**1. Introduction**

Despite the use of metal compounds in empirical medicines since the ancient civilization time of Mesopotamia, Egypt, India, and China, the pharmacological bases of their therapeutic action were just began to be understood in the last 50 years [1].

A milestone in the development of inorganic medicinal chemistry was represented by the serendipitously discovery of the anticancer agent cisplatin (Platinol) [2], which opened the gate of extensive and rigorous research for anticancer metal-based drugs. Cisplatin quickly became a successful antitumor agent, but over time, its severe side effects and installation of resistance led to the orientation of research toward finding new cisplatin analogs. Thus, "the

second-generation platinum drugs" (e.g., carboplatin) with improved toxicological profiles and "the third-generation drugs" (e.g., oxaliplatin) overcoming cisplatin resistance have been developed [3].

Having in view the systemic administration, the patients experienced severe symptoms since cisplatin and its analogs, carboplatin and oxaliplatin, were introduced in cancer therapy. Moreover, the intrinsic or acquired resistance and the fact that many cancers are insensitive to platinum-based drug therapy started an assiduous search for formulations that are able to deliver these drugs with reduced toxicity but with a similar or even enhanced cytotoxic profile [4–9].

A promising strategy able to overcome most of the above limitations consists in embedding either the original drug or a precursor in a proper matrix that is able to release a high amount of active species at target site. As result, several formulations based on organic, inorganic, or hybrid materials were designed. Among organic-based materials, a large variety of lipids, polymers, or mixed species were developed as platinum- and ruthenium-based drug carriers while magnetite, gold, graphene, and silica were studied as inorganic-based materials for the same purpose. Moreover, hybrid materials based on functionalized graphene, gold, iron oxides, silica, or polinuclear complexes and polysilsesquioxanes were studied in order to facilitate the delivery of these drugs [6–9].

Beyond improving solubility and reducing toxicity, a main challenge of these formulations was to increase their selectivity for tumor cells in order to achieve an optimum pharmacological profile. The first formulation developed by platinum-based drugs embedding through noncovalent interactions generated systems with a low loading capacity. A proper functionalization of the embedding matrix with Pt(II) drugs or Pt(IV)/Ru(III) prodrugs and/or with a responsive stimulus or a targeting moiety provided species with an increased cytotoxicity [6–9].

A large variety of encapsulation matrices and conjugations were developed, and formulations exhibit a promising cytotoxicity against either multidrug resistant or platinum insensitive cancer cells.
