## 4 Metal-Based Lipid and Nucleic Acid Drug Conjugates  
Lipids are a class of hydrophobic molecules that include fatty acids, phospholipids, sterols, sphingolipids and phenol lipids. In general terms, they play an important role in cellular metabolism as well as in the mechanisms of drug absorption and internalization. Moreover, in the prodrug approach, lipids can be used as carriers [98]. The most studied are the steroids, especially in bioconjugated structures, because of their particularly stable and rigid framework. The favourable lipid solubility makes them suitable to penetrate the cell membrane and bind the specific receptors; for these reasons, they are largely employed in many therapeutic protocols, and many examples are reported in the literature relating to neoplastic diseases [99; 100; 101]. Since two very important reviews concerning steroid's bioconjugation are published in 2021 [102] and 2022 [103], we will describe in this chapter only the most recent examples of bioconjugated lipid-metal complexes. The encapsulation of drugs in lipid nanoparticles is a common and effective strategy to improve the drug delivery. In this context, Ru(III) derivatives synthesized by [PERSON] and co-workers are particularly worthy of mention. These octahedral complexes are characterized by the presence of a pyridyll ligand functionalized with a lipid chain, which facilitates the self-assembly in pseudo physiological conditions, with the resulting system that remains stable for hours [104]. More in detail, the behaviour of complexes **54a-e** has been investigated and compared to the non-lipid functionalized pyridine precursor AziRu (Figure 10). In this way, it was possible to observe that the lipidic chain protects the complex from the chloride ligand exchange, and this effect is particularly pronounced in the case of complexes **54c** and **54e** bearing the longest lipidic chain and the cholesterol scaffold, respectively. The lipophilicity of complexes **54b-d** (logP \(\approx\) 0.7) seems to increase their cytotoxicity towards MCF-7, MDAMB-231, HCT-116 and A375 cancer cells, whereas the same compounds are inactive in non-malignant cells (HaCaT and enterocytes). The high level of internalization in MDAMB-231 cells recorded for complex **54b** (20 times higher with respect to AziRu precursor) may be one of the reasons of this increase in activity [104]. Steroids are important delivery vectors that can be used to target overexpressed oestrogen receptors (ER) cancer cells, such as those of breast, ovarian, colon and prostate tumours. The bioconjugation of oestrogen derivatives with the biocompatible copper metal centre has been studied by [PERSON] and colleagues with the aim of understanding the interaction of phenanthroline ligands with DNA [105]. The oestradiol-copper complexes **55a-d** (Figure 11A) are more effective than cisplatin against A431, MCF-7, 2008, A2780 ER+ and HCT-15 ER-cancer cells. The low and sub-micromolar activity has been confirmed even in 3D spheroids models, increasing with the lipophilicity of the phenanthroline ligands. The authors have shown that complex **55d** is the most active, stimulates the production of ROS, and its uptake improves in a time-dependent manner. Overall, the activity of this class of compounds can be mainly ascribed to the electrostatic interaction (intercalation) with DNA, being scarcely able to establish covalent bonds [105]. Figure 10: Structure of AziRu and Ru complexes synthesized by [PERSON] group. Taking advantage of the well-known _weak base route_, [59] [PERSON], [PERSON] and collaborators synthesized linear gold(I) complexes bearing \(N\)-heterocyclic carbene (NHC) and ethisterone ligands (compounds **56a-e**, depicted in Figure 11B) [106]. With the exception of compound **55e**, all complexes inhibited the proliferation of A549, HT-29, MDA-MB-231 and MCF-7 cancer cells. Remarkably, minor differences in the structure of coordinated NHC involve significant differences in activity.