New insights into ruthenium(ii) metallodendrimers as anticancer drug nanocarriers: from synthesis to preclinic behaviour†
Dendrimers have been studied as promising materials for the delivery of anticancer drugs. In this work, low-generation (0–2) nitrile poly(alkylidenamine)-based dendrimers were explored as nanocarriers for the organometallic complex [Ru(η5-C5H5)(PPh3)2]+ (RuCp+) and investigated for their anticancer action and involved mechanisms, which were evaluated both in vitro and in vivo. It was observed that their biological behaviour is generation dependent, where the highest generation metallodendrimer (G2Ru) was overall more effective than the other metallodendrimers. G2Ru was active against a set of six cancer cell lines, revealing its important selectivity for these cells (the IC50 values were about 4-fold lower than that for non-cancer cells). Importantly, the in vivo studies with G2Ru in an MCF-7 xenograft mouse model showed that it exhibited low systemic toxicity, low accumulation in the main organs of the mice, preferential accumulation in the tumour, and remarkable capacity to limit tumour growth. The in vitro and in vivo studies revealed that G2Ru caused high levels of cell necrosis and apoptosis. The in vitro cell death mechanism studies showed the capacity of G2Ru to induce mitochondrial depolarization and ROS production. Altogether, pre-clinical results indicated G2Ru as a promising anticancer drug and the potential of low-generation poly(alkylidenamine)-based dendrimers as drug nanocarriers.