**2. Anticancer metallodrugs**

Apart from extensive research undertaken in the field of platinum complexes, other metals or other therapeutic strategies have attracted attention in order to reduce the side effects, to mitigate the resistance, and to achieve the oral administration.

The anticancer metallodrugs known at this time belong to three main classes:


Numerous *chemotherapeutic metallodrugs* developed in the last 4 decades are based on a large variety of metals: Pt, Ru, Au, Sn, Al, Ga, In, Ti [11–16]. Among the metal-based compounds, complexes of platinum (Pt(II) and Pt(IV)), ruthenium (Ru(II) and Ru(III)), gold (Au(I) and Au(III)), and titanium (Ti(IV)) are the most studied [13].

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

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

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

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

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

Apart from extensive research undertaken in the field of platinum complexes, other metals or other therapeutic strategies have attracted attention in order to reduce the side effects, to

mitigate the resistance, and to achieve the oral administration.

The anticancer metallodrugs known at this time belong to three main classes:

developed [3].

cytotoxicity [6–9].

**2. Anticancer metallodrugs**

• anticancer therapeutics

• therapeutic radiopharmaceuticals

• photochemotherapeutic metallodrugs [10].

cancer cells.

facilitate the delivery of these drugs [6–9].

2 Descriptive Inorganic Chemistry Researches of Metal Compounds

[4–9].

*Therapeutic radiopharmaceuticals* include a β-emitting radionuclide (89Sr, 90Y, 153Sm, 213Bi) or a α-emitting radionuclide (223Ra). In general, α- and β-(electrons) emitters are used in radiotherapy, while β+ (positrons) and γ-emitters are used in radiodiagnosis [14].

Utilization of *photochemotherapeutic metallodrugs* is based on the photodynamic therapy (PDT). In PDT, a photosensitizing agent is delivered in tumor cells, which are activated with light, generating cytotoxic singlet oxygen. Starting to observation that Photofrin, a haematoporphyrin derivative is a strong chelator, forming a complex with ZnII *in vivo*, some photochemotherapeutic metallodrugs have been developed [15].

The main platinum-based anticancer drugs currently used in clinic are presented in **Table 1**, while the emerging platinum- and ruthenium-based anticancer agents are listed in **Table 2**.

**Table 1.** Platinum-based anticancer drugs currently used in clinic.

**Table 2.** Platinum and ruthenium-based anticancer drugs subjected to clinical trials.

#### **3. Platinum-based drugs nanoformulations**

The clinical use of cisplatin and its analogs evidenced pharmacological deficiencies such as poor water solubility, low bioavailability, and short circulating time, besides toxicity and resistance. Moreover, a few types of cancers are sensitive to platinum-based drugs treatment.

Therefore, in the last decades, the researches were focused in designing drug delivery systems that are able to overcome these issues, but with preserving or even enhancing the drug efficacy. A brief overview concerning nanoscale drug delivery systems based on worldwide approved platinum-based cytostatic drugs cisplatin, carboplatin, and oxaliplatin is presented with focus on systems that advanced in clinical trials or exhibited promising pharmacological profile *in vitro* or *in vivo* preclinical assays.
