Polyamidoamine (PAMAM)
dendrimers are among the most studied cationic
polymers as non-viral gene delivery vectors. However, an “ideal”
PAMAM-based gene delivery vector is still missing due to the high
manufacturing costs and non-negligible cytotoxicity associated with
the use of high-generation dendrimers, whereas low-generation dendrimers
are far from displaying efficient gene transfection. In order to cover
this gap in the literature, in this study, we propose the functionalization
of the outer primary amines of PAMAM G2 and PAMAM G4 with building
blocks bearing fluorinated moieties along with a guanidino functional
group. We have designed and synthetized two fluorinated arginine (Arg)-based
Michael acceptors which were straightforwardly “clicked”
to PAMAM dendrimers without the need for coupling reagents and/or
catalysts. The obtained conjugates, in particular, derivative1formed starting from the low-cost PAMAM G2 and a building
block bearing two trifluoromethyl groups, were able to efficiently
complex plasmid DNA, had negligible cytotoxicity, and showed improved
gene transfection efficiency as compared to undecorated PAMAM dendrimers
and a corresponding unfluorinated PAMAM–Arg derivative, with
derivative1being two orders of magnitude more efficient
than the gold standard branched polyethylenimine, bPEI, 25 kDa. These
results highlight the importance of the presence of trifluoromethyl
moieties for both gene transfection and a possible future application
in19F magnetic resonance imaging.