Synthesis of chemical tools to improve water solubility and promote the delivery of salinomycin to cancer cells

Abstract

Chemotherapy and radiation are unable to eliminate all cancer cells, particularly apoptosis-resistant cancer cells, despite their ability to kill cancer cluster cells. Thus, it is important to identify methods that eliminate all cancer cells in order to prevent relapse. Salinomycin has the ability to control and eradicate different types of cancer, including breast cancer; however, its molecular mechanism remains unclear. The main difficulty in testing salinomycin activity and understanding the governing mechanisms is its low solubility in water (17 mg/l), which can hinder convenient delivery of salinomycin to the protein receptor at the cell surface of stem cells. In the present study, salinomycin was conjugated to the trans-activator of transcription-protein in order to facilitate its delivery to the cancer cells. Conjugated salinomycin demonstrated improved solubility in both in vitro. Salinomycin was tested in breast cancer cells (MCF7 and JIMT-1) by the cleavage of the linker through photolysis at l≥365 nm during in vitro analysis, in the present study.

Salinomycin-Based Drug Delivery Systems: Overcoming the Hurdles in Cancer Therapy

“…Sali and its sodium salt have a solubility in water of less than 0.1 mg/mL, thus being considered practically insoluble. Since solubility is a crucial physicochemical property of drugs, a poor solubility in aqueous media results in low absorption from the active site and consequently poor bioavailability [ 6 , 41 ]. In veterinary medicine and animal husbandry, Sali-containing granules (Bio-cox, Sacox) are mixed with animal feed before use [ 5 ].…”

“…Considering the photo sensitivity of the linker, UV irradiation at a wavelength of 365 nm for 100 s allowed the total release of Sali from the conjugate which could be further translated into an immediate exposure of the cancerous cells to the therapeutic drug. Since this outcome depended on the cellular uptake of the formulation, the conjugate was further associated with an azido sugar moiety, which increased the cytotoxic response on MCF-7 and JIMT-1 human breast cancer cell lines and decreased the IC 50 value to half [ 41 ].…”

Salinomycin as a potent anticancer stem cell agent: State of the art and future directions

“… 159 In addition, as salinomycin displays a poor water soluble capability (17 mg/L), derivatives with improved aqueous solubility have also been reported by Awad aiming to promote the efficiency of drug delivery to cancer cells. 187 The cancel cell cytotoxicity was observed at two‐ to threefolds higher than that of salinomycin, while no data were showed regarding the effect of the derivative against normal cells. The tests of these derivatives and conjugates were mainly performed in mixed cancer cell populations such as drug‐resistant cell lines and ex vivo tumor tissues, the improvement of these derivatives on CSC selectivity is yet unknown.…”

“…However, the toxicity to normal cells of these conjugates were not tested in that study 159 . In addition, as salinomycin displays a poor water soluble capability (17 mg/L), derivatives with improved aqueous solubility have also been reported by Awad aiming to promote the efficiency of drug delivery to cancer cells 187 . The cancel cell cytotoxicity was observed at two‐ to threefolds higher than that of salinomycin, while no data were showed regarding the effect of the derivative against normal cells.…”

Salinomycin-Loaded High-Density Lipoprotein Exerts Promising Anti-Ovarian Cancer Effects by Inhibiting Epithelial–Mesenchymal Transition

“…Consequently, researching Sal as an anti-cancer drug is challenging. 20,21 Bionic targeting drug delivery systems increase anti-cancer drug accumulation in tumors by facilitating cellular uptake and intracellular retention, and reducing the drug's toxicity to non-cancerous tissues. 22 A high-density lipoprotein (HDL), which carries lipids as multifunctional aggregates in the plasma, can be used as an effective carrier for hydrophobic drugs because of its phospholipid core.…”