Since one of the first reports by Collier and Kraus¹  and subsequently by Rosenberg et al.² , metal-based anticancer agents continue to intrigue us by the myth that surrounds them. Especially, three platinums and one arsenic compound, together with several radiopharmaceuticals, are tremendously successful in the clinical setting and are frequently applied in anticancer therapy. These drugs are essentially able to cure patients suffering from different types of cancer, among which are testicular cancer and acute promyelocytic leukaemia. Despite their success and obvious relevance to oncology, metal-based anticancer drug discovery programs remain purely academic. This is a phenomenon that can be explained by the perceived risks and challenges associated with them. Very often, metal-based anticancer agents are reactive molecules that undergo ligand exchange and redox reactions, as well as complex speciation mechanisms. This reactivity represents a double-edged sword: on the one hand, it contributes to their prodrug character and unprecedented clinical effects, but on the other, it is difficult to control. This leads to a widespread and often categorical preconception of metal-based anticancer agents being toxic and having unspecific modes of action.

Nowadays, novel drug design strategies and holistic analytical approaches warrant a rethinking of these preconceptions, demonstrating that the biological effects of metal complexes are not only due to the metal ion but also to the compound's overall structure and types of ligands.

Several unresolved research questions are being intensively investigated in the field, including: (i) relating phenotypic observations to the metallodrug's chemical properties and molecular mechanisms of action; (ii) identifying molecular targets; (iii) tuning the reactivity and developing speciation methods; (iv) efficiently delivering the reactive payloads; (v) identifying reliable models for screening of anticancer activity in vivo; and, finally, (vi) convincing investors of the promise of novel metal-based anticancer agents, to fund their clinical development.

These points are also illustrative of the interdisciplinary nature of metal-based drug discovery, which necessitates combining knowledge across disciplines, from the inorganic and organometallic synthesis of metal-based anticancer agents and possible radioisotope labelling, to their bioanalytical and pharmacological/toxicological study, ultimately to establish and manage clinical trials. Thus, this book summarizes the recent developments in the field of metal-based compounds for biomedical applications in cancer treatment and diagnosis, while putting them in the context of the above-mentioned challenges.

The book is organized into three sections. The first covers the main classes of metal-based anticancer agents and is divided into eight chapters, including state-of-the-art knowledge about their respective pharmacological activities and modes of action. The second section highlights emerging concepts in metallodrug discovery, essentially discussing both novel anticancer drug delivery and therapeutic strategies, relying on supramolecular metal-based structures, and enabling analytical approaches for target identification. The third section is devoted to preclinical and clinical considerations for both metal-based radiopharmaceuticals and anticancer agents, including their potential impact on cancer immune recognition.

In summary, this book is a useful tool for experienced researchers, but also for people new to the field of metal-based anticancer agents, such as undergraduate or postgraduate students. The book also accounts for the inter- and cross-disciplinary character of this exciting research area in order to establish a common language among researchers of different backgrounds in chemical sciences, biology and medicine.

We would like to thank all the contributing authors for their valuable efforts in tailoring each chapter to reach out to a broad audience and in providing a critical discussion of the various topics. Additionally, we are grateful to Katie Morrey and Drew Gwilliams of the Royal Society of Chemistry for their excellent editorial assistance throughout the entire process, as well as to Prof. Dave Garner (Editor-in-chief, Metallobiology Series) who inspired this project. Finally, we would like to acknowledge all the colleagues in the field for sharing our passion for metal-based anticancer agents and for steadily advancing our knowledge of and insight into these fascinating and medically useful molecules. We keep in mind that the ultimate goal of our efforts is to cure diseases and improve the quality of life for cancer patients.

Angela Casini, Anne Vessières and Samuel M. Meier-Menches