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. 2020 Oct 1;5(40):25582–25592. doi: 10.1021/acsomega.0c02438

The Role of Imidazolium-Based Surface-Active Ionic Liquid to Restrain the Excited-State Intramolecular H-Atom Transfer Dynamics of Medicinal Pigment Curcumin: A Theoretical and Experimental Approach

Swati Rani †, Damayanti Bagchi ‡, Uttam Pal §, Mamta Kumari †, Manisha Sharma †, Arpan Bera ‡, Javaid Shabir †, Samir Kumar Pal ‡, Tanusri Saha-Dasgupta ∥, Subho Mozumdar †,*
PMCID: PMC7557247  PMID: 33073084

Abstract

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The naturally occurring polyphenolic compound curcumin has shown various medicinal and therapeutic effects. However, there are various challenges associated with curcumin, which limits its biomedical applications, such as its high degradation rate and low aqueous solubility at neutral and alkaline pH. In the present study, efforts have been directed towards trying to resolve such issues by encapsulating curcumin inside the micelles formed by imidazolium-based surface-active ionic liquid (SAIL). The shape and size of the micelles formed by the SAIL have been characterized by using DLS analysis as well as TEM measurements. The photo-physics of curcumin in the presence of ionic liquid (IL) and also with the addition of salt (NaCl) has been explored by using different optical spectroscopic tools. The time-dependent absorption studies have shown that there is relatively higher suppression in the degradation rate of curcumin after encapsulation by the imidazolium-based SAIL in an aqueous medium. The TCSPC studies have revealed that there is deactivation in the nonradiative intramolecular hydrogen transfer process of curcumin in the presence of IL micelles as well as with the addition of salt. Furthermore, the time-dependent fluorescence anisotropy measurement has been carried out to figure out the location of curcumin inside the micellar system. In order to correlate all experimental findings, density functional theory (DFT) and classical molecular dynamics (MD) simulations at neutral pH media have been performed. It has been found that the van der Waals force of interactions plays a major role in the stabilization of curcumin in the micelles rather than the coulombic forces. It also has been observed that the van der Waals interactions remain unaffected in the presence of salt. However, as revealed by the MD simulation results, the micelles are found to be more compact in size after the addition of salt. The RMSD results show that the micelles formed by the SAIL achieve greater stability after a particular time constraint. Our results have divulged that the SAIL could act as a promising drug delivery system.

1. Introduction

Curcumin is a golden yellow naturally occurring polyphenolic compound extracted from the plant Curcuma longa.(1) Curcumin has gained immense attention over the last few decades due to its proven potent pharmacological effects, such as antioxidant, antimicrobial, anti-inflammatory, and anticancer actions; an antifungal; and Alzheimer’s disease.2−5 Additionally, it has been used as a remedy to cure various health conditions, such as metabolic syndrome, inflammatory conditions and pain, etc.6−10 The versatile activities of curcumin are mainly linked to the presence of extended conjugation in an alkene group and the presence of hydroxyl groups on the benzene rings and the diketone moiety (Scheme 1A).11 However, despite of having a wide range of biological activities, its clinical applications have been limited due to various challenges, such as high sensitivity towards light and oxidation, rapid metabolism and rapid rate of degradation in a neutral and basic medium, and low cellular uptake.12 Moreover, curcumin possesses major drawbacks due to poor bioavailability13 and very low aqueous solubility.14 It has been reported that the solubility of curcumin and the partition coefficient in the aqueous medium were found to be 0.6 μg/mL and 3.2, respectively.15 Curcumin exists in two forms namely the diketo form and the enol form that are interconvertible via keto-enol tautomerization, but the later one has been found to be more stable by the energy difference of 7.75 kcal/mol.16 The higher stability of the keto–enol form is due to the planar confirmation rather than the twisted conformation in the diketo form.17 In a report, Jovanovic et al. have proposed that the hydrogen atom present on the central methylene group of the diketone form has a potent tendency to deprotonate in radical reactions, potentially mediating its biological activity.18 Wang et.al have reported that deprotonation is the main reason for the degradation of curcumin in the aqueous medium.19 Therefore, its poor aqueous solubility and low bioavailability need to be ameliorated to let curcumin act as a potential drug. To overcome these challenges, various drug delivery systems, such as vesicles,20 proteins,21−24 micelles,25 hydrogels,26,27 liposomes,28 cyclodextrin,29 polymer conjugates,30 supra molecular assemblies,31 and nanoparticles32,33 have been used to encapsulate curcumin in order to improve its stability, bioavailability, and to enhance its aqueous solubility. However, utilization of micelle-based drug carrier systems has been generally preferred over the other particulate drug carrier system for the encapsulation of hydrophobic drugs due to their small size (∼10 to 50 nm) and comparatively increased bioavailability.34−36 In addition, micelles provide greater stability to the drug and protects the drug from the attack of outer inactivating species, such as enzymes in the biological fluid via incorporation.37,38 Various studies related to surfactant-based self-assembly have been reported for their prospective applications in the field of drug delivery.39,40 However, many of these conventional cationic and anionic surfactants, such as tetradecyltrimethylammonium bromide, sodium dodecyl sulphate (SDS), hexadecyltrimethylammonium bromide (HDTMA), etc.,41,42 are cytotoxic, and their toxicity depends on the length of the hydrocarbon chain and the presence of polyoxymethylene groups;43 hence, attempts could be made toward exploring the applications of surface-active ionic liquids (SAILs).42,44−46 The Ionic liquids (ILs) are a sort of material that shows excellent properties like high ionic conductivity, high thermal stability, high solvating power, low volatility, nonflammability, etc., and these properties could be easily tuned by perturbing the cationic and the anionic moieties.47 In past decades, ionic liquids (ILs) have achieved much attention due to their remarkable applications in the field of electrochemistry, organocatalyst, and drug delivery.48−53 The introduction of a long alkyl chain in the ILs can allow them to show surface active properties,54,55 and this class of ionic liquids is referred to as SAILs. In a similar manner to cationic surfactants, SAILs also have the capability to self-assemble.53,56−58 The imidazolium-based SAILs have been mostly used in biological applications because of their high solubility and strong interaction behavior with water molecules.59 Various studies have revealed that the imidazolium-based SAILs exhibit high surface activity as compared to traditional surfactant molecules and can be used as greener surface active agents in place of conventional cationic surfactants.60 Numerous reports have been published regarding the utilization of SAILs for the encapsulation of hydrophobic molecules/drug.61−63 Roy et al. have studied the effect of 5-methyl salicylic acid-induced thermo-responsive reversible transition in SAILs using coumarin 153 and rhodamine 6G (R6G) perchlorate as probe molecules through spectroscopy.64 Chowdhury et al. have synthesized a curcumin–ionic liquid complex (CCM–IL) through a freeze-drying process where the ionic liquid is composed of choline and oleic acid as a cation and anion, respectively.65 The complex has shown greater solubility (8 mg mL–1) and higher stability compared with free curcumin in an aqueous medium. The improved properties of the CCM–IL complex, such as solubility, stability, and activity have inspired us to study the interaction mechanism of ILs with the biologically efficient drug “curcumin”. However, the study of interaction of curcumin with surface-active ionic liquids (SAILs) by using optical spectroscopy combined with detailed theoretical analysis is still an area of research that needs to be explored.

Scheme 1. (A) Structure of Curcumin (Keto and Enol Form) and (B) Structure of Ionic Liquid (1-Hexadecyl-3-methylimidazolium Chloride).

Scheme 1

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In this work, self-assembling SAIL, 1-hexadecyl-3-methyl-imidazolium chloride ([C16mim] Cl) (Scheme 1B) has been used to encapsulate the curcumin molecules inside the micellar system. The curcumin–[C16mim] Cl micelles thus formed are characterized by using DLS analysis and TEM measurements. It is also more interesting to analyze the type of interactions that are playing a key role in stabilizing the curcumin molecules encapsulated by SAILs. To serve this purpose, different steady state and time-dependent spectroscopic studies like absorption, fluorescence, and TSCPC have been carried out. The time-dependent fluorescence anisotropy measurements have been performed to determine the location of the drug inside the micellar system. Furthermore, in order to understand all of the experimental findings in a more realistic way and the basis of interactions, DFT studies and molecular dynamics studies have been carried out in detail.

2. Results and Discussion

While dealing with the self-assemblies, it is very important to understand the structural aspects of the micelles that have been used as a carrier for drugs. SAILs have the tendency to form micelles beyond a certain concentration, and it can be that minimum concentration that can fine tune the stability and binding location of the drug molecule.

Curcumin-containing ionic liquid micelles were characterized with the help of DLS and TEM analyses (Figure 1A,B). Figure 1A depicts the results of the DLS measurements that gives the intensity vs size distribution histogram of [C16mim] Cl micelles with curcumin encapsulated inside. The average diameter of the curcumin-loaded [C16mim] Cl micelles was found to be about 38 nm. The size distribution in the DLS measurements clearly indicates the formation of micelles. DLS measurements can only provide information about the size and not much information about the shape and morphology of the nanocarrier system. In order to further get a direct indication about the formation of spherical micelles, the TEM measurement was conducted. Figure 1B represents the TEM images of curcumin-loaded [C16mim] Cl micelles, which showed that the micelles are spherical in shape. The size distribution histogram obtained from TEM images has been presented in Figure 1C, which shows that the average diameter of the micelles is around 39 nm. Therefore, the average diameter obtained from the size distribution histogram was in accordance with the DLS studies.

Figure 1.

Figure 1

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(A) Hydrodynamic diameter of curcumin-loaded IL micelles, and (B) TEM micrograph of curcumin-loaded ionic liquid micelles (the yellow circle represents the spherical micelles). (C) Size distribution histogram of curcumin-loaded IL micelles.

By studying the spectral properties of curcumin encapsulated inside [C16mim] Cl micelles, it is possible to understand the microenvironment experienced by the curcumin molecules inside the SAILs. Alterations in the spectral characteristics of curcumin in the presence of micelles could be monitored using steady-state UV–visible absorption spectroscopy. In pure water, curcumin displays a broad peak with maxima at around 430 nm, accompanied by a shoulder at around 355 nm. The peak at 430 nm denotes the lowest energy (π–π*) transitions of conjugated curcumin, and the shoulder band at 355 nm refers to the transitions (π–π*) involved in the feruloyl unit.66Figure 2A,B depicts the absorption and emission spectra of curcumin in the presence of the ionic liquid, respectively. When encapsulated inside the ionic liquid micelle, curcumin shows an absorption band at 426 nm with a shoulder at around 450 nm (Figure 2A). However, it can be clearly observed that the peak at 355 nm is absent (which is due to the interaction of curcumin with water molecules), suggesting a lack of interaction of curcumin with the water molecules in this environment. A similar type of phenomenon has been reported for interactions of curcumin with zwitterionic,67 cationic,68 anionic,61 and neutral micelles.69 A careful inspection of the absorption spectra reveals that it is very close to the UV spectra that were noticed inside TX-100,70 CTAB,71 Tween 20, Tween 80,72 DTAB,66 and several polymeric micelles, such as 2-ethyl-2-oxazoline-grad-2-(4-dodecyloxyphenyl)-2-oxazoline73 and Soluplus69 in methanol and DMSO.74 In the case of cationic and nonionic surfactants such as CTAB and TX100 micellar aggregates, the presence of a vibronic structure with the shoulder band could be seen, which suggests the lower level of interaction of the curcumin molecule with the water molecule.75 However, in the case of an anionic surfactant such as NaDc bile salts and SDS micelles, the shoulder band and less vibronic structure could be seen, suggesting the presence of curcumin on the outer surface of water where the chances of interaction of curcumin with water is more likely.75,76 Here, in Figure 2A, the peak at 426 nm and a shoulder band at around 450 nm suggests that the interaction of curcumin with the water molecules is minimal. Furthermore, upon increasing the concentration of [C16mim] Cl, a significant enhancement in the absorption intensity of curcumin could be observed. This substantial increment in the absorption intensity can be attributed to the presence of the micellar phase, and it indicates that the interaction between the drug and [C16mim] Cl micelles is large enough to partition curcumin molecules from the bulk water phase to the micellar environment. A careful look at the structure of curcumin reveals that it contains two hydrophobic aryl groups and a central hydrophilic β-diketone group that can interact with the hydrophobic and cationic part of the [C16mim] Cl ionic liquid through both van der Waals and coulombic interactions. In order to further confirm the interactions between a curcumin molecule and an ionic liquid molecule, we performed a molecular dynamics simulation in a water medium. It was observed that two types of interactions are possible: (1) Hydrophobic interaction with the long tail of the ionic liquid molecule (H-type aggregate); (2) coulombic attraction with the head group (J-type aggregate) (Supporting Information: Video S1 and Figures S8 and S9.

Figure 2.

Figure 2

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(A) Absorption spectra of curcumin in the presence of ionic liquid micelles (from 0 to 10 mM). (B) Emission spectra of curcumin in the presence of ionic liquid micelles (from 0 to 10 mM) (Inset: normalized emission spectra). (C) Pictorial representation of J- and H- aggregates of curcumin ionic liquid using density functional theory, and (D) absorption spectra of curcumin calculated from density functional theory.

Therefore, these two types of complexes were further optimized using density functional theory, and the ground state and excited state electron densities were probed (Figure 2C). While studying the interaction with the head group, ground-state electronic delocalization could be observed, suggesting the formation of a charge transfer complex (salt bridge). However, while looking at the interaction with the tail of the ionic liquid, no such electronic delocalization could be observed. The absorption spectra of pure curcumin and curcumin in the presence of ionic liquid could be calculated (Figure 2D), and the computed absorption spectrum of curcumin could show a very good match with the experimental absorption spectrum (Figure 2A, and Supplementary Figure S6). It could be observed that the computed absorption spectra of curcumin displayed very little redshift, and this was quite consistent with the experimental observations.

In order to reveal the excited-state dynamics of curcumin, it is necessary to measure its emission spectra. The emission spectra of curcumin were monitored at different concentrations of [C16mim] Cl (Figure 2B). Curcumin in an aqueous medium displays weak fluorescence with a broad peak at around 550 nm. However, with increasing the concentration of [C16mim] Cl, a remarkable enhancement in the emission intensity could be observed. Moreover, with increasing the concentration of IL, there is also a large blueshift (∼45 nm) in the emission maxima, which has been depicted through the normalized emission spectrum (Inset Figure 2B). The shift of 45 nm in the emission spectra could be due to the gradual incorporation of curcumin molecules from a much polar environment to the hydrophobic region of the micelles. The shift in the peak position of the fluorescence spectra is because of the fact that the local environment around the probe molecules is affected by various parameters, such as polarity, H-bonding ability, etc. In the present system, the presence of a long hydrophobic chain and ahydrophobic imidazolium ring could be the reason behind the accumulation of curcumin from the bulk water phase to the less polar site.

These observations could be further supported by the determination of solvent polarity parameter (ET (30)). The polarity parameter of probe molecules in different microenvironments could be evaluated by studying spectral features of a probe molecule in a solvent mixture of known polarity. By the measurement of ET (30) of curcumin, we can reveal the surrounding experienced by the curcumin inside the ionic liquid micelles. Hence, the fluorescence spectra of curcumin were recorded in different ratios of a 1,4-dioxane/water mixture. Figure 3A shows the emission spectra of curcumin in different ratios of a 1,4-dioxane/water mixture. We have taken the values of the ET (30) parameter (solvent polarity parameter) of different 1,4-dioxane/water mixtures having different compositions from the literature.77 Then, we have plotted a correlation graph between the emission maxima (λmax) of curcumin and the ET (30) of the 1,4-dioxane/water mixture (Figure 3B). After that, ET (30) values were determined at different IL concentrations using the value of emission maxima of curcumin inside the micelles (Table 1). From the table and figure, it is clear that upon the addition of IL, there is a decrease in ET (30) values and an increase in fluorescence intensity, suggesting the shifting of curcumin molecules from a water-rich medium to the hydrophobic phase of micelles. In continuation to know more about the reorganization of curcumin inside the micelles, fluorescence Stokes shift measurements were done. This is because when a chromophore molecule is excited from ground state, there occurs various changes in the properties, such as polarizability, charge distribution, dipole moment, etc. If there is no change in the local environment around the probe, the fluorescence and absorption will take place at the same frequency and no Stokes shift would be observed. There is an increase in the Stokes shift with the increase in IL concentration as shown in Table 1.

Figure 3.

Figure 3

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(A) Emission spectra of curcumin in the presence of different 1,4-Dioxane:water mixtures, and (B) determination of solvent polarity parameter ET (30) for ionic liquid micelles (Yellow dot: represents the calculated ET(30) value of curcumin in the presence of SAIL).

Table 1. λmax Value of Absorption and Emission Spectra, Stokes Shift, and ET (30) of Curcumin at Different Concentrations of Ionic Liquid (Error within ±5%).

concn of IL (mM) λmax (abs) (nm) λmax (emsn) (nm) Stokes shift (nm) ET (30) (kJ/mol)
0 432 543 111 58.27
0.2 426 519 93 48.64
0.6 426 512 86 45.2
1.2 425 509 84 43.97
2 425 507 82 43.36
10 424 506 82 42.68
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Picosecond-resolved fluorescence decay transients of curcumin at different concentrations of ionic liquid were measured to understand the excited-state dynamics. The curcumin was excited at 426 nm, and the decay was monitored at 504 nm. The decay profiles are shown in Figure 4A, and the components of lifetime with their relative percentages are presented in Table 2. The fluorescence transient of curcumin in the presence of 4 mM ionic liquid could be fitted biexponentially with 32.93 ps (τ1) due to solvation dynamics and 102.52 ps (τ2) due to excited-state intramolecular H-atom transfer (ESIHT), with an average lifetime of 43.52 ps. However, the two components of lifetimes of curcumin at the 10 mM concentration of ionic liquid were found to be 40 ps (τ1) and 169.39 ps (τ2) with an average lifetime of 54.98 ps. This increase in lifetime of curcumin with the increase in concentration of ionic liquid for the longer component could be due to deactivation in the ESIHT process in the constrained environment of the ionic liquid. In order to figure out the geometrical restrictions on the curcumin molecule inside the ionic liquid micelles, time-resolved rotational anisotropy studies were conducted. The time-resolved anisotropy decay profile of curcumin in 10 mM ionic liquid has been shown in Figure 4B. The rotational time constant of curcumin in the ionic liquid micellar environment was found to be 175.5 ps, which suggests that the curcumin molecule was probably present in the palisade layer of the micelle as the average rotational time of curcumin was considerably larger as compared to that of free curcumin. This observation could be well supported by the MD simulation and DFT analysis (Figure 2C; Supporting Information: Video S1 and Figures S7 and S8) where it could be seen that the curcumin molecule in the presence of a small concentration of ionic liquid could form a salt bridge. However, upon further addition of ionic liquid, the van der Waals interactions could be seen to dominate over the coulombic interactions and the curcumin molecule could be seen to remain partially embedded in the micelle for the whole duration of the simulation (Figures 5 and 7 and Supporting Information: Figure S10).

Figure 4.

Figure 4

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(A) Picosecond-resolved fluorescence transients of curcumin (red), Curcumin-IL (4 mM Olive), and Curcumin-IL (10 mM Wine) in water, and (B) decay of fluorescence anisotropy of curcumin in the presence of 10 mM ionic liquid micelles.

Table 2. Time-Resolved Decay Parameter of Curcumin at Different Concentrations of Ionic Liquid and NaCl in an Aqueous Medium (Error within ±5%).

concn of [C16 mim]Cl τ1 (ps) τ2 (ps) A1 (%) A2 (%) τavg (ps)
0 mM 20 149 94 6 27.74
4 mM 32.93 102.52 85 15 43.52
10 mM 40 169.39 88 12 54.98
10 mM [C16mim]Cl + 0.05 M NaCl 50 220.95 88 12 70.95
10 mM [C16mim]Cl + 0.25 M Nacl 63.57 262.43 87 13 89.73
10 mM [C16mim]Cl + 1 M NaCl 65 258.40 79 21 105.52
10 mM [C16mim]Cl + 1.5 M NaCl 67.12 272.37 74 26 121.10
10 mM [C16mim]Cl + 2.0 M NaCl 82 297.53 74 26 138.85
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Figure 5.

Figure 5

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(A) Binding energy of curcumin with ionic liquid micelle as obtained from the MD simulation. Coulombic and van der Waals contributions are also shown; (B) UV–visible absorption spectra of curcumin in the presence of ionic liquid micelles (Inset: absorbance versus time plot), and (C) snapshot of the MD at t = 0 ns of a fully equilibrated curcumin-ionic liquid micelle and another snapshot at t = 12 ns of the production MD simulation.

Figure 7.

Figure 7

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(A) Binding energy profile of curcumin with ionic liquid micelles in the absence and in the presence of salt. (B) Radius of gyration of curcumin-ionic liquid micelle in the absence and in the presence of salt. (C) Localization of curcumin in the ionic liquid micelle in terms of the distance between the center of the micelle to the center of curcumin in the absence (black) and presence (red) of salt. (D) RMSD of curcumin-ionic liquid in the absence and in the presence of salt.

Subsequent to the study of excited-state dynamics, the degradation profile of curcumin in IL micelles could be studied (Figure 5B). A study of the degradation profile of a drug inside a micellar environment can be studied by monitoring the UV–visible absorption spectra of curcumin with time. Using this information, one can get a better idea about the stability of the system, which can allow one to get the fundamental understanding of the acceptability of the system as a potential drug carrier. It has been reported that curcumin shows rapid degradation at neutral78 and alkaline79 pH in an aqueous medium, and the degradation of curcumin in phosphate buffer (pH 7.2)19 at 310 K follows first-order kinetics with a rate constant of 0.073 min–1. The degradation products of curcumin are vanillin, trans-6-(40-hydroxy-30-methoxyphenyl)-2, 4-dioxo-5-hexanal, ferulic acid, and feruloyl methane.19 Based on the data presented in Figure 5B, it could be inferred that the degradation of curcumin was substantially reduced after the entrapment of curcumin molecules in the ionic liquid micelles and was observed to be about 2% in 3 days. Since the degradation of curcumin in an aqueous environment is typically catalyzed by hydroxyl anions (OH–) present in water molecules, the rate of degradation of curcumin in the presence of imidazolium-based SAILS could be substantially reduced due to the strong interactions of the OH– group of water molecules with the cationic imidazolium ring of the IL. Furthermore, the binding of curcumin to the hydrophobic sites of SAILs could make the approach of OH– toward the curcumin molecules more difficult. In order to get a better understanding of this high stability of curcumin in the presence of ionic liquid micelles, energies for both types of interactions were computed. Figure 5A shows that the van der Waals force of interactions plays a major role in stabilizing the curcumin molecules in the presence of ionic liquid more than the coulombic interactions (the interaction energies of curcumin and ILs have been represented in the Supporting Information(Tables S2 and S3). Figure 5C and Figure S10 are the pictorial representation of curcumin molecule partially embedded in the micelles, and the hydrophobic tail of the ionic liquid is protecting the curcumin molecules from the interactions with water molecules. Distribution of water around curcumin in the free state and when embedded in a micelle is given by the radial distribution function (Supporting Information, Figure S11), which indicates a significant decrease in the water exposure. Throughout the MD simulation the orientation of curcumin in the micelle remains tangential rather than radial as evident from the tilt angle of curcumin (Supporting Information, Figure S12).

Figure 6 depicts the effect of the addition of salt on the emission spectra of curcumin in the ionic liquid system. Figure 6A,B represents the effect of salt on the emission spectra of curcumin under varying concentrations of ionic liquid and the effect of salt on the emission spectra of curcumin when the concentration of the IL was 10 mM. It could be observed that the fluorescence intensity of curcumin increased with the increase in salt concentration, and the critical micellar concentration of the ionic liquid micelles also kept getting lower with the addition of the salt. This could be because the salt could act as a dehydrating agent and could protect the curcumin molecule from interacting with the water molecules. Figure 6C represents the effect of salt on the ESIHT of curcumin loaded inside the ionic liquid system. At a 0.05 M salt concentration, curcumin shows two components, 50 ps (τ1) and 220.95 ps (τ2) with an average lifetime of 70.95 ps. However, upon the increase in the salt concentration up to 2 M, the longer component lifetime of the curcumin molecule (which is due to ESIHT) is found to get slower. All these results indicate that the salt does help in protecting the curcumin molecule from the interaction with the water molecules.

Figure 6.

Figure 6

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(A) Emission spectra of curcumin in the presence of different concentrations of ionic liquid and at varying salt concentrations; (B) effect of salt on the emission spectra of curcumin-ionic liquid micelles (Inset: emission intensity versus concentration of NaCl), and (C) picosecond-resolved fluorescence transients of curcumin-ionic liquid micelles in the presence of salt (0 to 2 M).

In order to explain the role of salt on the curcumin–ionic liquid micellar system in a more realistic manner, binding energies were computed when the salt concentration was 2 M. Figure 7A shows that there was no change in the binding energies in the presence of the salt. However, the micelles were found to become more compact in the presence of salt as was evident from the lower radius of gyration as compared to that in the absence of salt (Figure 7B). With salt, the ionic interaction of curcumin with the head groups of ILs decreases (Supporting Information, Figure S13), which is compensated by the van der Waals interaction with the tail part of the ILs. Figure 7C shows the exact localization of curcumin placed inside the ionic liquid micelles in the absence and presence of salt in terms of the distance of curcumin from the center of the micelle. It can be seen that the curcumin molecule remains just below the surface of the micelle where it can interact with both the head groups of ILs and their hydrophobic tails. The root-mean-square deviation (RMSD) profile reflects the fluid nature of the micelle as it keeps changing with time with reference to the initial structure. However, the constant compact gyrating radius of the micelle confirms the stability of the curcumin–ionic liquid micellar system in the presence of the 2 M salt. It could be clearly seen that curcumin-containing ionic liquid micelles both in the absence and in the presence of salt could reach a very stable confirmation (Figure 7D).

3. Conclusions

Solubility and Stability of curcumin has been successfully improved in the presence of imidazolium-based ionic liquid. All optical characterizations show that the curcumin molecule is encapsulated in the micelles, and there is good agreement of observed absorption spectra with the computed absorption spectra. The picosecond-resolved TCSPC technique confirms that the lifetime of the nonradiative process of curcumin–ionic liquid micelles in an aqueous medium and in the presence of salt is slower due to interactions with the ionic liquid. Time-dependent fluorescence anisotropy shows that there is geometrical restriction on the curcumin molecule inside the ionic liquid micelles. All the experiments are further supported by DFT and MD simulation studies. These studies confirm that two types of interactions are possible with the ionic liquid: one with the cationic head group (coulombic interactions) and other with the hydrophobic tail (van der Waals interactions). Energy calculations show that the van der Waals interaction plays a major role in stabilizing the curcumin molecule inside SAILs. MD simulations show that the curcumin molecule is partially embedded in the micelles present in the palisade layer of micelles and confirm that the binding energies remain unaffected in the presence of salt. Calculation of the radius of gyration confirms that the micelles are getting more and more compact in the presence of salt and suggests that the curcumin–ionic liquid micelles in both the presence as well as in the absence of salt reaches to the formation of a highly stable system. We believe that ionic liquid micelles have more potential for the delivery of hydrophobic drugs for further biological applications.

4. Experimental Section and Theoretical Methods

4.1. Materials

For this study, curcumin was purchased from Sigma–Aldrich (purity 80%) and used without further purification.67 Methanol and HPLC water were used for the preparation of a stock solution of curcumin and SAILs, respectively. All the other chemicals used were of analytical grade. Ionic liquid (i.e., [C16mim] Cl) was synthesized in our laboratory according to the reported procedure, and characterized by 1H NMR, and 13C NMR, mass and FT-IR techniques (Supporting Information, Note S1, Figures S1, S2, and S3), respectively.

4.2. Preparation of Samples

First, the stock solution of curcumin and [C16mim] Cl were prepared in methanol and buffer (pH 7.2), respectively. A fixed amount of curcumin was added in a round-bottom flask and allowed to evaporate in order to maintain a constant concentration of curcumin. After that, a fixed amount of ionic liquid was added in a round-bottom flask and the solution was stirred at room temperature for about 1 h. All the samples were prepared using a fixed concentration of curcumin, i.e., 10 μM and by changing the concentration of ionic liquid from 0 to 10 mM. Similarly, to study the effect of salt, NaCl was added according to their respective concentration to the samples prepared by the above-mentioned method.

4.3. Characterization Techniques

For optical characterization, an Agilent UV spectrophotometer model Specord 250 was employed to measure the absorption spectra of curcumin–IL micelles in the aqueous medium in the wavelength range of 300–700 nm using a quartz cell with a path length of 1 cm.

A Carey eclipse spectrofluorometer was employed to record the emission spectra of curcumin. The emission spectra of all the samples were recorded at an excitation wavelength of 426 nm. The fluorescence measurements were performed at a band slit of 5 nm.

Dynamic light scattering (DLS) experiments were carried out for the measurements of the size distribution of samples using a Zetasizer Nano ZS90 (Malvern Instruments Ltd., UK) at 25 °C. For the structural analysis, transmission electron microscopy analysis (TEM) was performed using a Technai at an operating voltage of 200 kV. Transmission electron microscopy analysis (TEM) grids were prepared by adding a diluted drop of the samples on the copper-coated grid, and the grid was negatively stained using the 2% phosphotungstic acid. The size of the particles was determined from the micrograph collected at high magnification.

Time-resolved studies of samples were carried out using a time-correlated single photon counting (TCSPC) setup from Edinburgh instrument (Instrument Response time, IRF: 75 ps). A picosecond-pulse laser diode was used to excite the sample at 409 nm. A filter with a cutoff at 420 nm was incorporated in the emission channel to effectively diminish the scattered excited light. The excitation was vertically polarized, and the emission of samples was recorded through a polarizer oriented at an angle of 55° from the vertical position. Fluorescence transients were fitted by using the nonlinear curve with F900 software from Edinburgh instrument.

The average fluorescence lifetime could be calculated by using the decay time constant and relative contribution of the components. The equation could be expressed as

4.3. 1

where τ1 and τ2 denote the first and second component of the decay time of curcumin, and a1 and a2 show the percentage contributions of the components with respect to the decay time.

Anisotropy measurements were done using the same Edinburgh instrument. For the fluorescence anisotropy measurements r(t), the emission polarizer was adjusted to be parallel and perpendicular to that of the excitation and the corresponding fluorescence transients are collected as I∥ and I⊥, respectively. The magnitude of the grating factor G of the emission monochromator of the TCSPC system was determined using a long tail matching technique.

The time-resolved anisotropy is calculated by using the formula

4.3. 2

4.4. Theoretical Studies

4.4.1. Density Functional Theory (DFT)

The structure of curcumin and 1-hexadecyl-3-methylimidazolium chloride molecule and their complexes were geometrically optimized at the level of density functional theory (DFT) using the B3LYP exchange correlation and Pople’s double zeta basis set 6–31 + g(d) with the diffuse and polarization function on heavy atoms as implemented in Gaussian 16 software.80,81 Grimme’s empirical dispersion correction (GD3) was added to account for the nonbonded intermolecular interactions.82 All the optimizations were done in a polarizable continuum model (IEFPCM) of water, where the molecule was placed in a solvation cavity and a constant dielectric field was assumed on the outside.83,84 Structures for all the conformers of curcumin, ground-state dipole moment, and their relative energies of ground-state conformers were obtained using DFT with the B3LYP functional. Thereafter, UV–visible spectra of curcumin for all the configurations and in the presence of ionic liquid were computed using time-dependent density functional theory (TD-DFT) with the same exchange correlations and basis sets.85−87 Coordinates of all the optimized geometries are given in the Supplementary Information (Note S2).

4.4.2. Molecular Dynamics Simulation

The micelle structure with a molecule of curcumin and 60 molecules of ILs was constructed by using Packmol software.88 Molecular dynamics analysis was carried out in the Schrödinger Maestro molecular modeling environment (Academic release 2018–1) by using the Desmond molecular dynamics program.89 The whole complex was placed in a cubic periodic boundary box with a ±2.5 nm buffer region on each side. The simulation box was filled with a pre-optimized simple point charge (SPC) water model. An amount of 32,294 water molecules were required to fill the simulation box. Charge was neutralized by adding appropriate counter ions. To study the effect of salt, 2 M NaCl was added for the simulation in the presence of salt. The MD simulation was run in an OPLS force field.90−92 The systems (with and without salt) were subjected to five-step relaxation according to the previously published protocol.93 Then, the systems were equilibrated in an isothermal-isobaric (NPT) ensemble with a constant pressure of 1 bar and a temperature of 298.15 K for 4.8 ns. Final MD simulations were run in the same condition for 12 ns. RESPA (reference system propagator algorithm) integrator was used with near, far, and out time steps of 2, 2, and 6 fs, respectively. The isotropic pressure was applied using the Martyna–Tobias–Klein barostat method with relaxation time of 2 ps. The Nose–Hoover chain thermostat method was used with relaxation time of 1 ps. Long-range coulombic interaction was treated with the PME (particle mesh Ewald) method. For short-range coulombic interactions, the cutoff radius was 9 Å. Interaction energies (along with van der Waals and coulombic contributions), radius of gyration of the complexes, and the overall structural changes in terms of root-mean-square deviation (RMSD) were computed on the simulation trajectories. Radial distribution functions, g(r), were also computed from the simulation trajectory.

Acknowledgments

S.R. thanks the University Grants Commission, Government of India for providing the Senior Research Fellowship. The authors thank DST-SERB EMR/2016/006678 for the financial support, the U.S.I.C., and the Department of Chemistry, University of Delhi for providing the advanced characterization facilities. The authors thank S.N. Bose institute for providing the TCSPC facility.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c02438.

  • Synthesis and spectral data, 1H and 13C NMR spectrum and FT-IR spectra of 1-hexadecyl-3-methyl imidazolium chloride, optimized geometries of different conformers of curcumin, energies of the optimized geometries, absorption spectra of curcumin conformers, comparison of computed and experimental absorption spectra, computed formation energies of J- and H-aggregates, binding energies and Rg of curcumin with micelle from the MD simulation, salt bridges as observed in DFT optimized geometry of J-aggregate, salt bridges as observed in OPLS-2005 optimized geometry of J-aggregate, comparison of H-aggregate geometries, a snapshot of curcumin-embedded micelle from an MD simulation, the tilt angle of curcumin in an IL micelle, water distribution around free and micelle bound curcumin, radial distribution g(r) function of N+ of the ILs with respect to O– of curcumin, and coordinates of optimized geometries (PDF)

  • Hydrophobic interaction with the long tail of the ionic liquid molecule (H-type aggregate), and coulombic attraction with the head group (J-type aggregate) (AVI)

The authors declare no competing financial interest.

Supplementary Material

ao0c02438_si_001.pdf (1.1MB, pdf)
ao0c02438_si_002.avi (1MB, avi)

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