Interaction of Congo Red, Evans Blue and Titan Yellow with doxorubicin in aqueous solutions. A molecular dynamics study

Congo Red, Evans Blue and Titan Yellow were studied in pure component solutions and in mixtures with doxorubicin. Congo Red was analyzed in both unprotonated and protonated forms which mimics the neutral and acidic pH of solutions. The analysis was based on the molecular dynamics simulations with the second generation of the general amber force field, gaff2. The calculations results led to the conclusion that in pure component solutions the dyes and also doxorubicin exist in forms of single molecules or a few molecule aggregates. The exception is the protonated CR which forms large all-molecule aggregate. However, in the case of mixtures of dyes with doxorubicin we observed formation of larger aggregates consisting of dyes and doxorubicin molecules and accompanied by a few molecule clusters or just single molecules of the remaining dyes molecules. Within the aggregates the dyes molecules reveal a tendency to parallel alignment with, however, diverse intensities. The strongest tendency to formation of ribbon-like structures revealed Evans Blue and the ordering was the longest range in the case of Evans Blue. Other dyes revealed only short-range parallel alignment with the exception of the protonated Congo Red for which the formation of ribbon-like structures was strong. Among studied systems the strongest binding of doxorubicin was found in the case of the unprotonated Congo Red while the weakest - for the protonated Congo Red. Binding free energy of doxorubicin to the aggregates formed by other dyes was generally significant and the spontaneous detachment of doxorubicin from those aggregates was found as rather unlikely at normal conditions. This effect can be utilized in targeted delivery of this drug to immune complexes where it can be released from the aggregates. (C) 2019 The Author(s). Published by Elsevier B.V.