Copper metallodendrimers effectively deliver proapoptotic siRNA to human liver carcinoma HepG2 cells.

The delivery of therapeutic nucleic acids to target cells faces many challenges, and novel carriers continue to be investigated. Metallodendrimers present several beneficial features as drugs and nucleic acid carriers, including specificity toward pathological cells, low toxicity to normal cells, and the capacity to cross cellular membranes. In the present work, we investigated the efficacy of synthesized Cu(II) metallodendrimers in delivering pro-apoptotic siRNAs, specifically siBCL2 and siMCL1, to human liver carcinoma HepG2 cells. The resulting siRNA/dendrimer complexes exhibited a strong pro-apoptotic effect, characterized by increased levels of reactive oxygen species, mitochondrial membrane depolarization, and activation of caspases 3 and 7. Quantitatively, second-generation Cu(II) dendriplexes reduced HepG2 cell viability to approximately 40% of control (siBcl-2/CCD NO-2), downregulated BCL2 and MCL1 mRNA by up to 3.5- and 4.9-fold respectively, increased the combined early- and late-apoptotic populations from <5% in untreated cells to 43% (siBcl-2/CCD NO-2), and inhibited HepG2 migration almost completely, ≤15% of wound closure for second generation dendriplexes, while sparing peripheral blood mononuclear cells. These findings highlight the potential of the siRNA/Cu dendrimers to inhibit cancer cell invasion and metastasis, which is critical for effective cancer therapy, making them a promising tool in the treatment of human hepatocellular carcinoma and other cancers.