Anatoly S. Buchelnikov

Complexation of C60 Fullerene with Aromatic Drugs

The contributions of various physical factors to the energetics of complexation of aromatic drug molecules with C(60) fullerene are investigated in terms of the calculated magnitudes of equilibrium complexation constants and the components of the net Gibbs free energy. Models of complexation are developed taking into account the polydisperse nature of fullerene solutions in terms of the continuous or discrete (fractal) aggregation of C(60) molecules. Analysis of the energetics has shown that stabilization of the ligand-fullerene complexes in aqueous solution is mainly determined by intermolecular van der Waals interactions and, to lesser extent, by hydrophobic interactions. The results provide a physicochemical basis for a potentially new biotechnological application of fullerenes as modulators of biological activity of aromatic drugs.

Evidence of entropically driven C60 fullerene aggregation in aqueous solution

In the present work, we report the first experimental evidence of entropically driven C60 fullerene aggregation in aqueous solution, occurring with nearly zero enthalpy change.

General analysis of competitive binding in drug–interceptor–DNA systems

A general model of competitive binding in drug–interceptor–DNA systems has been developed in order to quantify both the interceptor and protector mechanisms. The model involves full parameterization of the basic equations governing the mutual competition between drugs binding to DNA and incorporates as partial cases various similar models existing in the literature. The generality of the model results from strict accounting of the statistical effects of the binding of the drug and interceptor with DNA according to the McGhee-von Hippel formalism, and to the strict treatment of hetero-association between the drug and interceptor, which includes formation of all possible types of self- and hetero-complexes in solution. Indirect experimental evidence is provided for the importance of the protector mechanism in drug–caffeine–DNA systems, which is sometimes ignored in the literature because of the small magnitude of the CAF-DNA binding constant.

C60 fullerene enhances cisplatin anticancer activity and overcomes tumor cell drug resistance

We formulated and analyzed a novel nanoformulation of the anticancer drug cisplatin (Cis) with C60 fullerene (C60+Cis complex) and showed its higher toxicity toward tumor cell lines in vitro when compared to Cis alone. The highest toxicity of the complex was observed in HL-60/adr and HL-60/vinc chemotherapy-resistant human leukemia cell sublines (resistant to Adriamycin and Vinculin, respectively). We discovered that the action of the C60+Cis complex is associated with overcoming the drug resistance of the tumor cell lines through observing an increased number of apoptotic cells in the Annexin V/PI assay. Moreover, in vivo assays with Lewis lung carcinoma (LLC) C57BL/6J male mice showed that the C60+Cis complex increases tumor growth inhibition, when compared to Cis or C60 fullerenes alone. Simultaneously, we conducted a molecular docking study and performed an Ames test. Molecular docking specifies the capability of a C60 fullerene to form van der Waals interactions with potential binding sites on P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP-1), and multidrug resistance protein 2 (MRP-2) molecules. The observed phenomenon revealed a possible mechanism to bypass tumor cell drug resistance by the C60+Cis complex. Additionally, the results of the Ames test show that the formation of such a complex diminishes the Cis mutagenic activity and may reduce the probability of secondary neoplasm formation. In conclusion, the C60+Cis complex effectively induced tumor cell death in vitro and inhibited tumor growth in vivo, overcoming drug resistance likely by the potential of the C60 fullerene to interact with P-gp, MRP-1, and MRP-2 molecules. Thus, the C60+Cis complex might be a potential novel chemotherapy modification.

Indistinguishability of the models of molecular self-assembly

Numerous applications dealing with molecular aggregation at the interface of biology, physics and chemistry use either the dimer or the indefinite equilibrium constant models even though there is the well-known property of indistinguishability of the models with respect to fitting experimental data by various experimental techniques. The problem of indistinguishability is uncovered in the present work and the way in which the existing paradigm of how these models should be applied to analysis of molecular self-association is suggested.

On the reliability of quantitation of biological effect in drug–interceptor–DNA systems

Relative insensitivity of theoretical estimation of biological effect in drug–interceptor–DNA systems is found with respect to variation of parameters of quasiphysiological conditions. The “inertness” of the biological response, in part, justifies the use of parameters of intermolecular interaction, derived from independent physicochemical experiments, in estimation of relative biological effect in the theory of interceptor/protector action.

Development of an Analytical Approach to Study a Three-Component Hetero-Association by Means of Spectrophotometry

A case of 1:m:n complexation in a three-component system containing any possible heterocomplexes formed between the non-self-aggregating, absorbing ligand A and two self-aggregating, non-absorbing ligands B and C was considered for the first time in an application for molecular spectroscopy. All expressions necessary for full quantitative analysis of experimental data in three-component mixtures were obtained, viz., the law of conservation of mass and the expression for an experimentally observed parameter. These expressions can be directly utilized in mathematical software for performing standard curve-fitting procedures or solutions of specific tasks such as calculations of the concentration of various types of complexes. The numerical test of the 1:m:n model, accomplished with the aid of ultraviolet-visible light experimental data in a three-component system (proflavine-caffeine-nicotinamide), proved the validity of the developed approach.

Quantitative correlation of the in vitro biological effect with parameters of molecular complexation in mutagen-interceptor systems.

According to the theory of interceptor-protector action a quantitative link between the physico-chemical parameters of molecular complexation and in vitro biological effect in aromatic drug-interceptor systems must exist. In the present communication such link between relative change in mutagenicity of IQ-type aromatic mutagens on addition of aromatic interceptor molecules with equilibrium hetero-association constants of mutagen-interceptor complexation has been found using the published in vitro data in bacteria cell systems.