Safe decontamination of cytostatics from the nitrogen mustards family. Part one: cyclophosphamide and ifosfamide

Irena R Štenglová Netíková,1 Luboš Petruželka,2,3 Martin Štastný,1,2 Václav Štengl1 1Department of Oncology, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic; 2Department of Material Chemistry, Institute of Inorganic Chemistry ASCR v.v.i., Rež, Czech Republic; 3Faculty of Environment, J.E. Purkyne University in Ústí nad Labem, Ústí nad labem, Czech Republic Introduction: Macrocrystalline oxides of alkaline earth metals (Mg and Ca) or light metals (Al and Ti) can respond to standard warfare agents such as sulfur mustard, soman, or agent VX. In this paper, we compared the decontamination ability of sodium hydroxide (NaOH) and sodium hypochlorite (NaClO) for nitrogen mustards (cyclophosphamide [CP] and ifosfamide [IFOS]) with a new procedure using a destructive sorbent based on nanocrystalline and nanodispersive titanium dioxide (TiO2) as a new efficient and cheap material for complete decontamination of surfaces.Methods: Titanium (IV) dioxide nanoparticles were prepared by the homogeneous hydrolysis of titanium(IV) oxysulfate (TiOSO4) with urea. The as-prepared TiO2 nanoparticles were used for the fast and safe decontamination of cytostatics from the nitrogen mustard family (CP and IFOS) in water. The adsorption–degradation process of cytostatics in the presence of TiO2 was compared with decontamination agents (0.01 M solution of sodium hydroxide and 5% solution of sodium hypochlorite). The mechanism of the decontamination process and the degradation efficiency were determined by high-performance liquid chromatography with mass spectrometry.Results: It was demonstrated that a 0.01 M solution of sodium hydroxide (NaOH) decomposes CP to 3-((amino(bis(2-chloroethyl)amino)phosphoryl)oxy)propanoic acid and sodium hypochlorite formed two reaction products, namely, IFOS and 4-hydroxy-cyclophosphamide. IFOS is cytotoxic, and 4-hydroxy-cyclophosphamide is a known metabolite of CP after its partial metabolism by CYP/CYP450. IFOS degrades in the pres¬ence of NaOH to toxic IFOS mustard. Titanium(IV) dioxide nanoparticles adsorbed on its surface CP after 5 minutes and on IFOS after 10 minutes. The adsorption–degradation process of CP in water and in the presence of TiO2 led to 4-hydroxy-cyclophosphamide and IFOS, respectively, which decayed to oxidation product 4-hydroxy-ifosfamide.Conclusion: Nanodispersive TiO2 is an effective degradation agent for decontamination of surfaces from cytostatics in medical facilities. Keywords: cyclophosphamide, ifosfamide, ifosfamide mustard, titanium(IV) dioxide, degradation, decontamination agent