Synthesis, Characterization, Pharmacokinetics and Evaluation of Cytotoxicity for Docetaxel-Oleate Conjugate Targeting MCF-7 Breast Cancer Cells

Abstract

The present work envisages synthesis of an ester conjugate of anticancer drug docetaxel with oleoyl chloride, with the aim to selectively target the breast cancer cells MCF-7 so as to minimize non-specific hemolytic side effects. The synthesized docetaxel-oleate conjugate was characterized and confirmed by physicochemical and spectral methods. Solubility and partition coefficient determination indicated increased solubility and lipophilicity, while protein binding studies revealed low protein binding capacity of the conjugated drug. Subsequently, the conjugate was evaluated for its in vitro cytotoxicity, drug release, and hemolysis effects. The results indicated a lesser RBC lysis at a more significant anticancer activity of the parent drug and a selective diffusion at pH of cancer cells (compared to the pH of normal cells), thereby increasing specificity and decreasing adverse effects. In addition, an analytical HPLC method was developed for hydrolytic study of the conjugated drug. The proposed method showed good separation of the target compounds with high accuracy and precision. Hydrolysis study indicated a minimum hydrolysis of the conjugate at various pH that simulated gastric and intestinal fluids. Thus, the synthesized conjugate proves to be a useful prodrug in reducing systemic toxicity of docetaxel as well as selectively targeting cancerous cells.