Dynamic combinatorial approach as synthetic strategy for the formation of non-viral vectors for gene therapy

The next level in Drug Discovery is the easy building and self-generation of multifunctional nanostructures from commercially available or “easy to prepare” units, which will further self-assemble in a complex, tunable and... [ view full abstract ]

The next level in Drug Discovery is the easy building and self-generation of multifunctional nanostructures from commercially available or “easy to prepare” units, which will further self-assemble in a complex, tunable and multifunctional materials, suitable for specific targeted drug/gene delivery. DNA and target cells are highly variable and therefore, rational design is limited to a relatively small number of components and a high number of synthetic steps. One possible solution to this problem is to employ the constitutional dynamic chemistry (CDC) as a new evolutionary approach to produce chemical diversity. A specific advantage with constitutionally generated systems addresses the possibility to self-adjust to biological target species at a given time, in a certain environment at nanoscale dimensions. The key concept is exploring the multivalent molecular recognition and self-assembly by using adaptive platforms interacting with biological targets. The use of reversible interactions as dynamic interfaces between the target and Dynamical Constitutional Frameworks (DCF) components will allow one to self-adjust the system’s tridimensional geometry and functional properties. In presented work adaptive dynamic vectors based on polyethylene glycol, cationic moiety components and in some cases squalene derivative, which are reversibly connected to core centers are prepared and tested as vectors for DNA transfection. Depending on their tuneable composition, these modular vectors dynamically self-adapt to their DNA targets, allowing the rapid screening of most effective vectors, optimally matched to DNA 3D surrounding space. Our strategy allows easy and efficient identification of adaptive vectors with high DNA complexation ability, good transfection efficiency, and well tolerated by mammalian cells.

This work was supported by Horizon 2020 WIDESPREAD 2-2014: ERA Chairs Project no 667387 and a grant of the Romanian National Authority for Scientific Research and Innovation, CNCS/CCCDI – UEFISCDI, project number PN-III-P3-3.6-H2020- 2016-0011, within PNCDI III.