Ionic Liquids for Anticancer Application
Cancer is a serious life-threatening and/or chronic disease with a considerable social and economic impact on a global scale. The World Health Organization reports for 18.1 million newly registered cancer patients and 9.6 million cancer deaths in 2018 (https://www.who.int/cancer/PRGlobocanFinal.pdf). While searching for innovative and effective anticancer drugs, researchers have focused their attention on ionic liquids (ILs) as potential anticancer therapeutics. ILs are compounds composed of large organic cations and organic or inorganic anions . In general, they are characterized with low melting points (below 100 °C), low volatility, and high-temperature stability . Their chemical structure can be easily modified; therefore their physicochemical properties and biological activities are easily tunable. ILs are synthesized via reactions of neutralization or metatheses .
Cellular toxicity is a complex process involving multiple pathways, e.g., treatment with exogenous toxicant may stimulate nitric oxide or cytokine overproduction, which causes DNA damage, and toxicants may also affect cell membrane and cell redox system or cause mitochondrial dysfunction. Other targets to cell toxicity could be cellular proteins, receptors, and energy metabolism .
ILs Potential Anticancer Agents
Anticancer properties of ILs have not been yet revealed in details. The major studies in this field are limited only to the evaluation of the effect of the ILs on the cell viability, and only a few reports go deeper in an attempt to elucidate the mechanism of IL cytotoxicity.
There are numerous literature data on the cytotoxic effect of various compound representatives of this group of ILs on more than 60 cell lines among which colon carcinoma, breast cancer, melanoma, cervical and ovarian cancers, and hepatocarcinoma are the most studied [2, 3, 4]. Depending on the IL structure and the cell line, half-maximum inhibitory constant (IC50) varying from micromolar to millimolar range is reported.
As outlined in various studies, the cytotoxic effect of the ILs on tumor cell lines could be accounted for the cation moiety . ILs based on hydrophobic and aromatic cations (e.g., pyridinium and imidazolium) are more toxic than ILs containing hydrophilic or nonaromatic cations such as pyrrolidinium, piperidinium, ammonium, or phosphonium . It is noteworthy to be mentioned that not the structure itself but the chain length of the alkyl substituents in the cation appears to be the dominating factor for the cation toxicity. While comparing ILs containing the same anion, numerous authors concluded that the toxicity of the cation increases with the increase of the chain length of the substituent [5, 6]. In general, if we compare cations with the same substituents, guanidinium cation is more toxic to cancerous cells than imidazolium or pyridinium cations. Guanidinium ILs with long alkyl-chain substituents (C6-C12) are highly cytotoxic to cervical cancer cells, melanoma, and hepatocarcinoma cells. The compound with the dodecyl substituent was even ten times more cytotoxic than mitomycin C, a commonly used chemotherapeutic .
The effect of the anion on the anticancer activity of the ILs is adverse. Some authors have shown that the structure of the anion has minimal contribution to the anticancer activity of the ILs [2, 8]. However, for a series of 1, 3-dialkylimmidazolium salts tested against cervical cancer cells, Stepnowski et al. found that hexafluorophosphates are 450 times more toxic than chlorides and more than 20 times more toxic than tetrafluoroborates . On the contrary, Malhotra and Kumar observed that in some cases 1,3-dialkylimmidazolium chlorides and tetrafluoroborates are more active than hexafluorophosphates, bis(triflic)imides, and tris(pentafluoroethyl)trifluorophosphates [5, 6]. Additionally, the 1-methy-3-undecylimidazolium chloride and the 1-methy-3-undecylimidazolium tetrafluoroborate showed remarkable activity against 60 tested human tumor cell lines. The two compounds exhibit also some cell selectivity, and for leukemia cell lines, the estimated IC50 was below 1 μM .
Moshikur et al. reported the conversion of methotrexate, a class IV drug and a chemotherapeutic, into ILs containing cholinium, tetramethylammonium, 1-ethyl-3-methylimidazolium, tetrabutylphosphonium, or amino acid ester cations . All methotrexate ILs are characterized with a substantially improved solubility in water and body fluids, which exceeded at least 5000 times that of the free methotrexate or the sodium salt . Methotrexate tributhylphosphonium, 1-ethyl-3-methylimidazolium, and phenylalanine ester salts show more than ten times lower IC50 values toward cervical cancer cells in comparison to the methotrexate sodium salts, which are attributed to strong π-π interactions between the hydrophobic or lipophilic nature of the cation and the cell membrane resulting in cell destruction .
Egorova et al. reported the synthesis of an IL based on doxorubicin, commonly used DNA-interacting anticancer agent. The obtained 1-(doxorubicin- 10-carboxydecyl)-3-methylimidazolium bromide and doxorubicin exhibited comparable cytotoxicity toward colon adenocarcinoma cells, and the estimated IC50 for 24 h was approximately 6–9 μM .
Mitoxantrone, an antineoplastic drug and an inhibitor of DNA topoisomerase II used for the treatment of various types of cancer, was conjugated to 3-(10-carboxydecyl)-1-methylimidazolium bromide . The resulting ILs characterized with high solubility prevent polymorphism and show cytotoxicity toward human colon carcinoma and human colorectal adenocarcinoma cells compared to that estimated for the mitoxantrone .
In vitro cytotoxicity of some ILs based on natural cations and/or anions has also been evaluated. For example, cholinium and benzylakonium betulinates exhibit stronger inhibitory effect than betulinic acid against melanoma, neuroblastoma, and breast cancer cells [Suresh 2012]. In addition, more than four times lower IL50 values were reported for the cholinium salts, which are attributed to the enhanced water solubility of the organic salts .
Interestingly, amino acid tetrafluoroborates demonstrated enhanced cytotoxicity which is ascribed to facilitate transport of the toxic anion into the cell .
Other Related Anticancer Applications of ILs
Many of the approved anticancer drugs, e.g., doxorubicin, daunorubicin, paclitaxel, and other, are highly hydrophobic and poorly soluble, and drug delivery systems based on ILs can be an alternative approach to solve solubility problems and to improve their inefficiency, enhancing the bioavailability of the active compounds. For example, the anticancer drug paclitaxel is currently formulated with Cremophor EL, a formulation vehicle for poorly soluble drugs, which, however, induce hypersensitivity reactions during intravenous administration and cause precipitation of the drug by aqueous dilution . Chowdhury et al. propose novel paclitaxel formulation based on cholinium glycinate, which characterizes with an enhanced solubility of the drug, good storage stability of the formulation, and preserved anticancer activity while avoiding the side effects of Cremophor EL . On the other hand, Pyne et al. observed that doxorubicin hydrochloride forms spherical aggregates in aqueous solutions of 1-octyl-3-methylimidazolium chloride, which in the presence of sodium cholate can be converted into rod-like aggregates . The authors propose 1-octyl-3-methylimidazolium chloride/sodium cholate as a delivery system where the drug itself aggregates to form the delivery system .
Recently, some investigations on the development of IL-based sensors for anticancer drugs and biomarkers have been conducted. For example, Alavi-Tabari prepared an electroanalytical sensor based on ZnO nanoparticles and 1-butyl-3-methylimidazolium tetrafluoroborate that can be used for a simultaneous determination of the concentration of doxorubicin and dasatinib in injections, urine, and blood samples . The authors reported a detection limit of doxorubicin and dasatinib, 9 nM and 0.5 μM, respectively . Fouladgar reported the development of a new sensor based on CuO-carbon nanotubes amplificated with 1-ethyl-3-methylimidazolium tetrafluoroborate that has detection limits for doxorubicin and 5-fluorouracil in serum samples of 6.0 and 0.4 μM, respectively .
On the other hand, Ye et al. proposed an Au-Pd alloy/ionic liquid holding of glassy carbon electrode that was able to detect lung cancer factor (VEGF165) in the ultra-trace level . The sensor exhibited a linear relationship with the concentration range of VEGF165 between 1 and 150 pM, and a detection limit of 0.5 pM was reported . This sensor could be useful for the early detection of lung cancer.
ILs are currently in the focus of increasing attention in view of their medicinal application. Considering the large number of synthesized ILs during the last decade, yet a scarce number of them are tested in view of their anticancer properties. Most of the studies are limited to in vitro evaluation of the cytotoxic effect of IL on various cancer cell lines, and only a few in vivo studies are reported. As a whole, the mechanism of IL cytotoxicity is not fully revealed, although some assumptions that IL cytotoxicity is due to the interaction between ILs and lipid membrane, which results in cell membrane destruction. Thorough understanding of cancer molecular and cellular mechanisms of ILs could contribute to the design of novel compounds with targeted antitumor activity and higher selectivity. Still, it is believed that ILs have the potential for the development of new anticancer and therapeutic and diagnostic tools.
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