Unveil the Anticancer Potential of Limomene Based Therapeutic Deep Eutectic Solvents

Abstract

Deep eutectic solvents have been recently reported as an interesting alternative to improve the therapeutic efficacy of conventional drugs, hence called therapeutic deep eutectic solvents (THEDES). The main objective of this work was to evaluate the potential of limonene (LIM) based THEDES as new possible systems for cancer treatment. LIM is known to have antitumor activity, however it is highly toxic and cell viability is often compromised, thus this compound is not selective towards cancer cells. Different THEDES based on LIM were developed to unravel the anticancer potential of such systems. THEDES were prepared by gently mixing saturated fatty acids menthol or ibuprofen (IBU) with LIM. Successful THEDES were obtained for Menthol:LIM (1:1), CA:LIM (1:1), IBU:LIM (1:4) and IBU:LIM(1:8). The results indicate that all the THEDES present antiproliferative properties, but IBU:LIM (1:4) was the only formulation able to inhibit HT29 proliferation without comprising cell viability. Therefore, IBU:LIM (1:4) was the formulation selected for further assessment of anticancer properties. The results suggest that the mechanism of action of LIM:IBU (1:4) is different from isolated IBU and LIM, which suggest the synergetic effect of DES. In this work, we unravel a methodology to tune the selectivity of LIM towards HT29 cell line without compromising cell viability of healthy cells. We demonstrate furthermore that coupling LIM with IBU leads also to an enhancement of the anti-inflammatory activity of IBU, which may be important in anti-cancer therapies.

Optimal Design of THEDES Based on Perillyl Alcohol and Ibuprofen

“…Similar data was obtained for the other THEDES systems, being a plausible reason for the establishment of intermolecular interactions between the counterparts and the supramolecular arrangement of the counterparts while in THEDES form [ 39 , 42 , 43 ]. Overall, the DSC data are in good agreement with the naked-eye observations, being also aligned with previous data reported in the literature for the THEDES based on limonene:IBU [ 35 ].…”

“…In this context, ibuprofen is an ideal candidate being one of the most widely applied NSAIDs in clinical practice with a known association with tumor reduction. Furthermore, recent studies have highlighted the potential of deep eutectic systems containing ibuprofen as an API for cancer treatment [ 34 , 35 ].…”

“…Their potential goes way beyond being a mere solvent for chemical engineering processes. DES already have extensive applications in the pharmaceutical and biomedical fields [ 36 , 38 , 41 , 44 ], being extremely interesting as eutecticity has shown the ability to tune the solubility and permeation of several compounds, including various APIs [ 35 , 39 ].…”

D‐limonene: A multifunctional compound with potent therapeutic effects

“…Recently, use of plant based chemopreventive and chemotherapeutic agents to prevent and treat cancer is drawing considerable attention. Monoterpenes are reported to show promising anticancer properties (Pereira et al., 2019). The anti‐tumorigenic property of D‐limonene is assessed in various types of cancer such as lung (Yu et al., 2018), breast (Crowell et al., 1996), gastric (Lu et al., 2004), prostate (Rabi & Bishayee, 2009), bladder (Ye et al., 2020), colon (Jia et al., 2013) etc.…”

“…properties (Pereira et al, 2019). The anti-tumorigenic property of D-limonene is assessed in various types of cancer such as lung (Yu et al, 2018), breast (Crowell et al, 1996), gastric (Lu et al, 2004), prostate (Rabi & Bishayee, 2009), bladder (Ye et al, 2020), colon (Jia et al, 2013) etc.…”