Encyclopedia of Ionic Liquids

Living Edition
| Editors: Suojiang Zhang

Ionic Liquids for Anticancer Application

  • Maya GunchevaEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-981-10-6739-6_6-1



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 [1]. In general, they are characterized with low melting points (below 100 °C), low volatility, and high-temperature stability [1]. 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 [1].

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 [2].

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.

Based on their structure, ILs with anticancer activities can be organized into the following groups:
  1. 1.

    Second-Generation ILs

Up to date, the second-generation ILs are the most extensively studied group of ILs with respect to their anticancer potential (Scheme 1). Here belong non-haloaluminate ILs containing alkyl-substituted imidazolium, pyridinium, piperidinium, morpholinium, quaternary ammonium, and phosphonium cations and tetrafluoroborate [BF4], hexafluorophosphate [PF6], methylsulfate [MeSO4], bis(trifluoromethylsulfonyl)amide [NTf2], trifluoromethylsulfonate [TfO], acetate [Ac], and halide [X] anions [3].
Scheme 1

Some second-generation ILs with anticancer properties

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 [2]. 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 [5]. 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 [7].

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 [9]. 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 [6].

Frade et al. tested the cytotoxicity of two series of ILs containing a 1-methyl-3-octyl-imidazolium or alkyl modified-choline [chol-Cn] cation and a magnetic anion (e.g., [FeCl4], [GdCl6], [MnCl4], and [CoCl4]) against colorectal adenocarcinoma CaCo-2 cells [10]. Cell viability of the tumor cells was not affected in the presence of [Choline-Cn][FeCl4], except for octyl-substituted derivative applied at a concentration as high as 1.7 mM. The toxicity of the cholinium-based ILs with the other magnetic anions was also negligible. For the ILs containing 1-methyl-3-octyl-imidazolium cation was established the following order of decreasing toxicity for anions: MnCl4 > CoCl4 > CdCl6 > FeCl4 [10]. Expectedly, the cytotoxicity of the ILs increases with the increase of the chain length of the substituent in a dose-dependent manner.
  1. 2.

    Third-Generation ILs

Organic salts consisting of natural, biodegradable, or pharmaceutically active (API) cation and/or anion, e.g., choline, amino acid, secondary plant metabolite, API, and others, belong to the third-generation ILs (Scheme 2). In some cases, they are characterized with improved anticancer properties in comparison to those of the parent molecules. For example, the ampicillin tetraethylammonium salt was highly cytotoxic toward osteosarcoma and breast cancer, and the estimated IC50 values were as low as 42 and 30 nM, respectively [11]. Ferraz et al. showed that 1-ethyl-3-methylimidazolium analog exhibits greater toxicity toward colon carcinoma cells in comparison to the ampicillin sodium salt [11]. In addition, the ampicillin cholinium salt is not only more toxic toward osteoblastoma cells than the sodium analog but also showed higher cell selectivity [11]. On the other hand, the ampicillin salts containing trihexyltetradecylphosphonium [P6,6,6,14] or cetylpyridinium [C16Pyr] are highly toxic to both cancerous and noncancerous cells [11].
Scheme 2

Some third-generation ILs with anticancer properties

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 [12]. 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 [12]. 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 [12].

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 [13].

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 [14]. 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 [14].

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 [15].

Interestingly, amino acid tetrafluoroborates demonstrated enhanced cytotoxicity which is ascribed to facilitate transport of the toxic anion into the cell [3].

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 [16]. 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 [16]. 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 [17]. The authors propose 1-octyl-3-methylimidazolium chloride/sodium cholate as a delivery system where the drug itself aggregates to form the delivery system [17].

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 [18]. The authors reported a detection limit of doxorubicin and dasatinib, 9 nM and 0.5 μM, respectively [18]. 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 [19].

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 [20]. 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 [20]. 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.



  1. 1.
    Welton T (1999) Room-temperature ionic liquids. Chem Rev 99(8):2071–2084CrossRefGoogle Scholar
  2. 2.
    Dias AR, Costa-Rodrigues J, Fernandes MH, Ferraz R, PrudÞncio C (2017) The anticancer potential of ionic liquids. Chem Med Chem 12:11–18CrossRefGoogle Scholar
  3. 3.
    Egorova K, Gordeev EG, Ananikov V (2017) Biological activity of ionic liquids and their application in pharmaceutics and medicine. Chem Rev 117:7132–7189CrossRefGoogle Scholar
  4. 4.
    Liu G, Zhong R, Hu R, Zhang F (2012) Applications of ionic liquids in biomedicine. Biophys Rev Lett 7(3–4):121–134CrossRefGoogle Scholar
  5. 5.
    Kumar RA, Papaıconomou N, Lee J-M, Salminen J, Clark DS, Prausnitz JM (2009) In vitro cytotoxicities of ionic liquids: effect of cation rings, functional groups, and anions. Environ Toxicol 24:388–395CrossRefGoogle Scholar
  6. 6.
    Malhotra S, Kumar V (2010) A profile of the in vitro anti-tumor activity of imidazolium-based ionic liquids. Bioorg Med Chem Lett 20:581–585CrossRefGoogle Scholar
  7. 7.
    Zhang Z-B, Fu S-B, Duan H-F, Lin Y-J, Yang Y (2010) Brand-new function of well-designed ionic liquid: inhibitor of tumor cell growth. Chem Res Chinese U 26(5):757–760Google Scholar
  8. 8.
    Rezki N, Messali M, Al-Sodies SA, Naqvi A, Bardaweel SK, Al-blewi FF, Aouad MR, El Ashry ESH (2018) Design, synthesis, in-silico and in-vitro evaluation of di-cationic pyridinium ionic liquids as potential anticancer scaffolds. J Mol Liq 265:428–441CrossRefGoogle Scholar
  9. 9.
    Stepnowski P, Składanowski AC, Ludwiczak A, Laczyńska E (2004) Evaluating the cytotoxicity of ionic liquids using human cell line HeLa. Hum Exp Toxicol 23(11):513–517CrossRefGoogle Scholar
  10. 10.
    Frade R, Simeonov S, Rosatella AA, Siopa F, Afonso CAM (2013) Toxicological evaluation of magnetic ionic liquids inhuman cell lines. Chemosphere 92:100–105CrossRefGoogle Scholar
  11. 11.
    Ferraz R, Costa-Rodrigues J, Fernandes MH, Santos MM, Marrucho IM, Rebelo LPN, PrudÞncio C, Paulo Noronha J, Petrovski Z, Branco LC (2015) Antitumor activity of ionic liquids based on ampicillin. Chem Med Chem 10:1480–1483CrossRefGoogle Scholar
  12. 12.
    Moshikur RM, Chowdhury MR, Wakabayashi R, Tahara Y, Moniruzzaman M, Goto M (2019) Ionic liquids with methotrexate moieties as a potential anticancer prodrug: synthesis, characterization and solubility evaluation. J Mol Liq 278:226–233CrossRefGoogle Scholar
  13. 13.
    Egorova KS, Kucherov FA, Posvyatenko AV, Ananikov VP (2016) Synthesis of doxorubicin-containing ionic liquid and study of its biological activity. Med Chem. ISSN: 2161–0444.  https://doi.org/10.4172/2161-0444.C1.028
  14. 14.
    Kucherov FA, Egorova KS, Posvyatenko AV, Eremin DB, Ananikov VP (2017) Investigation of cytotoxic activity of mitoxantrone at the individual cell level by using ionic-liquid-tag-enhanced mass spectrometry. Anal Chem 89(24):13374–13381CrossRefGoogle Scholar
  15. 15.
    Suresh C, Zhao H, Gumbs A, Chetty CS, Bose HS (2012) New ionic derivatives of betulinic acid as highly potent anti-cancer agents. Bioorg Med Chem Lett 22:1734–1738CrossRefGoogle Scholar
  16. 16.
    Chowdhury MR, Moshikur RM, Wakabayashi R, Tahara Y, Kamiya N, Moniruzzaman M, Goto M (2018) Ionic-liquid-based paclitaxel preparation: a new potential formulation for cancer treatment. Mol Pharm 15(6):2484–2488CrossRefGoogle Scholar
  17. 17.
    Pyne A, Kundu S, Banerjee P, Sarkar N (2018) Unveiling the aggregation behavior of doxorubicin hydrochloride in aqueous solution of 1-octyl-3-methylimidazolium chloride and the effect of bile salt on these aggregates: a microscopic study. Langmuir 34(10):3296–3306CrossRefGoogle Scholar
  18. 18.
    Alavi-Tabari SAR, Khalilzadeh MA, Karimi-Maleh H (2018) Simultaneous determination of doxorubicin and dasatinib as two breast anticancer drugs uses an amplified sensor with ionic liquid and ZnO nanoparticles. J Electroanal Chem 811:84–88CrossRefGoogle Scholar
  19. 19.
    Fouladgar M (2018) CuO-CNT nanocomposite/ionic liquid modified sensor as new breast anticancer approach for determination of doxorubicin and 5-fluorouracil drugs. J Electrochem Soc 165(13):B559–B564CrossRefGoogle Scholar
  20. 20.
    Ye H, Qin B, Sun Y, Li J (2017) Electrochemical detection of VEGF165 lung cancer marker based on Au-Pd alloy assisted aptasenor. Int J Electrochem Sci 12:1818–1828CrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of SciencesSofiaBulgaria

Section editors and affiliations

  • Zhonghao Li
    • 1
  • Maya Guncheva
    • 2
  1. 1.Key Laboratory of Colloid and Interface Chemistry, Ministry of EducationShandong UniversityJinanChina
  2. 2.Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of SciencesSofiaBulgaria