Fine-Tuned “Click” Functionalization\nof PAMAM Dendrimers with a Linear Fluorinated Guanidino Linker: Synthesis,\nCharacterization, and Applications

This\nstudy presents the synthesis, characterization, and application\nof multifunctional PAMAM G2 and G4 dendrimers decorated with a linear\nfluorinated guanidino linker designed to improve gene delivery efficiency\nwhile minimizing cytotoxicity. For the first time, we were able to\nfine-tune the degree of grafting (DG) during the functionalization\nprocess through efficient “click” Michael addition,\nachieving the synthesis of a collection of six PAMAM conjugates that\nshowed a significant enhancement in transfection efficiency (TE),\nsurpassing the performance of traditional nonviral vectors. The incorporation\nof fluorinated moieties not only facilitated better deoxyribonucleic\nacid (DNA) condensation and TE but also introduced potential applications\nin <sup>19</sup>F magnetic resonance imaging thanks to the sharp and\nintense fluorine nuclear magnetic resonance signals and favorable\nrelaxation parameters. The new dendrimer conjugates demonstrated a\npromising balance between low cytotoxicity and high TE, with the low-generation\nPAMAM G2 with lower DG being the best-performing conjugate, making\nthem strong candidates for further development in gene therapy. These\nfindings highlight the potential of these multifunctional PAMAM dendrimers\nas efficient, nontoxic, and trackable gene delivery vectors.