On the Interaction of Doxorubicin with Oleate Ions: Fluorescence Spectroscopy and Liquid-Liquid Extraction Study

Abstract

Doxorubicin (DOX) is an antineoplastic agent of the anthracycline family used as a first-line treatment in numerous neoplastic diseases, particularly in breast cancer.1) The progression of tumor cell resistance, in particular multidrug resistance (MDR), is one of the main factors which limit its employment.2) MDR is generally associated with a decreased intracellular accumulation of drug related to a membrane glycoprotein, the P-gp that contributes to a rapid expelling of the drug from the cell.3) An interesting way to overcome this active efflux would be to support the drug accumulation into the cell, in particular by increasing its capacity to cross lipidic membranes. One can act upon the membrane fluidity or act upon the hydrophilic/lipophilic properties of the drug.DOX molecule (see structure on Fig. 1) is considered hydrophilic at physiological pH because it presents a positive charge on the sugar moiety. The more lipophilic molecular form of DOX is dominant at moderately alkaline pHs, between 8.2 and 9.5, the pK a values of the amine and the phenol in position 11 respectively.4) The hydrophilicity of DOX is also depending on the drug concentration, since beyond a concentration of 30 mM DOX molecules are prone to form less hydrophilic dimmers (stacking effect) which precipitate in aqueous solution. The increase of the pH, i.e. of the neutral form percentage, is in favor of the stacking phenomenon. 5,6) It has been recently shown that lipophilicity of cationic drugs 7,8) can be increased by association with an anion, namely with a long chain ion of a fatty acid.9,10) Nevertheless, no study is devoted to the molecular interaction between the drug and the ion. On the other hand, combined use of an anticancer drug, paclitaxel, with different fatty acids, has been shown to enhance mortality of cancer cells in vitro.11) It has not yet been established whether this gain in efficacy is dependent on an assembly between the drug and the fatty acid ion.Association DOX-fatty acid could be more lipophilic than DOX alone, and enter more efficiently into the cell. It could also facilitate drug encapsulation into pharmaceutical formulations based on hydrophobic polymers or liposomes. 7,9) Oleic acid is a good candidate for such an association within a feasibility study: it is the simplest of the w-9 fatty acid family (Fig. 1), and possesses a long hydrophobic chain that could contribute to a gain of lipophilicity of the association. Moreover, oleates are non-toxic and the behavior of oleic acid and its ion (oleate, OA Ϫ ) in aqueous solution is rather well studied. [12][13][14][15] Fluorescence spectroscopy has been successfully used to study interactions between DOX and its surrounding, for instance when the drug intercalates DNA 16,17) or penetrates within membrane models or liposomal drug carriers. 18,19) Indeed, the dihydroanthraquinone moiety of DOX is a well known fluorophore excitable with visible light (absorption maxima at 480-500 nm). Fluorescence spectroscopy Increase of lipophilicity of cationic doxorubicin (DO...

Magnetic Driven Nanocarriers for pH-Responsive Doxorubicin Release in Cancer Therapy

“…These results were similar to values obtained in previous studies using other magnetic carriers, such as chitosan-coated magnetite nanoparticles (18 wt.%) [17] and magnetic polymersomes (12 wt.%) [67]. In aqueous solution, DOX molecules adopt different conformations depending on the solution pH ( Figure S3, supporting information) [68]. At pH 6, it is expected that drug loading is promoted by electrostatic interactions between the primary amine groups of DOX and the sulfonate groups of the carrageenan.…”

Development of citrate-stabilized Fe3O4 nanoparticles: Conjugation and release of doxorubicin for therapeutic applications

“…This result strongly suggested that positively charged drug molecules are bound to negatively charged CA-MNP through electrostatic interactions. The impressive affinity of doxorubicin for negatively charged molecules such as oleate ions and phospholipids has been the subject of numerous earlier investigations [37][38][39][40]. The interaction of DOX molecules with CA-MNP was also evident from the predominant quenching of DOX fluorescence in presence of CA-MNP (Fig.…”

Water-dispersible polyphosphate-grafted Fe3O4 nanomagnets for cancer therapy

“…2,[40][41][42][43] We have performed zeta-potential and fluorescence spectroscopic studies to explore the binding of DOX with PPNM. DOX a cationic drug used in chemotherapy is chosen as a model drug to estimate the drug loading and release behavior of PPNM.…”