Metallodrugs in cancer nanomedicine

Metal complexes are extensively used for cancer therapy. The multiple variables available for tuning (metal, ligand, and metal-ligand interaction) offer unique opportunities for drug design, and have led to a vast portfolio of metallodrugs that can display a higher diversity of functions and mechanisms of action with respect to pure organic structures. Clinically approved metallodrugs, such as cisplatin, carboplatin and oxaliplatin, are used to treat many types of cancer and play prominent roles in combination regimens, including with immunotherapy. However, metallodrugs generally suffer from poor pharmacokinetics, low levels of target site accumulation, metal-mediated off-target reactivity and development of drug resistance, which can all limit their efficacy and clinical translation. Nanomedicine has arisen as a powerful tool to help overcome these shortcomings. Several nanoformulations have already significantly improved the efficacy and reduced the toxicity of (chemo-)therapeutic drugs, including some promising metallodrug-containing nanomedicines currently in clinical trials. In this critical review, we analyse the opportunities and clinical challenges of metallodrugs, and we assess the advantages and limitations of metallodrug delivery, both from a nanocarrier and from a metal-nano interaction perspective. We describe the latest and most relevant nanomedicine formulations developed for metal complexes, and we discuss how the rational combination of coordination chemistry with nanomedicine technology can assist in promoting the clinical translation of metallodrugs.