based carrier system needs to be achieved, however and unfortunately, the current best results are only accomplished with the rather toxic poly(ethylene imines) (PEI).
Polycationic polymers, based on PEI structures, are synthesized in large libraries to find the least toxic candidates. Furthermore, it has been demonstrated that PEI oligomers have a reduced toxicity compared to their corresponding polymers.
In conclusion, based on own developed drug carrier systems at UNIGE, which in their current form as purely PEG-hexPLA polymeric micelles are non-toxic, we aim to tailor our promising carriers by addition of the minimum necessary cationic side groups along the core forming polymer backbone. This number will be optimized by computer modeling in Prof. Danani’s group, on the one hand by adjusting the number of cationic amino groups for efficient DNA and siRNA, respectively complexation and on the other hand by optimizing this number to a minimum to guarantee DNA and siRNA, respectively release and least toxicity of the material.
The novel carrier systems will be fully characterized and evaluated in in vitro experiments on cell cultures, further optimized by back and force theoretical and experimental evaluations, and hopefully lead to a suitable pharmaceutical formulation, which will further permit to test the efficiency and efficacy in in vivo models.
There are numerous publications and initiatives, and lots of hope around the world, for tackling genetic based diseases with better means than we have currently at hand. More and more DNA or siRNA entities are discovered which have the potential to cure severe diseases. However, this will only happen when suitable delivery systems will be available, too. We believe that our work can give a major contribution to improve the situation on the lacking appropriate materials for ensuring successful pharmaceutical formulations.