Structural bases for rational design of new biomaterials based on metallodrug/β-lactoglobulin adducts

β-lactoglobulin is a whey carrier protein of 18.4 kDa. Due to its high solubility, safe status, biodegradable nature, gel forming ability, abundance, stability at acidic pH and stability against gastric pepsin, β-lactoglobulin can be considered as a good system for the preparation of micro- or nanoparticles for pharmaceutical industry. In this frame, it has been demonstrated that β‐lactoglobulin–pectin nanoparticles are able to transfer cytotoxic Pt compounds to cancer cells. With the aim to unveil the molecular basis of the metallodrug recognition by β‐lactoglobulin, we are analyzing the interactions between this protein and a number of metallodrugs. The interaction between cisplatin (CDDP), the most used Pt-based anticancer agent, and β-lactoglobulin have been investigated both in solution and in solid state. UV-vis absorption spectroscopy and circular dichroism data indicate that the protein retains its conformation upon CDDP binding. X-ray crystallography analysis reveals that b-lactoglobulin interacts with CDDP through coordination of Pt fragments to the side chain of Met7, His146 and Lys8, with the number of binding sites increasing over time. Electrospray Ionization Mass Spectrometry data indicate that [Pt(NH₃)₂Cl⁺], [Pt(NH₃)₂OH²⁺] and [Pt(NH₃)₂²⁺] fragments interact with the protein, and confirm that the number of the cisplatin binding sites increases over time. These results open the way for a rational design of new biomaterials based on metallodrug/β-lactoglobulin adduct nanoparticles.