Interaction Of Anticancer Drug Mitoxantrone Research Articles

Spectroscopic Study of the Interaction of Anticancer Drug Mitoxantrone with Sodium Cholate Aggregates

The focus of the present work is to investigate the interaction of anticancer drug mitoxantrone with sodium cholate (NaC) bile salt in phosphate buffer (pH 7.4) and carbonate buffer (pH 10) by UV-Visible absorption spectroscopy. The results indicate that mitoxantrone may bind to NaC monomers and micelles through electrostatic and hydrophobic interactions and the interaction with NaC induces the dissociation of dimers and higher aggregates of mitoxantrone. The stoichiometric ratio, binding constant, micelle/water partition coefficient and the corresponding thermodynamic parameters for binding and partitioning processes were estimated from the monomer absorbance changes occurred as a result of the interaction between mitoxantrone and NaC micelles. The binding process of mitoxantrone to NaC micelles is spontaneous and entropy controlled over the range of studied temperatures, at both pH values. The partition process of mitoxantrone between micellar and bulk aqueous phases is spontaneous and entropy controlled at pH 7.4 but enthalpy controlled at pH 10.

Studies on the anticancer drug mitoxantrone–DNA–sodium dodecyl sulfate system

The interaction of anticancer drug mitoxantrone with sodium dodecyl sulfate (SDS) in the presence of two fixed DNA concentrations (1.75×10−5M, when electrostatic binding of positively charged mitoxantrone at negatively charged DNA prevails and 1.50×10−4M, when mitoxantrone molecules intercalate between DNA base pairs) was investigated by UV–Visible absorption spectroscopy.For both DNA concentrations, the spectral results indicate two processes: process I in premicellar SDS concentration assigned to electrostatic interaction between positively charged mitoxantrone and negatively charged SDS monomers, and process II in micellar SDS concentration when the surfactant micelles are formed and mitoxantrone is encapsulated in micelles as monomer. Absorption and circular dichroism spectroscopy, and thermal denaturation studies evidenced the exclusion of intercalated mitoxantrone from DNA and further their encapsulation in SDS micelles.The values of the total binding free energies show that the interaction of (mitoxantrone–DNA)complex with SDS is favored in the presence of low DNA concentration (−15.96kcal/mol), when drug molecules are electrostatically bound to DNA, than in the presence of high DNA concentration (−10.62kcal/mol) when drug molecules are intercalated between base pairs of DNA. This difference in the total binding free energies can be attributed to the cost of the deintercalation process of mitoxantrone from DNA.

Interaction of anticancer drug mitoxantrone with DNA hexamer sequence d-(CTCGAG)2 by absorption, fluorescence and circular dichroism spectroscopy

The interaction of mitoxantrone with d-(CTCGAG)2 has been studied by absorption, fluorescence and circular dichroism (CD) spectroscopy. The hypochromism and quenching of fluorescence showed that about four mitoxantrone molecules may be binding externally to DNA hexamer sequence at high drug to nucleic (D/N) acid duplex ratios (28.0–1.1). At lower D/N ratios (1.0–0.2), a red shift in absorption maxima at 610 and 660nm by 15 and 20nm, respectively and a red shift in emission maxima by 11nm accompanied by increase in absorbance and emission has been observed. The equilibrium constant for binding at low (1.0–0.2) and high (28.0–1.1) D/N ratios is 1.8×105M−1 and 1.38×106M−1, respectively. The CD spectra show change in intensity of bands accompanied by appearance of induced bands at 325nm and 650–700nm. The 251nm band shows blue shift at D/N ratio of 0.25 and 0.5. The binding isotherms show stoichiometry of 0.25 and 0.5 mitoxantrone molecules binding per duplex. The results suggest stacking of aromatic chromophore of mitoxantrone with terminal base pair of DNA strand forming a sandwiched structure of mitoxantrone between four and two duplex molecules. These investigations are relevant to the formation of ternary complex with topoisomerase enzyme and hence an understanding of anti tumor action of mitoxantrone.

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

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. 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. 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. 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.

Calorimetric and spectroscopic studies on the interaction of anticancer drug mitoxantrone with human serum albumin

Binding of the anticancer drug mitoxantrone with the protein human serum albumin (HSA) has been studied by using isothermal titration calorimetry (ITC), in combination with fluorescence, UV–visible, and circular dichroism spectroscopy. The thermodynamic parameters of binding have been evaluated from ITC and spectroscopic results and compared. The ITC results demonstrate that the binding of mitoxantrone with HSA occurs according to two sets of binding sites on the protein as opposed to the fluorescence and UV–visible spectroscopic results. Blockage of one binding site on HSA for mitoxantrone in the presence of NaCl indicates strong involvement of electrostatic interactions in the binding of the drug with the protein. An insignificant temperature dependence of the association constant observed in fluorescence measurements suggests a very low enthalpy of binding which is in close agreement with the results obtained from ITC measurements. Fluorescence life time measurements suggest formation of a static complex between mitoxantrone and HSA. The discrepancies in the ITC and fluorescence results suggest that one of the binding sites on the protein for mitoxantrone does not contain tryptophan residue in its immediate vicinity. The calorimetric and spectroscopic results have provided quantitative information on the binding of mitoxantrone with HSA and suggest that the binding is dominated by electrostatic interactions.

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.

Interaction of mitoxantrone, as an anticancer drug, with chromatin proteins, core histones and H1, in solution

In the present study, for the first time we have investigated the interaction of anticancer drug mitoxantrone with histone H1 and core histone proteins in solution using fluorescence, UV/Vis, CD spectroscopy and thermal denaturation techniques. The results showed that mitoxantrone reduced the absorbencies of H1 and core histone proteins at 210 nm (hypochromicity) and fluorescence emission intensity was decreased in a dose dependent. Binding of mitoxantrone changed secondary structures of the proteins as circular dichroism analysis confirmed it. Also, mitoxantrone increased the melting temperature of core histones at the final step of denaturation. The results suggest higher affinity of mitoxantrone to histone H1 compared to core histones providing histone proteins as a new target for mitoxantrone action at the chromatin level.

Coupled spectral and electrochemical evaluation of the anticancer drug mitoxantrone–sodium dodecyl sulfate interaction

In-vitro evaluation of the interaction of anticancer drug mitoxantrone with anionic surfactant sodium dodecyl sulfate (SDS), was performed in physiological conditions (phosphate buffer, pH 7.4) by spectral (UV–vis absorption) and electrochemical (cyclic and linear voltammetry) methods. The stoichiometry of interaction, the binding constants and diffusion coefficients of free and bound drug were determined. The partition coefficient of mitoxantrone between aqueous phase and SDS micelles was calculated, and the results indicated that it is strongly dependent on the drug concentration. Both absorption and cyclic voltammetry results have outlined two distinct processes depending on the surfactant concentration: process I in premicellar range, assigned to the interaction of the drug with the surfactant molecules, when electrostatic forces play an important role in the formation of the mitoxantrone-SDS complex with a defined stoichiometry; and process II in micellar range, when the surfactant micelles are formed and the drug is encapsulated in micelles in monomer form. The spectral results have indicated that the drug is most probably located in the micelle surface layer, both electrostatic and polar interactions playing important role in the binding of drug to SDS micelles. Possible application of this system as a micellar drug–carrier was also considered.

Interaction of anticancer drug mitoxantrone with DNA analyzed by electrochemical and spectroscopic methods

Cyclic voltammetry coupled with different spectroscopic (UV/Vis, fluorescence and Raman) techniques were used to study the interaction of mitoxantrone (MTX), an antitumor drug, with calf thymus DNA in acetate buffer solutions (pH 4.5). The interaction of MTX with DNA could result a considerable decrease in the MTX peak currents and a hypochromic and bathochromic shift in the maximum adsorption bands of MTX as well as the emission quenching in the MTX fluorescence spectra. The variations in the electrochemical and spectral characteristics of MTX indicated MTX bind to DNA by an intercalative mode. This conclusion was reinforced by Raman data. The merely particular vibrations were affected in Raman, suggesting that only a portion of the chromophore of MTX was involved in the intercalation into DNA duplex. These studies are valuable for a better understanding the detailed mode of MTX–DNA interaction, which should be important in deeper insight into the therapeutic efficacy of MTX and design of new DNA targeted drug.