Nanomicellar Formulation of Clotrimazole Improves Its Antitumor Action toward Human Breast Cancer Cells

BACKGROUND: Although demonstrated as a selective anticancer drug, the clinical use of clotrimazole (CTZ) is limited due to its low solubility in hydrophilic fluids. Thus, we prepared a water-soluble nanomicellar formulation of CTZ ((n)CTZ) and tested on the human breast cancer cell line MCF-7 biology. METHODOLOGY/PRINCIPAL FINDINGS: CTZ was nanoencapsulated in tween 80 micelles, which generated nanomicelles of, approximately, 17 nm of diameter. MCF-7 cells were treated with (n)CTZ and unencapsulated DMSO-solubilized drug ((s)CTZ) was used for comparison. After treatment, the cells were evaluated in terms of metabolism, proliferation, survival and structure. We found that (n)CTZ was more efficient than (s)CTZ at inhibiting glycolytic and other cytosolic and mitochondrial enzymes. Moreover, this increased activity was also observed for lactate production, intracellular ATP content, ROS production and antioxidant potential. As a consequence, (n)CTZ-treated MCF-7 cells displayed alterations to the plasma membrane, mitochondria and the nucleus. Finally, (n)CTZ induced both apoptosis and necrosis in MCF-7 cells. CONCLUSIONS/SIGNIFICANCE: MCF-7 cells are more sensible to (n)CTZ than to (s)CTZ. This was especially evident on regard to antioxidant potential, which is an important cell defense against drugs that affect cell metabolism. Moreover, this water-soluble formulation of CTZ strengths its potential use as an anticancer medicine.