Selective terpene based therapeutic deep eutectic systems against colorectal cancer

Abstract

Cancer remains a major health problem worldwide, with colorectal cancer (CRC) being the third most incident and the second most lethal. Inflammation, on the other hand, has been highly associated with cancer development and maintenance, therefore, the reduction of the inflammatory microenvironment represents a promising therapeutic strategy. Deep eutectic systems (DES) are based on the combination of different components which together, at a certain molar ratio, present a deep decrease in their melting point compared with the individual compounds. When an active pharmaceutical ingredient is part of a DES it is designated by therapeutic deep eutectic system (THEDES). New THEDES combining terpenes with anticancer properties, such as safranal, menthol and linalool, with nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen, ketoprofen and flurbiprofen were produced. To evaluate THEDES anti-CRC therapeutic potential, their physico-chemical properties, bioavailability and bioactivity, were explored. Our results show that safranal:ibuprofen (3:1), safranal:ibuprofen (4:1) and menthol:ibuprofen (3:1) present promising therapeutic activity towards CRC cells due to a selective cytotoxic action towards cancer cells. menthol:ibuprofen (3:1) anti-proliferative action seems to be related with cell membrane disruption, reduction of the inflammation through the reduction of reactive oxygen species (ROS) production, and induction of apoptosis via caspase-3. On the other hand, safranal:ibuprofen (3:1) and safafranal:ibuprofen (4:1) seem to prevent tumour expansion only through the induction of apoptosis via caspase-3. Besides, these systems present an increase in ibuprofen permeability, with menthol:ibuprofen (3:1) increasing also ibuprofen's solubility thus its overall bioavailability. Knowing that cancer is a huge problematic situation that requires alternative therapies with less side effects, improved efficacy, associated with less costs and environmentally friendly, a new opportunity emerges for DES to be part of the pharmaceutical industry.

Keywords: Colorectal cancer; Deep eutectic systems; Natural compounds; Nonsteroidal anti-inflammatory drugs; Terpenes; Therapeutic deep eutectic systems.