Arsthinol nanosuspensions: pharmacokinetics and anti-leukaemic activity on NB4 promyelocytic leukaemia cells

Abstract

Objectives: The organoarsenical arsthinol was used in the 1950s in the treatment of amoebiasis and yaws and was considered as 'highly tolerated'. The aim of this work was to study its anti-leukaemic activity and to develop nanosuspensions of the drug, thereby limiting brain concentrations and the risk of encephalopathy. Methods: Arsthinol nanosuspensions were produced by high-pressure homogenization. The anti-leukaemic activity was assessed on NB4 acute promyelocytic leukaemia cells (vs solutions of arsthinol, As 2 O 3 and melarsoprol). In addition, a pharmacokinetics study was performed to compare the nanosuspensions and the solution of arsthinol. Key findings: Arsthinol induced growth inhibition of NB4 cells at lower concentration (IC50 (concentration inhibiting growth by 50%) = 0.78 ± 0.08 μmol/l after 24 h) than As 2 O 3 (IC50 = 1.60 ± 0.23 μmol/l after 24 h) or melarsoprol (IC50 = 1.44 ± 0.08 μmol/l after 24 h). When formulated as nanosuspension, arsthinol remained cytotoxic (IC50 = 1.33 ± 0.30 μmol/l after 24 h). This formulation also reduced the drug's access to the brain (C max = 0.03 μmol/g) whereas bone marrow concentrations remained very high (Cmax = 2 μmol/g). Conclusions: Nanosuspensions of arsthinol could be proposed for further studies in the treatment of acute promyelocytic leukaemia. © 2009 The Authors.