## 3 Metal-Based Protein, Peptide and Antibody Drug Conjugates  
Specific sequences of amino acids form complex structures known as peptides and proteins, which are biomolecules involved in a wide range of organism vital functions. In recent times, amino acid derivatives have been investigated as anticancer agents, and in particular, poli-peptides [73] and antibodies [74,75] have been largely included in studies based on the immunotherapeutic approach. Furthermore, they can be conjugated with a metal-based scaffold in order to deliver the active moiety to the desired target taking advantage of their biocompatibility. Strategies to radiolabel bioconjugated metal complexes and to prepare photo-functional derivatives have been recently exhaustively reviewed [19,76, 77, 78, 79, 80, 81, 82]. In these contributions, the interaction between proteins and metallodrugs and the synthesis and characterization of the challenging bioconjugated drugs have been well described. Therefore, only the most relevant examples developed in the last three years will be illustrated in this section. Among the conjugated proteins, HSA (human serum albumin) is certainly one of the most studied, being the most abundant blood protein, with important implications in transport processes and therefore for the pharmacokinetics of metallodrugs [83]. So far, only ruthenium and platinum-HSA conjugate were prepared with the aim of achieving the desired target and act after release of the active form [84]. As already mentioned in the previous sections, octahedral Pt(IV) complexes are usually prodrugs [51]. The conjugation with a protein requires a water-compatible procedure that does not affect the protein conformation and allows the release of the cytotoxic payload once it reaches the tumour. [PERSON] and [PERSON] have described the photoactivable Pt(IV) azido compounds conjugated to myoglobin and trastuzumab antibody (complexes **38-39** in Figure 7) [85]. The conjugation with myoglobin is higher than with trastuzumab, and although both derivatives are stable in the dark, unfortunately, an extensive photodecomposition was observed during the preliminary tests. Figure 6: (**A**) Iron complexes synthesized by [PERSON], [PERSON] and [PERSON]; (**B**) Re(I) complexes prepared by [PERSON] and [PERSON]. The general structure of a bioconjugated metal peptide/antibody consists of three distinct building blocks: the metal, the linker and the peptide/antibody carrier [84]. Peptides conjugation is common, attractive and useful because of the cost-effective synthesis, biocompatibility, possibility of chemical optimization and the opportunity to take advantage of cell-penetrating peptides (CPP). CPP are sequences of 5-30 amino acids which form positively charged peptides able to cross the plasma membrane [82]. On the other hand, antibody-drug conjugates (ADC) represent a valid strategy for target therapy of blood and solid tumours. Usually, immunoglobulin or monoclonal antibody (mAb) produced by clones of a unique parent immune cell are employed. These systems, while ensuring a high selectivity, often present several problems for their synthesis, stability in plasma, efficient drug release and internalization. Furthermore, the cost of their synthesis is much higher than that of peptides [86, 87]. However, in general, conjugation with metallodrug is easier than with organic molecules, facilitating a reduction in production costs [78, 84]. Ruthenium complexes, whose structures are reported in Figure 8, are interesting examples of bioconjugated metal peptides. In 2021, [PERSON] reported the synthesis and DNA interaction studies of three cationic ruthenium polypyridyl dppz-CPP complexes (**40** and **41**, see Figure 8A) [88]. As known, they are usually investigated as luminescent probes in which the presence of the dppz ligand is crucial for DNA intercalation. Argin TAT-9 and non-arginine Xentry neutral CPP have been chosen.