Fluorinated Redox-Responsive Cross-Linked Poly(amidoamine) G2 as Smart Theranostic Dendrimers

This work presents a novel strategy for enhancing the gene delivery capabilities of low-generation poly(amidoamine) (PAMAM) dendrimers by employing a fluorinated, redox-responsive cross-linker. The synthesized cross-linker, featuring both disulfide bonds and trifluoromethyl groups, facilitates efficient "click" Michael addition with PAMAM G2, producing cross-linked polymers with strong ¹⁹F nuclear magnetic resonance signals and favorable relaxation properties, enabling their use as ¹⁹F nuclear magnetic resonance tracers. The resulting fluorinated PAMAM G2 polymers also demonstrated excellent plasmid DNA complexation, glutathione-triggered degradation, and notably enhanced transfection efficiency, especially in cancerous HeLa cells notoriously associated with a reducing environment, while maintaining low cytotoxicity. The best-performing system, derived from PAMAM G2 reacted with the redox-responsive cross-linker in a 1:1 molar ratio, outperformed both unmodified PAMAM G2 and 25 kDa branched polyethylenimine, the current nonviral transfection gold standard. These findings highlight the potential of fluorinated bioreducible dendrimer networks as multifunctional, low-toxicity, and trackable platforms for efficient gene delivery and theranostic applications.