## 5 Metal-Based Vitamin Drug Conjugates  
The last topic presented in this review concerns vitamin metal complexes. Vitamins are essential organic molecules with a specific role in several phases of cell metabolism. Group B and C vitamins are water soluble, whereas those of A, D, E and K groups are lipid-soluble species. As usual, with platinum being the pioneer chemotherapeutic metal, its complexes are the most studied in this context too. In fact, biocompatibility of platinum prodrugs to vitamin E [115], its interactions with vitamin B [111] and catalytic properties of Pt-vitamin B\({}_{12}\) complexes have already been extensively described in previous publications [116]. Pyridoxal, the natural form of vitamin B\({}_{6}\), is a co-factor in enzymatic processes which is engaged in the metabolism of proteins, lipids and carbohydrates. Vitamin B\({}_{6}\) mediates a wide range of biochemical reactions and influences cell growth. A few transition metal complexes based on pyridoxal exhibit strong antimicrobial and anticancer activities [111, 117, 118], and the first example of a Pt(II) derivative has been recently published by [PERSON], [PERSON] and co-workers [119]. More specifically, a vitamin B\({}_{6}\) scaffold has been incorporated into a Schiff base ligand bearing ONS-donor atoms. Complexes **61** and **62**, depicted in Figure 14A, induce follicular thyroid cancer (FTC) cell apoptosis showing a dose-dependent manner cytotoxicity. IC\({}_{50}\) values have been determined by MTT assay and have been found comparable to cisplatin (IC\({}_{50}\) = 9.6, 7.2 and 6.2 \(\upmu\)M for **61**, **62** and cisplatin, respectively). As free ligands are inactive, their coordination with the platinum centre is essential to promote their activity [119]. Calcitrol is the most bioactive form of Vitamin D\({}_{3}\), a potent steroid hormone which regulates calcium and phosphate homeostasis. The gemini-type analogue of 19-norcalcitrol reported in Figure 14B has been coordinated to Pt(II) centres via two N donor atoms of 2-(2'-aminoethyl)pyridine moiety or via S and N donor atoms of the L-methionine fragment. Only complex **64** was a positive fit with the vitamin D receptor (VDR) binding assay. The cytotoxicity of complex **63** against CEM, MCF-7 and HeLa cancer cells is always in  
Figure 14: (**A**) Vitamin B6 platinum complexes; (**B**) Vitamin D platinum complexes. the low micromolar range (IC\({}_{50}\) = 2.2-5.7 \(\upmu\)M), outperforming the benchmark cisplatin. Remarkably, the anticancer activity of complex **64** is one order of magnitude lower than **63**. Unfortunately, they are also both cytotoxic towards normal BJ fibroblast cells [120]. Ruthenium phenanthroline complexes including a vitamin moiety were reported by [PERSON] group in 2022 [121]. In particular, the influence of biotin (vitamin B\({}_{8}\)) was investigated in sodium-dependent multivitamin transport (SMVT)-overexpressed cell lines. SMVT are responsible for biotin uptake, which was therefore introduced in the coordination sphere of the complexes in order to enhance their uptake and cytotoxicity. Sometimes, biotin-based scaffolds are used even as nanocarriers in assembled systems. With the aim of improving the water solubility, pegylated derivatives were included in the study. The four complexes **65-68**, depicted in Figure 15A, are generally hydrophilic but able to invert their affinity in physiological conditions, above all in the presence of plasma proteins, thanks to their propensity to form nanoparticles. It is noteworthy to mention that complex **67** showed the highest internalization in A549, CT26, HEK-293 and RPE-1 cells without showing significant cytotoxicity, due to its accumulation in the cell membrane. As a consequence, the common uptake by endocytosis observed for all four complexes has led to a final accumulation in lysosomes, excluding SMVT-dependent internalization.