Spectroscopic investigations of the molecular interaction of anticancer drug mitoxantrone with non-ionic surfactant micelles.

OBJECTIVES: The aim of this study was to investigate the interaction of the anticancer drug mitoxantrone with non-ionic micelles, as simple model systems of biological membranes. METHODS: UV-VIS absorption spectroscopy was used to quantify the drug-surfactant micelle interactions in terms of the binding constant and the micelle-water partition coefficient of the drug. KEY FINDINGS: Interaction of mitoxantrone with non-ionic micelles reduces the dimerization process of mitoxantrone, the drug molecules being encapsulated into micelles as monomer. The strength of the interaction between mitoxantrone and non-ionic micelles is higher at pH10 than at pH7.4, and depends on the surfactant in the order Tween 80>Tween 20>Triton X-100. The higher partition coefficient at pH10 compared to pH7.4 suggests that at basic pH the deprotonated mitoxantrone is incorporated more efficiently into the hydrophobic medium of non-ionic micelles compared to physiological pH, when the protonated drug is predominant. CONCLUSIONS: These results on simple model systems miming the drug-membrane interactions contribute to the elucidation of the behaviour of the drug in vivo, as well as the possible utilization of surfactant micelles as drug carriers.

Evidence for OH radical production during electrocatalysis of oxygen reduction on Pt surfaces: consequences and application.

Multielectronic O(2) reduction reactions (ORR) at Pt surface (and at Au surface for comparison purpose) were examined both in water and in organic solvents using a strategy based on radical footprinting and scanning electrochemical microscopy (SECM). Experiments reveal a considerable and undocumented production of OH radicals when O(2) is reduced at a Pt electrode. These observations imply that the generally admitted description of ORR as simple competitive pathways between 2-electron (O(2) to H(2)O(2)) and 4-electron (O(2) to H(2)O) reductions is often inadequate and demonstrate the occurrence of another 3-electron pathway (O(2) to OH radical). This behavior is especially observable at neutral and basic pH's in water and in organic solvents like dimethylformamide or dichloromethane. In view of the high reactivity of OH radical versus organic or living materials, this observation could have important consequences in several practical situations (fuel cells, sensors, etc.) as far as O(2) reduction is concerned. This also appears as a simple way to locally produce highly reactive species as exemplified in the present work by the micropatterning of organic surfaces.

Scanning electrochemical microscopy studies of glutathione-modified surfaces. An erasable and sensitive-to-reactive oxygen species surface.

A surface sensitive to reactive oxygen species (ROS) was prepared by reduction of a diazonium salt on glassy carbon electrode followed by the chemical coupling of glutathione (GSH) playing the role of an antioxidant species. The presence of active GSH was characterized through spectroscopic studies and electrochemical analysis after labeling of the -SH group with ferrocene moieties. The specific reactivity of GSH vs ROS was evaluated with scanning electrochemical microscopy (SECM) using the reduction of O(2) to superoxide, O(2)(•-), near the GSH-modified surface. Approach curves show a considerable decrease of the blocking properties of the layer due to reaction of the immobilized GSH with O(2)(•-) and the passage of GSH to the glutathione disulfide (GSSG). The initial surface could be regenerated several times with no significant variations of its antioxidant capacity by simply using the biological system glutathione reductase (GR)/NADPH that reduces GSSG back to GSH. SECM imaging shows also the possibility of writing local and erasable micropatterns on the GSH surface by production of O(2)(•-) at the tip probe electrode.

Spectral studies on the molecular interaction of anticancer drug mitoxantrone with CTAB micelles.

The interaction of anticancer drug mitoxantrone with cationic surfactant cetyltrimethylammonium bromide (CTAB) has been investigated by absorption spectroscopy as a function of surfactant concentration ranging from the premicellar to postmicellar region at pH 7.4 and 10. Interaction of mitoxantrone with CTAB micelles induces a bathochromic shift of both absorption maxima and spectral data showed that the micellization reduces the dimerization process and mitoxantrone is bound into micelles in the monomeric form. Binding constant and partition coefficient were estimated using the red shifts of the absorption maxima in the presence of surfactant. From the resulting binding constants for mitoxantrone-surfactant interactions, it was concluded that the hydrophobic interactions have a great effect on the binding of mitoxantrone to CTAB micelles. Also, by comparing the partition coefficients obtained using pseudo-phase model, the hydrophobic interactions have a major role in the distribution of mitoxantrone between micelle-water phases. Gibbs free energy of binding and distribution of mitoxantrone between the bulk aqueous medium and surfactant micelles were calculated.

Potential-induced conformational changes in an alpha-CN-terthiophene thiolate film on GaAs(110).

Second harmonic generation (SHG) investigations on alpha-CN-terthiophene-thiolate-covered GaAs(110) electrodes in 1 N H2SO4 solution revealed significant changes in the rotational anisotropy of the SH response. The enhancement of the 1- and the 3-fold contributions around -250 mV suggests changes in the symmetry properties of the delocalized electron system due to an alteration of the adsorption geometry induced by the applied potentials. The analysis of the EIS data showed that in the potential region where the SH signal exhibits the more important changes the Mott-Schottky plot undergoes a pronounced shift to more negative potentials as a result of the charging of the surface states grouped about 1.06 eV below the conduction band edge. Semiempirical MO calculations suggest that the most energetically favorable interaction implies electron transfer from the semiconductor conduction band to the lowest unoccupied molecular orbital of the organic molecule with epsilon(LUMO)=-1.707 eV. Such a chemisorption bond bringing the organic molecule to a quasi-planar position is well supported by the major changes in the XPS spectra of the electrochemically biased samples with respect to the as-prepared ones. Two distinct N 1s species instead of one and a shift of 1.6 eV to higher BE of the terthiophene S 2s core level are strong evidence for a potential-induced change in the adsorption geometry. Taking into account that the acceptor-like surface state group located close to the semiconductor valence edge (EC,S=-1.06 eV) may correspond to the LUMO level (shifted downward by the adsorption process), we assume that the organic molecule, initially adsorbed by the thiolate end, undergoes a conformational change from a tilted to an almost flat position when the applied potential brings the semiconductor Fermi level into its neighborhood. This assumption is in a very good agreement with the potential-induced variation in the thiol thickness estimated from the thiol capacitance.

Spectroelectrochemistry of the redox activation of anti-cancer drug mitoxantrone.

The redox behaviour of the anti-cancer drug mitoxantrone was investigated in aprotic media (dimethylsulfoxide-DMSO) by coupled electrochemical and spectral EPR and UV/VIS absorption techniques. The cyclic voltammetry study with stationary and rotating disc electrode (RDE) of the reductive pathway of mitoxantrone points to two-electron transfers and evidences as intermediate species the anion radical, the dianion and the corresponding protonated species. EPR and optical spectra registered during the electrochemical reduction allow the identification of these species and suggest the possibility of back oxidation of the drug by electron transfer to molecular oxygen. The possibility of reductive activation of molecular oxygen by the intermediate species in the redox processes of mitoxantrone is discussed in connection with the cardiotoxicity of the drug. Gas phase and solvent-dependent AM1 and PM3 semiempirical MO calculations allow a rationalization of the experimental results regarding the reactivity in redox processes.

Analysis of actinomycin D-DNA model complexes using a quantum-chemical criterion: Mulliken overlap populations.

The binding of the antitumoral drug actinomycin D to single- and double-stranded DNA was investigated using molecular modeling in the frame of MM+ molecular mechanics and AM1 semi-empirical method. Two other programs, especially conceived to analyze hydrogen-bonding patterns in biological macromolecules, HBexplore, based on geometrical criteria and SHB_interactions, based on quantum-chemical criteria (Mulliken overlap populations), were also used. The results account for the non-cooperative intercalative binding process previously investigated, and outline the contribution of specific hydrogen bonding as well as CH...O(N) and other atom-atom intermolecular interactions to the stabilization of the actinomycin D-DNA complexes. They also support the hemi-intercalation model proposed in literature for the actinomycin D-ssDNA complex.