Evaluation of the role of ionic liquid as a modifier for carbon paste electrodes in the detection of anthracyclines and purine-pyrimidine-based anticancer agents

Ionic liquid has become a very fascinating modifier in the past few years. With the help of an ionic liquid-modified carbon paste electrode (CPE), electrochemistry has become a great way to find different drugs with a lower detection limit and high sensitivity and selectivity. The circulation of electrons of the ring in the cationic part of ionic liquid enables in lowering of the electron resistance and further enhancing the electrical conductivity. The combination of ionic liquids with various kinds of materials such as Nobel metals, metal oxides, graphene oxides, carbon nanotubes (CNT), etc has further improved its catalytic activity as a modifier enabling faster electron transfer. Additionally, the ability of an ionic liquid to dissolve other chemicals allows for the incorporation of the electrolytes and redo-active species into the electrode, enhancing its performance. Anti-cancer drugs are life-saving but have a lot of side effects, but one of the biggest is cardiotoxicity, which is very important for saving patients’ lives. So figuring out what these drugs are is a big task for scientists all over the world. Therefore, the current review enlightens the path for using ionic liquid as a modifier for the detection of anthracycline and purine-pyrimidine-based anti-cancer drugs.


Introduction
There are several cases of people who are suffering from cancer and dying daily.Cancer is among the top three causes of death around the world and is one of the major problems that causes several deaths [1].There are more than 100 types of cancer that cause a serious effect on human health, widely named for organs and tissues where cancer forms in its initial stage.Furthermore, the uses of some anticancer drugs have appreciably increased [2].Initially, when cancer is in its first stage, it does not show any kind of symptoms.Symptoms and changes come out as the bunch grows or ulcerates.Scientists around the globe have been constantly working to find ways to combat cancer.In this journey, they have discovered various drugs that slow down or terminate the cancerous processes occurring in the tissues.One such important result of their efforts is anti-cancer drugs.
Cancer is believed to have its roots back in ancient Greek and Egyptian civilizations.The first historical record exists of breast cancer which was recorded around 300 B.C. but its actual consideration as a disease is believed to be in 400 B.C. Modern oncology can be tracked after the 1700s and anticancer pharmacological approaches ( mainly drugs) have revolutionized greatly in the past 20 years [3,4].Many therapeutic protocols have paved the way for efficient drug design, delivery, and efficiency.Epirubicin, dasatinib, doxorubicin, mitoxantrone, benserazide, topotecan, paclitaxel, etc, are the most popular and widely used anticancer drugs [5].
Since from mid-20th century, tumor virology has had its major importance in cancer research and we can say that in the 21st century, tumor virology will carry on with a partnership in cancer research efforts [6].Solid tumors account for more than 85% of all human cancers.Traditional cancer treatments may have unintended side effects on tumor cells by reducing their blood supply.However, there is only weak evidence for this impact, at least when high intermittent chemotherapy dosages are used.Some of the physiological characteristics of tumors, including the interstitial space, interstitial fluid pressure, tumor cell density, and micro-vessel density, are dynamic and fluctuate over time [7].They may also be impacted by drug-induced apoptosis or necrosis.Interestingly, several tumor biological variables are interconnected and dependent upon one another [8].
The anticancer drug development process frequently starts with a promising target; nevertheless, there are various reasons why the result for a specific cancer target may be unsatisfactory [9].Drugs are frequently quite pricey.Furthermore, as compared to medications used for other therapeutic purposes, they frequently have unfavorable side effects, little impact on survival, and/or low response rates.As a result, they can encounter obstacles to payment in healthcare systems that are becoming more and more cost-constrained.Taking an overdose of too much quantity of the drug or any drug dose without a doctor's advice can also cause many side effects or serious problems, so taking advice from a doctor or nurse before taking the drug is very important.Following all the precautions before taking the drug must be one's responsibility.Using drugs on the patient's body by the doctor or a nurse is very difficult without any suitable analytical methods.Some main side effects that a person can face after the treatment of cancer are constipation, anemia, diarrhea, fatigue, appetite loss, delirium, bleeding, and bruising [10].Different types of chemotherapy can cause hair fall and the drugs used to treat cancer can cause a problem with their remembering and thinking power.

Analytical approaches for anticancer drug detection
Different kinds of analytical methods are used for the determination of anticancer drugs.As a result, the requirement for analytical techniques to identify anticancer medicines is of paramount significance [11].The initial techniques for cytotoxic substance analysis were based on liquid chromatography with UV detection.For the examination of samples containing high quantities of target pharmaceuticals, these approaches demonstrated satisfactory quantitative performance.LC-UV has many advantages, but it also has some limitations and disadvantages.These include limited specificity, low sensitivity for some compounds, lack of structural information, limited selectivity, interference from matrix components, and limited wavelength range.These limitations can be problematic when analyzing complex samples with overlapping peaks or co-eluting compounds.However, a sample preparation step allowing a pre-concentration of target compounds must be applied before the LC-UV analysis in the case of samples containing low amounts of cytotoxins.Mass spectrometry's great selectivity and sensitivity transformed the entire analytical process in the 1990s by streamlining and shortening the sample preparation phase [12].LC-MS systems are expensive to buy, run, and maintain, and they require specific knowledge and skills to set up, run, and interpret the data.It needs appropriate calibration, optimization, and troubleshooting and includes the integration of two difficult methods, liquid chromatography, and mass spectrometry.The creation of methods can be time-consuming and difficult, and susceptibility to matrix effects can be decreased.Instrument maintenance and troubleshooting can take time and may necessitate specialized knowledge.Data complexity and analysis need modern software and mass spectrometry data processing capabilities.Today, LC-MS is unquestionably a technique option for analyzing anticancer medications with really alluring analytical results [13,14].
Voltammetric methods are electroanalytical techniques that are used to investigate and quantify the electrochemical behavior of analytes in solution.Cyclic Voltammetry (CV), Differential Pulse Voltammetry (DPV), Square Wave Voltammetry (SWV), Linear Sweep Voltammetry (LSV), and Stripping Voltammetry (Anodic Stripping Voltammetry, ASV and Cathodic Stripping Voltammetry, CSV) are all common voltammetric procedures.These techniques give useful information on analytes' redox characteristics, kinetics, and concentration, making them effective instruments in electroanalytical chemistry.Voltammetric techniques are employed by inorganic, physical, and biological chemists for a variety of reasons, such as basic research on redox processes in different mediums, adsorption kinetics of the interfaces, mechanisms governing electron transfer reactions, the kinetics of these processes, and the transport, speciation, and thermodynamic characteristics of solvated species [15,16].Several dissolved inorganic and organic chemicals may be quantitatively determined using voltammetric methods [17].With a wide range of temperatures, a quick analysis time, the ability to determine multiple analytes simultaneously, the capacity to assess kinetic and mechanistic criteria, a well-developed theory, and the simplicity upon which various potential waveforms can be obtained and minimum currents recorded, they have excellent sensitivity [18,19].These methods when combined with HPLC, are powerful instruments for the investigation of complicated mixtures.
1.2.Ionic liquid as potent material in pharmaceuticals Ionic liquids (Ils) typically consist of two asymmetrical ions with different charges, usually bigger organic cations and smaller anions, that only loosely bond together.Sometimes they are also classified as those substances that are entirely made up of ions with a melting point lower than 100 °C [20].In these salts, the ions are poorly coordinated due to this reason ionic liquids are liquid at temperatures below 100 °C and room temperature [21].These substances are variously called liquid electrolytes, ionic metals, ionic fluids, fused salts, and liquid salts.Ils have many different and useful properties, some of them are chemical stability and thermal stability high, vapor pressure low, less combustibility, eco-friendly, and have different solvating properties for several polar and nonpolar compounds [22,23].They are characterized by high transparency and are insusceptible to environmental conditions [24].With time, a huge variety of chemicals are also grown, so the Ils have been divided into many types including room-temperature Ils (RTIls) [25], task-specific Ils (TSIls), poly ionic liquids (PIls), and supported Il membranes (SIlMs).These types include composites of Ils supported on metal-organic frameworks (MOFs) and the hybrid organic-ionic character of Ils, as well as the intermolecular interactions that arise, give birth to a complex collection of events, making this an interesting as well as hard area of research [22].The RTIls are the most widely studied type of ionic liquids.To save time by making a certain process fast, scientists and engineers are frequently asked to find suitable Ils for making that process fast.Ils have various applications and many useful properties such as low vapor pressure, great thermal as well as chemical stability, low combustibility, environmental friendliness, and unique solvating capabilities for many polar and non-polar molecules [26].Ils have many potential applications that can be used as hydrogen fuel cells [27], solar cells for the next generation [28], and lithium batteries [29,30].
These new materials are organic compounds that have a wide range of applications in many different fields and have different properties they can be used as an industrial solvent, nuclear fuel radwaste, enzymatic catalysis, solar energy conversion, nanomaterials, batteries fuel cells, lubricants heat transfer, etc If we add Ils to resins then we can use them as an antistatic agent [31].They can be utilized in high-temperature procedures since they are inert and have high heat resistance [32].They're also known for their exceptional transparency and resistance to environmental changes.
Ils attracts interest as a 'solvent' in pharmaceutical manufacturing [33].These ionized salts are commonly dispersed poorly into the lipid membranes.In the pharmaceutical sector, Ils is being examined as an alternative to organic solvents.Ils have many unique properties that make them very useful as a green tool in drug detection [34].There are several advantages of Ils in drug detection such as the extraction of drugs from organic or natural products.Pharma manufacturing industries face many problems but one of the commonly faced problems that they have to overcome in their procedure is the purification and separation of both the water-dissolved and water-undissolved reaction components.In this case, Ils play the main role as a desirable solvent used to dissolve compounds as these ionized salts have very high stability and low volatility [35].Ils may create biphasic systems with a variety of conventional organic solvents, which frequently enables straightforward separation of reaction products using Il layer extraction.The ionic nature of Ils also enables the immobilization and recycling of a variety of catalysts inside the Il.The lowest possible environmental impact, noticeable job specialization, and a wide variety of applications in electrochemistry, separation, extractions, solvent, and catalysts, analytical, physical, synthetic, biological, engineering chemistry, and other fields widen the horizons for the widespread utilization of Ils.

Role of carbon-based electrodes in electrochemical studies
Several papers in physical chemistry deal with electrochemistry.Adams′ initial application [36] of a CPE demonstrated the idea of a paste consisting of carbon particles and an organic liquid.Combining conductive graphite powder with a pasting liquid produces a CPE as shown in figure 1.The electrode's sensitivity diminishes as the pasting liquid concentration increases.Even the carbon before mixing is heated at a high temperature followed by sterilizing its pores using ceresin wax, hydrogen reduction, or nitrogen saturation to remove adsorbed electroactive species, primarily oxygen [37].Thus, these electrodes are simple to make and offer a readily renewable electron exchange surface.
CPEs are a sort of heterogeneous carbon electrode that comes in many different shapes and sizes depending upon the graphite to liquid ratio [38].The most typical application for these electrodes is voltammetry, but carbon paste-based sensors can also be used for coulometry [39] and amperometry [40].
CPEs are popular because they are affordable and may be used to manufacture electrode materials that have been altered with a mixture of chemicals to give the electrode pre-determined characteristics.When compared to solid graphite or noble metal electrodes, CPEs have low background currents.Further, an important aspect of these types of electrodes is that they have a lipophilic nature [41].The primary goal of electrode modification is often to create a qualitatively new sensor with desired, frequently predetermined qualities.Regarding this, carbon paste surely ranks among the materials that are most practical for making modified electrodes.The electrode can be modified by mixing the modifier along with the preparation of the CPE or by electrode immobilization (electrochemically or by various other surface modification techniques [42].The modification allows the accumulation of the analyte concentration at the electrode interface, thereby enhancing the electrochemical properties.These types of modified electrodes are very selective for both inorganic and organic electrochemistry.
Apart from having virtuous electrochemical properties, CPE is inexpensive and non-toxic and thus is used as an anode material.CPEs have a wide potential range for different reactions and also have high melting points and methodical conductors.It has very low resistance and the cost of carbon paste electrodes is much less than miniaturization [43].
But the electrode surface has to be renewed manually which is a major concern while using CPEs [44].Therefore, the biggest disadvantage of CPEs, which limits their applicability in practical analysis, is that success in working with CPEs depends on the experience of the user.In contrast to commercially available solid electrodes for which basic electrochemical characteristics are comparable for almost all products from each manufacturer, each carbon paste unit is an individual, where the physical, chemical, and electrochemical properties may differ from one preparation to another [45].Due to this reason, each study must be rectified individually.While this may not be an issue in a research environment, it would be a considerable burden in production service.

Ionic liquid-modified CPE
Carbon has some properties like innocuous, and good electrochemical characteristics and is also not that expensive this carbon is used as an anode [46].Modified carbon paste is commonly a mixture of non-electrolytic binder and graphite in a powder form.Il plays an important role as a binder in the modification of the CPE [47].Ils can be used to replace traditional non-conductive binding liquids (such as liquid paraffin, mineral oil, and polymerizable compounds) for the construction of CPEs [48].This replacement increased conductivity and this novel electrode demonstrated an excellent enhanced conductivity and significant current response from electroactive substrates.These modified CPEs are widely applicable in the electroanalytical community [49].In this way, Ils plays the role of an excellent binder [50].Ils are fascinating materials for electrochemical detection because of the following distinctive qualities: a wide electrochemical potential window even greater than the majority of aqueous electrolytes (about 4.5 V), greater conductivity, and thermal stability [25,34,51].Because of their strong solvating characteristics, they may also be used as a dispersant for other materials, such as carbonbased particles, to make homogeneous and consistent electrode combinations [52].They also have a very low vapor pressure due to this they are non-flammable, and have low toxicity, Ils are attractive alternatives to organic solvents for electrochemical applications [53].
Also having low volatility enables the study of their surface morphology using electron microscopy techniques and it has been observed that the Il modified electrode surface is smooth consisting of high surface homogeneity [54].This leads to the accumulation of analyte at the electrode surface, thereby increasing the electrode sensitivity [37].Therefore, Ils can be used as an electrolyte in a variety of electroanalytical procedures, including CV, chronoamperometry, and stripping voltammetry, for sensing, electrolysis, batteries, fuel cells, corrosion, etc [55].They show several benefits over acid-aqueous solutions and other techniques for creating smooth or mirror-like surfaces, which are necessary for a variety of applications [56].The non-volatility along with wide polarizability, excellent solvating properties, and high conductivity makes Il an attractive class of material for CPE modification [57].Due to ion pairing, ion aggregation, or reduced ion mobility brought on by bigger ions, the conductivity of Ils is lower than that of concentrated aqueous electrolytes.However, compared to organic electrolytes, they have a high conductivity.Their role in enhancing ionic conductivity has been investigated by Maleki et al [58], in 2007.They studied the effect of two Ils n-octylpyridinum hexafluorophosphate and 1-octyl-3-methylimidazolium hexafluorophosphate for the electrocatalytic activity towards the Fe(CN) 6 3-/ 4-.It was discovered that the binder's (Il) ionic conductivity increased electrocatalytic activity and lowered charge transfer resistance.For evaluating whether aromaticity had any strong influence on an increase in the charge transfer process they used anthracene as a binder instead of Il, but they discovered no prevalent effect.They concluded that, rather than the aromaticity of the cationic component of the ionic liquid, ionic conductivity plays a significant influence in the electrocatalytic activity.Various methods have been employed to modify CPE using Il as discussed previously such as electropolymerization, drop casting, addition as a binder, and as a solvent.
Out of these, the most common is the hand mixing of graphite powder and the Il is the most employed technique.The presence of Ils at the interface affects the mechanism of electrode processes at the modified electrode by forming droplets or films.They produce hydrophobic coatings throughout the electrode surface in an aqueous solution, also increasing their durability [59].This behavior can also be observed in CPE including Il as a binder.Apart from this, Il-modified electrodes show high stability as most of the Ils employed for electrocatalytic work are hydrophobic [60].Both Faradaic and capacitive currents are observed to increase at Il modified CPE.The increase in Faradaic current is caused by to presence of ion-exchange capabilities of Il which is responsible for the higher ionic conductivity with increased electroactive surface area [61].At the same time, the capacitive current is enhanced by the electron transfer occurring between the carbon particles in contact with the Il [62,63].Because of the ease with which they can be made, the rising availability of Ils, and the constant fall in their price, the latter electrodes are becoming increasingly popular [64].However, one of the major drawbacks of these electrode materials is enhanced signal-to-noise ratio due to increased Faradaic current [65].
Due to their high viscosity, they are used as a binder in the preparation of Il-modified CPE but the high viscosity of Ils as electrolytes may slow down mass transfer, although this can be mitigated by adding a cosolvent [66].
By changing the cations and anions, it is possible to greatly customize the properties of Ils.Additionally, their miscibility with other solvents can be managed by switching the cations and anions.From the perspective of electrochemical sensing.In this way, the hydrophobicity of Ils, lower conductivity, and various other properties, may be altered by the kind of forming ions and the length of the organic cations' alkyl chains.

Anti-tumor drugs
Anti-tumor drugs are the type of anticancer drug that inhibits cell growth by interfering with DNA, the genetic substance of cells, and also stop abnormal cells.The antitumor antibiotics must be able to either stop or slow down the growth of the tissues which is not normal because having a tumor is one of the primary causes of cancer, so we can say that, the anti-tumor drugs are used for the treatment of cancer and also shows a good result towards the treatment of the cancer in the human body [67].Chemically, antitumor medications include a broad variety of substances, including tiny molecules, peptides, antibodies, and therapies based on nucleic acids.These substances can influence cancer cell growth inhibition and cell death (apoptosis) through a variety of methods.They can interfere with crucial cellular functions, block certain proteins or signaling pathways, activate the immune system, or specifically target DNA structures [68].
Another major classification method of anticancer drugs is based on the mechanism of action and includes basic four classes [69].
Alkylating agents are a kind of anticancer medication.These medications function by introducing alkyl groups into DNA, which can disrupt replication and trigger cell death.Cyclophosphamide, cisplatin, and temozolomide are examples of alkylating agents [70].
Antimetabolites are another kind of anticancer medication.These medications function by interfering with the production of nucleic acids, which are required for DNA replication.Methotrexate, 5-fluorouracil, and gemcitabine are examples of antimetabolites [71].
Topoisomerase inhibitors are a third kind of anticancer medication.These medications function by interfering with the enzymes responsible for DNA replication and cell division.Etoposide, irinotecan, and doxorubicin are examples of topoisomerase inhibitors [72].
Microtubule inhibitors are a fourth class of anticancer medicines.These medications act by interfering with the production and function of microtubules, which are required for cell division.Paclitaxel, vinblastine, and colchicine are examples of microtubule inhibitors [73].
Broadly based on the chemical nature of the anti-tumor drugs we can classify them into the following four types:

Metal-based drugs
Metal-based anti-tumor drugs typically contain a metal ion, such as platinum, gold, or ruthenium, which is coordinated to one or more ligands that help to direct the drug to its target within the body.These drugs work by forming covalent bonds with DNA molecules in cancer cells, which ultimately leads to DNA damage and cell death [74].
Ever since the antitumor capability of cisplatin was discovered, a lot of research has been put into creating metal-based anticancer drugs that could be used in cancer treatment.Metal-based anti-tumor medications are significant because they can specifically target cancer cells while causing the least amount of harm to healthy cells.They are a viable option for treating cancer with fewer side effects than other chemotherapy medicines.In the last 40 years, a lot of research has been done in vitro and in vivo on a large number of metal complexes, and some of them were at different stages of clinical tests [75].The most studied metals in these complexes are platinum (Pt II and Pt IV), gold (Au I and Au III), ruthenium (Ru II and Ru III), and titanium (Ti IV) [76].On the other hand, they might be hazardous to the body.Platinum-based complexes, such as cisplatin and carboplatin, can, for example, induce kidney damage, hearing loss, and peripheral neuropathy [77].Gold-based complexes have been reported to induce skin rash, liver damage, and bone marrow suppression.While ruthenium-based complexes can cause gastrointestinal toxicity, neurotoxicity, and bone marrow suppression [78].Overall, the chemistry of anti-tumor medications based on metals is complicated and multidimensional, having both helpful and potentially detrimental consequences.Ongoing research in this area is aimed at generating safer and more effective medications that will improve tumor treatment outcomes while preventing unnecessary damage.

Anthracyclines
When compared to other anticancer drugs used in oncology, anthracyclines have the widest range of therapeutic uses.Anthracyclines are antitumor antibiotic medications derived from the bacterium Streptomyces.They function by causing DNA damage to cancer cells thereby inhibiting their ability to replicate.However, each has a slightly distinct chemical makeup.Doctors choose anthracycline drugs depending on the class of cancer cells they want to combat and the required potency of the drugs [79].Several mechanisms may be affected by anthracycline medications, including Free radical formation, direct membrane effects, lipid peroxidation, and enzyme interactions are reliable sources.The common types of drugs belonging to these are daunorubicin, doxorubicin, epirubicin, mitoxantrone, valrubicin, idarubicin, etc [80].Anthracyclines are often used in combination with chemotherapy treatments, even though their side effects are well known and include damage to the heart and a decrease in the number of blood cells [81].Anthracyclines like doxorubicin, epirubicin, and daunorubicin are still some of the most effective cancer drugs for treating a wide range of solid tumors and blood cancers.Chronic use of anthracyclines can cause cardiomyopathy and congestive heart failure, which are usually hard to treat.So far, no anthracycline equivalent has been shown to work better than doxorubicin.Anthracycline liposomal formulations are currently the best-known way to improve the index and spectrum of action of regular anthracyclines with less cardiotoxicity [82].The existence of quinone moiety in the structure of anthracycline rings is of great clinical value as it takes part in redox reactions that lead to highly reactive chemical species, which are mainly considered the cause of anthracycline-induced cardiotoxicity [83].
Here in the current section, we have described the role of ionic liquid in the detection of some of the commonly employed anthracyclines for the anti-tumor role.

Epirubicin
Epirubicin (having molecular formula C 27 H 29 NO 11 ) belonging to the anthracyclines family is a cancer chemotherapeutic medication comparable to doxorubicin that is used in combination with other anticancer agents to treat breast cancer [84].This medicine is indicated for people with breast cancer who have had surgery to remove the malignancy.It has fewer adverse effects than doxorubicin.Epirubicin is advised for patients suffering from breast cancer this surgery helps to remove the tumor.The symptoms include nausea or vomiting, low blood counts, and hair loss, epirubicin's most serious adverse effect.As a result, this medicine, in the right dose or advised amount of this drug in satisfactory quantity is essential in the treatment of breast cancer [85].The redox reaction of epirubicin is shown in figure 2.
CPE was modified by using hand mixing of CoFe2O4 NPs along with 1,3-dipropyl imidazolium bromide (DPIMB) for the determination of epirubicin [86].The authors have shown using CV that the presence of DPIMB alone at the CPE gave a higher peak current when compared to CoFe2O4 NPs present alone at the CPE.When both are present in combination peak current is even raised to a higher value indicating their synergistic behavior towards the electro-oxidation of epirubicin.This signified that DPIMB enhanced the surface area for faster electron transfer while metal oxide NPs provided the electroactive sites.Therefore, along with iron oxide with Co acted as a co-catalyst which enhanced the reaction process.Their prepared modified electrode showed good sensitivity (0.1426 A M −1 ) and selectivity along with a lower detection limit (10 nM).Even in the biological conditions, the modified electrode demonstrated highly catalytic activity for the electro-oxidation of epirubicin.Similarly, iron oxide in different oxidation states was used along with SWCNT with a different ionic liquid, 1-methyl-3-octyl imidazolium chloride, MOIC [87].The active surface area evaluation of different modified electrodes shows the highest area in the case of Fe 3 O 4 /SWCNT/MOIC /CPE (0.1835 cm 2 ) than the Fe 3 O 4 /SWCNT/CPE (0.1632 cm 2 ) and MOIC/CPE (0.1702 cm 2 ).This is indicative of the fact that the presence of MOIC is mainly responsible for the increase in the surface area.However, the presence of SWCNT further enhances the surface area.This has been further supported by the CV analysis which shows an increase in peak current in the following descending order: This shows that the surface area provided by the synergic combination of MOIC and SWCNT along with electroactive sites production by Fe 3 O 4 is mainly responsible for the lower detection limit (7 nM) of the prepared Fe 3 O 4 /SWCNT/MOIC/CPE.The presence of similar kinds of biological analytes (dasatinib, phenylalanine, methionine, abemaciclib, alanine, and anastrozole) also did not interfere with the working of the prepared sensor.Even real sample analysis of the prepared sensor using pharmaceutical injection and serum samples gave highly satisfying results.

Doxorubicin
Doxorubicin having molecular formula C 27 H 29 NO 11 is an anticancer drug that belongs to a family of medications known as anthracyclines, which are generated from bacteria of the genus Streptomyces [88].Doxorubicin is very helpful in the treatment of different hematopoietic malignancies and tumors.This drug is most commonly used for the treatment of blood cancer, the lymph system, bladder, lungs, breast, ovaries, stomach, kidney, nerves, and soft tissues, like muscles and tendons.Doxorubicin was introduced as a beneficial anti-cancer drug that is commonly used for the treatment of breast cancer [89].This drug also has some serious side effects, like irreversible cardiotoxicity, and gonadotoxicity.Doxorubicin also causes chromatin damage by evicting histones from specific locations in the DNA [90].According to the research, the results show that they are highly active toward different types of tumors [91].The redox reaction of doxorubicin is shown in figure 3.
Fe 3 O 4 @Au-rGO nanocomposite (FAG) along with n-butyl-3-methylimidazolium-hexafluorophosphate (BMIHF) modified CPE has been tested for selective determination of doxorubicin [82].To compare the properties and superiority of this modified electrode combination authors had prepared other electrodes such as bare CPE, FAG/CPE, and BMIHF/CPE.Their CV analysis showed the quasi-reversible nature of the doxorubicin at the electrode surfaces with peak current in the following decreasing order: Even the same trend was followed by the active surface.This showed that the electrode surface was enhanced by the BMIHF which is further responsible for the increase in the conductivity.Therefore, FAG/ BMIHF/CPE showed the highest peak current with the highest surface area (0.34 cm 2 ) with a detection limit of 1.7 nM.
Another combination consisting of the nitrogen-doped reduced graphene sheet (NGS) along with MOIC was also tested for simultaneous detection of doxorubicin and topotecan [92].They also studied the effect of NGS, and MIOC individually as well as in combination at the CPE using CV.They concluded that the combination of NGS and MIOC at the electrode surface showed a 4.86 times enhancement in the peak current when compared to the bare CPE which is highest when compared with individually modified CPE.In the presence of topotecan, the combination electrode showed high selectivity towards doxorubicin.The real sample analysis using serum and injection samples gave excellent and satisfactory results.This electrode combination gave a detection limit of 3.1 nM.
Doxorubicin has also been detected along with dasatinib at ZnO and 1-butyl-3-methylimidazolium tetrafluoroborate (BMIF) modified CPE [93].The authors prepared several combinations of electrodes (ZnO/ CPE, BMIF/CPE, CPE) to compare the properties of the combination electrode (ZBMIF/CPE).CV showed that the ZBMIF/CPE showed 5, 1.54, and 2 times increase in oxidation peak current when compared to CPE, BMIF/ CPE, and ZnO/CPE respectively.Additionally, the ZBMIF/CPE two distinct oxidation signals for the simultaneous detection of dasatinib and doxorubicin indicate good sensitivity.This electrode with ZBMIFmodified CPE gave detection limits of 9 nM and 300 nM for doxorubicin and dasatinib respectively.Using real samples ( injection and serum sample ) with ZBMIF/CPE gave good recoveries (>98%).
Even Cu-CNT composite along with EMITFB has been employed as a modifier at the CPE by by M. Fouladgar [94].The author prepared three different combinations of CPE Cu-CNT/CPE, EMITFB/CPE, and Cu-CNT/ EMITFB/CPE along with bare CPE.These electrodes have been analyzed based on the surface area for the analysis of the electrocatalytic activity of the individual component.Based on surface area analysis the author found the following decreasing order: These results were in consideration with the electrocatalytic activity of the prepared electrodes as per CV analysis.Hence, it can be concluded that the highest catalytic activity for the doxorubicin at the Cu-CNT/ EMITFB/CPE is due to the higher surface area provided by the EMITFB and catalytic activity of the Cu-CNT composite.Further, this electrode combination gave a good detection limit of 6 nM with excellent selectivity in the presence of another major anti-cancer drug 5-FU.

Daunorubicin
Daunorubicin is an anthracycline-based antibiotic used in cancer treatment, similar to doxorubicin.It slows down the growth and movement of cells.Daunorubicin stops the growth of Gram-positive bacteria and mycobacteria but is very effective against Gram-negative bacteria.It is also used as the starting point to make some other anthracycline drugs (doxorubicin, epirubicin, idarubicin, etc) [95].The daunorubicin molecule has tetracyclic anthraquinone aglycone of daunorubicinone connected to amino sugar daunosamine through a glycoside bond.some of the common side effects of this drug include nausea, vomiting, diarrhea, stomach pain, and red urine [96].The redox reaction of daunorubicin is shown in figure 4.
A combination of 1-butyl-2,3-dimethylimidazolium tetrafluoroborate (BDMITF) with noble metals (Pt and Pd) along with NiO 2 and SWCNT have been employed for the determination of the daunorubicin [97].Different combinations of electrodes as discussed in table 2 have been separately prepared and studied for their specific function in the electrochemical oxidation of daunorubicin.CV (figure 5) and specific surface area analysis show that ionic liquid, BDMITF enhances the surface area of the modified electrode which helps in faster electron transfer while in combination with SWCNT, both acts synergistically, thereby further enhancing the surface area.There is 9.8 times increase in the peak current with the modified electrode Pt/Pd/NiO/SWCNTs/BDMITF/CPE when compared to the bare CPE.But Pt/Pd/ NiO/SWCNTs modified CPE and BDMITF modified CPE shows 5.19 and 6.5-times current increase respectively Also, there is a reduction in the peak potential with each modification but a vast difference is found in the case of Pt/Pd/NiO/SWCNTs/ BDMITF/CPE.This event shows that Pd and Pt acted as co-catalysts for the electro-oxidation process.The modified electrode shows good sensitivity and selectivity with a detection limit of 3 nM.Even real sample analysis using pharmaceutical serums and injection samples in the presence of Tamoxifen showed recovery > 96.86%.
Another ionic liquid, 1-methyl-3-octyl imidazolinium chloride (MOIC) has been reported to determine daunorubicin along with SnO 2 /N-doped graphene quantum dot (SnO 2 /NGQ) at the CPE surface [98].This prepared MIOC/ SnO 2 / NGQ/CPE was compared with the bare CPE, SnO 2 / NGQ/CPE, and MOIC/CPE using CV.The electrodes showed an increased peak current:   The combination electrode not only showed the highest peak current but also showed the lowest electrode potential among all (380 mV).Therefore, the electrode showed high sensitivity and selectivity with a detection limit of 0.4 nM.In the presence of other anti-cancer drugs, the electrode gave good recoveries.

Mitoxantrone
Mitoxantrone is an experimental anticancer medication identified within a group of related anthraquinone chemicals.It is less toxic and does not have that many side effects as compared to the other drugs.This drug is going to be very useful in the upcoming days for the treatment of cancer.Antitumor antibiotics are derived from natural compounds generated by Streptomyces, a species of soil fungus [99].These medications are cell-cycle specific because they work at several stages of the cell cycle.The drug also has many side effects that are harmful to the human body, so it is very important to talk with a healthcare professional before taking the drugs [100].The redox reaction of mitoxantrone is shown in figure 6.
A high-performance DNA biosensor was developed using ZIF-8 and 1-butyl-3-methylimidazolium methane sulfonate as a novel analytical instrument to identify the anticancer medication mitoxantrone [101].The inclusion of ZIF-8 aids in high ds-DNA loading and enhances the sensor's performance under ideal circumstances.Additionally, the BMIMS served as a conductive binder to increase the sensitivity of the sensor for the measurement of trace levels of the anticancer medication mitoxantrone.Additionally, the DNA/ BMIMS/ZIF-8/CPE method for determining the nanomolar concentration of mitoxantrone was effective.

Pyrimidine and purine-based
pyrimidine shares many properties similar with pyridines and is considered one of the most privileged scaffolds in chemistry [102][103][104][105][106][107][108][109][110].Several drugs made from purines and pyrimidines have been shown to disable cancer cells in leukaemia, solid tumors, and lymphomas.Pyrimidine is an important structure found in naturally produced nucleotides and its anticancer properties are being studied.Six-member rings like pyrido and quinazoline showed less anticancer activity than five-member rings [111].Pyrimidine substitutes work as anticancer drugs by blocking kinase, stopping the cell cycle, turning on oncogenes, lowering the membrane potential of mitochondria, increasing ROS, and causing apoptosis.Common examples of pyrimidine-based anticancer drugs include cytarabine, capecitabine, fluorouracil, and gemcitabine [112].Purine-based drugs have a similar chemical makeup to adenosine or deoxyadenosine but differ in how they work with enzymes involved in purine metabolism.They compete with normal nucleosides and interact with intracellular targets, causing cytotoxicity and apoptosis [94].Common examples of purine-based anticancer therapeutics include mercaptopurine, thioguanine, clofarabine, azathioprine, fludarabine, etc [113,114].
Here in the current section, we have described the role of ionic liquid in the detection of some of the commonly employed pyrimidine-purine-based anti-tumor drugs.
4.3.1.5-fluorouracil 5-fluorouracil (5-FU) is one of the most popular antimetabolite chemotherapy drugs in recent years.Structurally, 5-FU is a derivative of uracil and is a weak acid (pK a = 7.6) with the presence of the fluorine atom in place of hydrogen at the C-5 with a molecular weight of 130.08 g mol −1 [115].Since 5-FU is a water-soluble medication, it is given intravenously for faster distribution and triphasic elimination [116].In the treatment of several malignancies, including colorectal, breast, head and neck, pancreatic, and stomach cancers, it has been employed as a first-line antineoplastic drug.It has been used as an anti-tumor agent alone or in combination with other drugs synergistically [117,118].However, its efficacy in cancer treatment is constrained by its poor bioavailability, brief half-life (almost half an hour), low bioavailability, significant cell toxicity, and insufficient selectivity for malignant cells [119].Research teams have concentrated on creating innovative 5-FU delivery methods that can lessen the cytotoxic effects of anticancer drugs on healthy tissues to overcome the drawbacks of 5-FU and improve its chemotherapeutic efficiency [120].However, evaluating its concentration in biological samples is necessary to study toxic effects using electrochemistry offers several advantages [121].The redox reaction of 5-FU is shown in figure 7.
Emamian et al [122] have employed the graphene quantum dots (QD) and ionic liquid, 1-butyl pyridinium bromide (BPB) modified CPE for the determination of 5-FU.They have studied the electro-oxidation of 5-FU using four different electrodes: QD/BPB/CPE, BPB/CPE, QD/CPE, and only CPE.They observed the highest oxidation current at the QD/BPB/CPE followed by the BPB/CPE, QD/CPE, and CPE.But the almost similar active surface area in the case of QD/BPB/CPE and QD/CPE (0.26 cm 2 ) while 0.27 cm 2 in the case of BPB/CPE which is approximately 1.29 and 1.25 times higher than the CPE.Similarly, they compared the oxidation potential values based on the SWV and found the lowest oxidation potential in the case of QD/BPB/CPE and the highest in the case of QD/CPE and CPE.Combining all the parameters they concluded the higher performance of the QD/BPB/CPE with a detection limit of 5 nM.Further, we can say that the QD provided the higher catalytic activity (due to higher oxidation current value) for the electrochemical oxidation while the BPB provided the exposure of maximum electro-active sites which further enhanced the oxidation current and led to the higher sensitivity of the combination electrode.
Shojaei et al [123] used zinc ferrite (ZF) in combination with 1,3-dipropyl imidazolium bromide (DPB) for sensing 5-FU at the CPE.Here the DBP acts as a conductive binder and a surface enhancer agent.The authors have evaluated the surface area of the CPE, ZF/CPE, DPB/CPE, and ZF/DBP/CPE using the Randles-Sevcik equation and found the surface area in the following decreasing order: The authors have seen a slight increase in current at the DPB/CPE when compared to ZF/CPE but a much larger increase in the peak current ZF/DBP/CPE when compared to both.This shows that the ZF provided the electroactive sites which enhanced the conductivity but the presence of DPB further enhanced the surface area for faster electron transfer which is mainly responsible for the excellent electrocatalytic performance of the ZF/ DBP/CPE.This has been further supported by the obtained Nyquist plots which show semicircular radius in the following decreasing order: This confirms that the ZF/DBP/CPE shows the minimum charge transfer resistance.This prepared sensor not only shows good electrocatalytic activity but also shows good sensitivity, selectivity, and reproducibility.Also, real sample testing with the prepared sensor using biological and pharmaceutical samples gives reliable results.
Zhan et al [124] modified CPE using 1-butyl pyridinium hexafluorophosphate (BPHFP).The authors observed irreversible behavior of the 5-FU at bare CPE and modified electrode.At the BPHFP/CPE, the high value of peak current has been observed, suggesting high accumulation due to a large active surface area leading to faster electron transfer.This electrode even indicated high antifouling properties with a lower detection limit of 13 nM.Real samples analysis using injection samples of the sensor gave satisfactory results.CuO-CNT along with 1-ethyl-3-methylimidazolium tetrafluoroborate (EMITFB) at CPE has also been used to detect 5-FU [64].The electrode oxidized 5-FU at the potential of 970 mV.If we compare the surface area of EMITFB/ CPE with CuO-CNT /EMITFB/CPE we can see only a slight increase in surface area which indicates the maximum contribution to the increase in surface area is due to EMITFB.The prepared sensor gave a detection limit of 4 × 10 3 nM.

Thioguanine
Thioguanine is a purine-based medication with a structure similar to guanine.The main difference is that in thioguanine, the oxygen atom of guanine is replaced by a sulfur atom, giving it new chemical characteristics and making it an efficient inhibitor of DNA synthesis and cell proliferation [125].It simply produces aberrant base pairs with cytosine during inclusion, which can induce DNA strand breakage and inhibit continued replication.This inhibits cell development and eventually leads to cell death.It is mostly utilized in the treatment of acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML).To increase its potency, it is frequently used with other chemotherapeutic drugs such as chemotherapeutic drugs such as methotrexate and mercaptopurine [126].Thioguanine, like other chemotherapeutic drugs, can have adverse effects such as bone marrow suppression, and gastrointestinal issues that must be carefully monitored.The redox reaction of thioguanine is shown in figure 8.
A combination of CuO and EMITFB has been used to detect thioguanine in the presence of 5-FU [127].Here the effect of different modifiers in the combination electrode has been analyzed using surface area and catalytic activity.The electrocatalytic activity has been studied using LSV by the author wherein the highest activity has been recorded for the CuO/EMITFB/CPE and lowest for the CuO/CPE excluding CPE.The active surface area at the CuO/CPE (0.31cm 2 ) and EMITFB/CPE (0.32 cm 2 ) does not show any significant variation when compared with CuO/EMITFB/CPE (0.33 cm 2 ), hence the electrocatalytic activity towards thioguanine of the combination of CuO/EMITFB/CPE is a result of synergy between the CuO and the EMITFB with a detection limit of 20 nM.In the presence of other drugs (5-FU) and other interferents, the electrode showed good sensitivity and selectivity towards thioguanine.
Similarly, by using MoWS 2 and N-(ferrocenyl methylidene) fluorene-2-amine (NFMF) as a modifier along with BPPF at the CPE.Somayeh Mohammadi et al [128] have detected thioguanine in the presence of folic acid.They have prepared three electrodes MoWS 2 /CPE, NFMF/CPE, and MoWS 2 /NFMF/BPPF/CPE for the analysis of electro-oxidation of thioguanine.Using, CV they found a significant increase in peak current at the MoWS 2 /NFMF/BPPF/CPE in comparison to the other two electrodes.Even the oxidation process occurred at very low potential at MoWS 2 /NFMF/BPPF/CPE (440 mV) in comparison to MoWS 2 /CPE (850 mV) and CPE (900 mV) but comparable to NFMF/CPE (440 mV).This signifies the potential role of NFMF in the electron transfer process which makes the oxidation of thioguanine easier at the MoWS 2 /NFMF/BPPF/CPE thereby giving a detection limit of 90 nM.Further real sample analysis using the pharmaceutical tablets (folic acid and thioguanine) and biological samples (urine and serum) using MoWS 2 /NFMF/ BPPF /CPE as the electrode material gave satisfactory recoveries comparable to HPLC analysis.Here, the authors have highlighted the role of NFMF as an electron mediator in detail but have not discussed the role of BPPF which may have further elaborated the reason for the higher peak current at the MoWS 2 /NFMF/BPPF/CPE.
Thioguanine has also been detected in the presence of other anti-cancer drugs such as 6-mercaptopurine and dasatinib by Maleh et al [129].Here the authors have modified the CPE using Pt and MWCNT along with 1-butyl-3-methylimidazolium hexafluoro phosphate (BMIHP) and studied the effect of potential and surface area.From table 1 and 2, we can clearly say that BMIHP mainly contributed towards the higher surface area in the case of Pt/MWCNT/BMIHP/CPE while Pt and MWCNT acted as a catalyst for mediating faster electron transfer, their synergistic combination enabled good electrical conductivity.Thereby, the electrode combination gave a very good detection limit of 9, 50, and 1 × 10 3 nM for mercaptopurine, thioguanine, and dasatinib respectively.Even real sample analysis of the modified electrode using pharmaceutical and biological samples gave good recoveries which were in consideration with the HPLC results.

Conclusion
Modified Carbon Paste offers versatility, adaptability, sensing and biosensing applications, downsizing and integration, and better performance in a wide range of electrochemical applications.CPE modification increases their capabilities and enhances their performance, making them useful instruments in a variety of sectors.Ionic liquids-modified Il/CPE are a promising area of research for the detection of anticancer drugs.For the detection of anticancer medicines in biological samples, these electrodes have demonstrated good electrochemical characteristics as well as high selectivity, sensitivity, and durability.
The ionic liquid not only enhances the surface area of the electrode but provides a variety of advantages at the electrode surface such as increased conductivity, hydrophobic-hydrophilic interactions, and enhanced ion exchange, due to the presence of charged species along with decreased charge resistance.Further, the combination of Ils and metal oxides or carbon nanotubes (CNTs) has been shown to enhance the electrocatalytic activity of Ils toward drug detection with lowered detection limits and high sensitivity.The combination of Ils along with nanoparticles enables overcoming the signal-to-charge ratio along with balancing the viscosity of the Ils.Ils provide a stable and conductive interface between the electrode and the catalytic material due to ring circulation enabling the decrease in resistance, while CNTs provide high surface area and facilitate charge transfer and other metal oxides provide electroactive sites for the redox reactions.Although a variety of classes of Ils have been extensively studied across the world, it can still be noticed that Ils containing imidazolium and pyridinium cations have only been studied for anticancer drug detection.Numerous other heterocyclic cations with varied chain lengths, such as piperidinium and pyrrolidinium, can be investigated and compared in this sector based on their electrochemical performance.This will undoubtedly contribute to a better understanding of Ils' catalytic behavior.Apart from that, Ils made from natural sources may be used, which may be a more environmentally friendly approach.
Future electrochemical approaches for anticancer drug detection employing Il/CPE are anticipated to make considerable strides.Here are a few probable developments in this area: • Creation of novel Il/CPE materials: To improve the sensitivity and selectivity of Il/CPE, researchers are looking into novel varieties of ionic liquids and carbon paste materials.The efficacy of the Il/CPE for detecting various anticancer medicines is expected to be enhanced by the development of novel materials with particular functional groups.
• Miniaturization and portability: Electrochemical sensors that are portable and small enough to be employed in point-of-care diagnostics are becoming more and more necessary.The Il/CPE-based sensors are being investigated for methods to make them portable and smaller so they may be utilized in distant areas and lowresource environments.
• Multi-analyte detection: Electrochemical techniques utilizing Il/CPE offer the ability to identify many analytes at once.Researchers are creating Il/CPE-based sensors that can concurrently detect many anticancer medications in a single sample.The effectiveness and precision of cancer detection and therapy will increase as • The integration of Il/CPE-based sensors with other technologies, such as microfluidics, nanomaterials, and machine learning algorithms, is being investigated by researchers.The sensors' performance will be improved by this integration, which will also make it possible to track anti-cancer medication in real-time in biological samples.
In conclusion, research in electrochemical techniques employing Il/CPE for anticancer drug detection is advancing quickly [130,131].This area has a bright future, and it is anticipated to substantially impact cancer diagnosis and treatment.

Figure 1 .
Figure 1.Showing mixing of various components for preparation of ionic liquid modified CPE.

Table 1 .
Different combinations of electrodes with their surface area, peak potential, and peak current.

Table 2 .
Different combinations of electrodes with their surface area and peak potential.Use in clinical practice: The early diagnosis and monitoring of cancer employing electrochemical sensors utilizing Il/CPE has the potential to be applied in clinical practice.These sensors are helpful in early diagnosis and therapy monitoring because they can identify minute quantities of anticancer medications in biological samples.