## 4 Metal-Based Lipid and Nucleic Acid Drug Conjugates
The strategy to choose a specific agonist of progesterone receptor was a winning one, giving high uptake values in MCF-7 ER+ cells. Moreover, specific cytotoxicity assays, carried out simultaneously, administering ethisterone and complex **56a** suggested that the coadministration might be competitive in the uptake process mediated by progesterone receptors [106]. As written in previous sections, rhenium complexes are usually employed in fluorescence imaging techniques. Therefore, cholesterol and cholestanol rhenium complexes have been recently prepared by [PERSON] and colleagues [107]. Cholesterol is an essential multifunctional lipid involved in the control of eukaryotic cell membrane stability and permeability as well as a precursor to steroid hormones, bile acid and vitamin D\({}_{3}\). Basically, its uptake takes place via endocytosis with low-density lipoproteins (LDL) to reach the endoplasmic reticulum. Cholesterol is present in high level in cancer cells, and for this reason, it is combined with rhenium for imaging applications, originating luminescent organometallic complexes which exhibit reduced photobleaching, large Stokes shift and long emission lifetimes compared to traditional organic fluorescent moieties. Adopting the classical _click chemistry_, it was possible to synthesize Re-cholesterol and cholestanol complexes **57a-b** and their tetra ethylene glycol (TEG)-linked analogues **58a-b** (see Figure 12). Unfortunately, for solubility issues, only complex **58b** was investigated towards PC-3, LNCaP and 22 Rv1 prostate cancer cells and PNT1a non-malignant cell line. The treatment with 5\(\upmu\)M solution showed a higher uptake on cancer cells than non-tumoral ones. In particular, the complexes exhibited high cytotoxicity towards androgen-independent PC-3 cells, with the major accumulation in endosomes/lysosomes compartments [107]. Figure 11: (**A**) Copper complexes described by [PERSON]; (**B**) Gold(I)-ethisterone complexes obtained by [PERSON] and [PERSON]. Nucleic acids are macromolecules dedicated to transport genetic information. DNA and RNA are constituted by nucleotides which are linked through a 3\({}^{\prime}\),5\({}^{\prime}\) phosphodiester bond. The main structural difference among them regards the nucleobases present in their sequences. More specifically, adenine, guanine, cytosine and thymine are involved in DNA sequences, while thymine is replaced by uracil in RNA (see Figure 13A). However, nucleic acids are usually not suitable for biological applications due to their sensitivity to nucleases, which causes a short half-life and therefore limits efficiency. For this reason, a wide range of synthetic nucleic acids, oligonucleotides, siRNA, miRNA, aptamer, plasmid nucleic acids, and purine and pyrimidine derivatives are usually employed [108; 109; 110]. Since a few recent reviews dealing with cisplatin [111] and other platinum complexes [112] bearing nucleic acid derivatives have been published, we have focused our attention on other metal centres. The main contributions in this research area involve the use of ruthenium complexes. In particular, in 2022, [PERSON], [PERSON] and collaborators reported the first example of a dinuclear Ru(III) adenine protonated complex [113]. Compound **59**, depicted in Figure 13B, was characterized from an electrochemical point of view and tested towards HCT-116 and AGS cell lines by MTT assay and cell cytometry after 48 and 72 h of treatment. This Ru(III) complex exhibits a specific cytotoxicity against AGS cancer cells in a time- and dose-dependent manner (IC\({}_{50}\) = 23.25 uM after 72 h) displaying an apoptosis pathway in the highest concentration [113]. In the same year, [PERSON], [PERSON] and colleagues have reported the synthesis and characterization of Ru(II) complexes bearing different oligonucleotides [114]. The real focus of their work was the investigation of the influence of the aptamer moiety.