Oxaliplatin bioconjugates with human ferritin obtained by protein surface decoration: Characterization and biological evaluation.

Abstract

Human H-type ferritin is an attractive protein candidate for the targeted delivery of anticancer metallodrugs. In this study, we report on the formation of ferritin conjugates with oxaliplatin via a direct reaction in solution. This process typically results in the decoration of the protein surface with metallofragments of the type ((R,R)-trans-1,2-diaminocyclohexane)platinum(II) (DACH)Pt. A series of oxaliplatin/ferritin conjugates were obtained and systematically characterized by ESI-MS and ICP measurements. The ESI-MS profiles obtained demonstrate that adduct formation is both time- and concentration-dependent. The nature, stoichiometry and likely anchoring sites of the ferritin-bound platinum fragments were elucidated by ESI-MS analysis coupled with trypsinization experiments. We then evaluated the biological effects of the oxaliplatin-ferritin cage bioconjugate (preprared at 120:1 metal to protein ratio) in comparison to the free drug on A2780 human ovarian cancer cells. We observed that conjugation of oxaliplatin to ferritin resulted in similar platinum uptake by the cells compared to the free drug. However, the anticancer activity of the drug was unexpectedly lost. We critically discuss the implications of these results for the design and preparation of new anticancer platinum-ferritin bioconjugates.