Selectively Fluorinated PAMAM-Arginine Conjugates as Gene Delivery Vectors

Polyamidoamine (PAMAM)dendrimers are among the most studied cationicpolymers as non-viral gene delivery vectors. However, an "ideal"PAMAM-based gene delivery vector is still missing due to the highmanufacturing costs and non-negligible cytotoxicity associated withthe use of high-generation dendrimers, whereas low-generation dendrimersare far from displaying efficient gene transfection. In order to coverthis gap in the literature, in this study, we propose the functionalizationof the outer primary amines of PAMAM G2 and PAMAM G4 with buildingblocks bearing fluorinated moieties along with a guanidino functionalgroup. We have designed and synthetized two fluorinated arginine (Arg)-basedMichael acceptors which were straightforwardly "clicked"to PAMAM dendrimers without the need for coupling reagents and/orcatalysts. The obtained conjugates, in particular, derivative 1 formed starting from the low-cost PAMAM G2 and a buildingblock bearing two trifluoromethyl groups, were able to efficientlycomplex plasmid DNA, had negligible cytotoxicity, and showed improvedgene transfection efficiency as compared to undecorated PAMAM dendrimersand a corresponding unfluorinated PAMAM-Arg derivative, withderivative 1 being two orders of magnitude more efficientthan the gold standard branched polyethylenimine, bPEI, 25 kDa. Theseresults highlight the importance of the presence of trifluoromethylmoieties for both gene transfection and a possible future applicationin F-19 magnetic resonance imaging.