Safety and Efficacy Evaluation In Vivo of a Cationic Nucleolipid Nanosystem for the Nanodelivery of a Ruthenium(III) Complex with Superior Anticancer Bioactivity

SIMPLE SUMMARY: The availability of selective, effective, and safe anticancer agents is a major challenge in the field of cancer research. As part of a multidisciplinary research project, in recent years our group has proposed an original class of nanomaterials for the delivery of new anticancer drugs based on ruthenium(III) complexes. In cellular models, these nanosystems have been shown to be effective in counteracting growth and proliferation of human breast cancer cells. Compared to conventional metallochemotherapeutics such as platinum-based agents whose clinical practice is associated with serious undesirable effects, ruthenium complexes share improved biochemical profiles making them more selective towards cancer cells and less cytotoxic to healthy cells. Their combination with biocompatible nanocarriers further enhances these promising features, as here showcased by our research carried out in an animal model which underscores the efficacy and safety in vivo of one of our most promising ruthenium-based nanosystems. ABSTRACT: Selectivity and efficacy towards target cancer cells, as well as biocompatibility, are current challenges of advanced chemotherapy powering the discovery of unconventional metal-based drugs and the search for novel therapeutic approaches. Among second-generation metal-based chemotherapeutics, ruthenium complexes have demonstrated promising anticancer activity coupled to minimal toxicity profiles and peculiar biochemical features. In this context, our research group has recently focused on a bioactive Ru(III) complex—named AziRu—incorporated into a suite of ad hoc designed nucleolipid nanosystems to ensure its chemical stability and delivery. Indeed, we proved that the structure and properties of decorated nucleolipids can have a major impact on the anticancer activity of the ruthenium core. Moving in this direction, here we describe a preclinical study performed by a mouse xenograft model of human breast cancer to establish safety and efficacy in vivo of a cationic Ru(III)-based nucleolipid formulation, named HoThyRu/DOTAP, endowed with superior antiproliferative activity. The results show a remarkable reduction in tumour with no evidence of animal suffering. Blood diagnostics, as well as biochemical analysis in both acute and chronic treated animal groups, demonstrate a good tolerability profile at the therapeutic regimen, with 100% of mice survival and no indication of toxicity. In addition, ruthenium plasma concentration analysis and tissue bioaccumulation were determined via appropriate sampling and ICP-MS analysis. Overall, this study supports both the efficacy of our Ru-containing nanosystem versus a human breast cancer model and its safety in vivo through well-tolerated animal biological responses, envisaging a possible forthcoming use in clinical trials.