Titanocene Y - Transport and Targeting of an Anticancer Drug Candidate

Grainne      Lally; Anthony      Deally; Frauke      Hackenberg; Susan   J.   Quinn; Matthias      Tacke

Abstract

The promising cytotoxic and anti-angiogenic anticancer drug candidate Titanocene Y, which shows good in vitro and in vivo activity is now studied in connection with its mode of action and transportation by employing spectroscopic methods. The active transportation into the cancer cell via binding to serum albumin was investigated using a competitive displacement titration of the known serum albumin binder 8-anilino-1-naphthalene sulfonic acid in combination with fluorescence spectroscopy. The Gibbs free energy of the system was calculated to analyse the binding degree which was calculated at ΔG = -33±3 kJ/mol. After confirming the ability of Titanocene Y to bind to serum albumin a number of Titanocene dichloride derivatives were investigated. These derivatives varied in ligand substitution pattern and metal centre from vanadium and iron to silver, and displayed a binding degree range from -24 up to -34 kJ/mol. The difference in the determined value of Gibb’s free energy may help to establish the optimal metal and substitution pattern for binding and transportation into target cells. Furthermore, the possible interaction of Titanocene Y with DNA was investigated by UV-Vis and CD spectroscopy. UV-Vis spectroscopy monitored DNA interaction of Titanocene Y via thermal denaturation studies, while Circular Dichroism spectroscopy indicated an interaction between Titanocene Y and the DNA double helix at ambient temperatures. The binding to serum albumin indicates the transport of the metallocene to the cancer cell via protein binding where interaction with DNA may occur

Keywords: Albumin-transported anticancer drugs, DNA-targeting anticancer drugs, Titanocene Y, Fluorescence spectroscopy, UV-Vis/CD spectroscopy.