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Original article
13 (
1
); 2271-2275
doi:
10.1016/j.arabjc.2018.04.011

Supramolecular drug inclusion complex of Capecitabine with cucurbit[7]uril and inverted cucurbit[7]uril

, , , , , ,
a Key Laboratory of Macrocyclic and Supramolecular Chemistry of Guizhou Province, Guizhou University, Guiyang 550025, China
b College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Key Laboratory of Fine Chemicals, Shandong Normal University, Jinan 250014, China
c Shandong University of Science and Technology, Qingdao 266590, China
d Yushan Central Crimary School of Taohong Township in Longhui County, Shaoyang 422200, China

⁎Corresponding author. gyhxxiaoxin@163.com (Xin Xiao)

Received: , Accepted: ,
© The Author(s) 2018
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Q[7] and iQ[7] could be promising candidates for excipients used in medicinal and pharmaceutical research fields.

Abstract

The interaction of capecitabine (CAP) with cucurbit[7]uril (Q[7]) and inverted cucurbit[7]uril (iQ[7]) was investigated using nuclear magnetic resonance, fluorescence spectroscopy, MALDI-TOF mass spectrometry and isothermal titration calorimetry. The obtained results revealed that the alkyl chain of CAP is located inside the cavities of Q[7] or iQ[7], whereas the other section of CAP remains outside the portal. Our results suggest that both Q[7] and iQ[7] could be promising candidates for excipients used in medicinal and pharmaceutical research fields.

1

1 Introduction

Macrocyclic host molecules have the ability to encapsulate biologically relevant guests and serve as drug carriers, drug synergists, drug stabilizers and drug bioavailability enhancers. This property has been widely exploited, both for naturally occurring hosts such as cyclodextrins (Stella and Rajewski, 1997; Uekama et al., 1998), and synthetic molecular receptors such as calixarenes and crown ethers (Gokel et al., 2004; Da Silva et al., 2004; Yan et al., 2012). Cucurbit[n]urils (Q[n], n = 5–8, 10, 14) (Freeman et al., 1981; Kim et al., 2000; Day et al., 2002; Cheng et al., 2013; Li et al., 2016a, 2016b), as a relatively new family of macrocyclic host molecules, have received increasing attention in recent years due to their special structure, composed of a rigid hydrophobic cavity and two identical carbonyl-laced portals, which can encapsulate small organic molecules, bio-macromolecules, metal ions or even nanoparticles using electrostatic forces, hydrogen bonding, hydrophobic effects, π-π stacking or charge transfer interactions (Liu et al., 2017; Shetty et al., 2015; Gao et al., 2016; Shan et al., 2017; Gao et al., 2016; Yu et al., 2015). Because of their excellent host-guest binding ability that enables the assimilation of a number of guests, considerable cucurbit[n]uril-based medicinal chemistry research has been undertaken (Isaacs et al., 2005; Liu et al., 2007; Li et al., 2017; Isaacs et al., 2007). Among the Q[n] family, cucurbit[7]uril (Q[7]) has received perhaps the greatest attention as a potential drug delivery vehicle, due to its good solubility in water and strong affinity with multiple types of guest molecules (Barrow et al., 2015; Assaf and Nau, 2015; Kaifer, and Acc, 2014; Huang et al., 2014; Urbach and Ramalingam, 2011; Liu and Yao, 2013; Bai et al., 2015; Yang et al., 2016; Ma et al., 2012). For example, Miao research group enhanced the in vitro and in vivo uptake of a hydrophobic model drug, namely coumarin-6, in the presence of Q[7] (Miao et al., 2016). Huang and colleagues demonstrated the antibacterial activity control of cationic polymer e-poly-L-lysine hydrochloride with different concentrations of Q[7], via the formation of polypseudorotaxanes (Huang et al., 2016). Importantly, in 2005, Isaacs and Kim separated and characterized the inverted cucurbit[n]urils (iQ[n]s, where n = 6 and 7) and their recognition properties (Isaacs et al., 2005). Inverted cucurbit[n]urils, which feature a reverse dioxide unit, have different properties compared to Q[n], some of which have already been detailed (Gao et al., 2017a, 2017b, 2017c, 2017d, 2017e; Li et al., 2016b; Li et al., 2015a, b). However, to the best of our knowledge, no paper has addressed the inverted cucurbit[7]uril-based supramolecular architectures with drug molecules. Capecitabine (CAP) has been widely used as a first line anticancer drug, due to its ability to convert into the active compound fluorouracil (5-FU) in vivo (Fig. S1). 5-FU and its pro-drug CAP are pyrimidine analogues characterized as antimetabolites, which can inhibit cell division and interfere with RNA and protein synthesis. CAP can extend the survival time of patients with various types of cancer, being extensively used in the treatment of advanced primary or metastatic breast, rectal, colon and gastric cancer. In this paper, we respectively explored the different properties of inverted cucurbit[7]uril (iQ[7]) and Q[7]. Moreover, the inclusion properties of the two host, Q[7] and iQ[7], in combination with CAP (Scheme 1), were contrasted based on nuclear magnetic resonance (NMR), mass, and fluorescence spectroscopic results, in addition to isothermal titration calorimetry (ITC).

Structures of hosts Q[7] and iQ[7], and guest CAP.
Scheme 1 Structures of hosts Q[7] and iQ[7], and guest CAP.

2

2 Experimental

2.1

2.1 Materials and measurements

Capecitabine were obtained from Aldrich and used without further purification. Q[7] and iQ[7] was prepared as described previously (Liu and Yao, 2013; Bai et al., 2015; Yang et al., 2016; Ma et al., 2012; Li et al., 2015a, 2015b; Gao et al., 2017a, 2017b, 2017c, 2017d, 2017e). All other reagents were of analytical grade and were used as received. Double-distilled water was used for all experiments.

2.2

2.2 1H NMR measurements

All 1H NMR spectra, including those for the titration experiments, were recorded at 298.15 K on a JEOL JNM-ECZ400S 400 MHz NMR spectrometer in D2O. D2O was used as a field-frequency lock, and the observed chemical shifs are reported in parts per million (ppm).

2.3

2.3 Isothermal titration calorimetry (ITC) experiments

Microcalorimetric experiments were carried out using an isothermal titration calorimeter Nano ITC 2G (TA, USA). The solution of Q[7] (1.00 × 10−4 mol/L) or iQ[7] (1.00 × 10−4 mol/L) was charged with the microcalorimetric reaction cell(1.3 mL) and the guest solution (1.00 × 10−3 mol/L)was continuously injected into it placed in the syringe (250 uL). The heat of the reaction was corrected for the heat of dilution of the guest solution determined in separate experiments. All solutions should be degassed by sonication before titration experiments. Computer simulations (curve fitting) were performed by using the Nano ITC analysis software.

2.4

2.4 Fluorescence spectroscopy measurements

All fluorescence spectra were recorded from samples in 1 cm quartz cells on a Varian RF-540 fluorescence spectrophotometer. The host and guests were dissolved in distilled water. Fluorescence spectra were obtained at 298.15 K at a concentration of 4.00 × 10−5 mol/ L CAP with different Q[7] or iQ[7] concentrations.

3

3 Results and discussion

3.1

3.1 1H NMR spectroscopy

To respectively investigate the complexation of CAP with iQ[7] and Q[7] in an aqueous solution, 1H NMR titration experiments were performed, by adding increasing amounts of Q[7] or iQ[7] to a solution of CAP in D2O. As shown in Fig. 1, with increasing amounts of iQ[7] to the solution of CAP, the methylene protons (Hg, Hh, Hi, and Hj) and methyl proton (Hk) attributed to the alkyl chain moiety, experiencing significant up-field shifts from 4.12, 1.57, 1.20 and 0.73 ppm to 3.92, 1.10, 0.79 and 0.31 ppm, respectively. Meanwhile, the signal Hf, corresponding to the heteroaromatic ring proton, shifted obviously downfield (Δδ = 0.16 ppm). Nevertheless, the other protons (Ha-He) of the guest had essentially no chemical shift, suggesting that the alkyl chain moiety of CAP was inserted into the cavity of iQ[7], whereas the foran ring was prevented from entering the cavity.

1H NMR spectra (400 MHz, D2O) of iQ[7] (A) in the absence and in the presence of (B) 1.0 equivalents of CAP and (C) neat CAP in D2O, at 298.15 K.
Fig. 1 1H NMR spectra (400 MHz, D2O) of iQ[7] (A) in the absence and in the presence of (B) 1.0 equivalents of CAP and (C) neat CAP in D2O, at 298.15 K.

In the presence of Q[7] (Fig. 2), all methylene and methyl protons of CAP, except proton Hg, were displaced up-field, which was very similar to the observations made in the iQ[7]-CAP cases. In detail, protons Hh, Hi, Hj and Hk on the alkyl chain moietyexperienced up-field shifts from 1.58, 1.21, 1.21 and 0.74 ppm to 1.34, 0.85, 0.85 and 0.09 ppm. However, the signal for proton Hg did not present any change in the 1H NMR spectra, which was different from the iQ[7]-CAP cases. In addition, the proton of signal Hf only displaced very slight down-field (Δδ = 0.01 ppm). The reason underlying these differences may be the smaller cavity of iQ[7], which contains a single inverted glycoluril unit. In order to expediently compare, the chemical shifts of all the protons in the iQ[7]-CAP and Q[7]-CAP system are shown in Table S1.

1H NMR spectra (400 MHz, D2O) of Q[7] (A) in the absence and in the presence of (B) 1.1 equivalents of CAP and (C) neat CAP in D2O, at 298.15 K.
Fig. 2 1H NMR spectra (400 MHz, D2O) of Q[7] (A) in the absence and in the presence of (B) 1.1 equivalents of CAP and (C) neat CAP in D2O, at 298.15 K.

3.2

3.2 ITC analysis

ITC analysis on the complexation of CAP with both Q[7] and iQ[7] can account for the thermodynamic parameters (Fig. 3 and Fig. S2). A solution of CAP was consecutively injected into a solution of Q[7] or iQ[7], at 298.15 K, to record the binding constants and associated thermodynamic parameters (Fig. 3), resulting in the resolution of the binding molar ratio value of N = 0.959 and 0.917, respectively. These suggest that the interaction ratio of the host (either Q[7] or iQ[7]) with the guest (CAP) was 1:1. It is worth mentioning that, the association constant of CAP with Q[7], Ka = (2.76 ± 0.49) × 105, was greater than that of CAP with iQ[7], Ka = (2.04 ± 0.75) × 104, indicating that the complex Q[7] -CAP was more stable than complex iQ[7]-CAP. In addition, the relatively large negative enthalpy values for the Q[7]-CAP and iQ[7]- CAP systems (ΔH = −30.03 ± 0.81 kJ mol−1, ΔH = −19.83 ± 2.1 kJ mol−1, respectively), indicate that a favorable enthalpy change is the main driving force behind the formation of the inclusion complex of CAP with Q[7] and iQ[7] (Table S2).

ITC data for the binding of Q[7] with CAP in aqueous solution at 298.15 K.
Fig. 3 ITC data for the binding of Q[7] with CAP in aqueous solution at 298.15 K.

3.3

3.3 Fluorescence emission spectra

To further research the interaction between Q[7] or iQ[7] and CAP, fluorescence titration experiments were conducted. The curves of the fluorescence spectra of the Q[7]-CAP and iQ[7]-CAP systems were shown in Fig. 4 and Fig. S3, respectively. The guest, CAP, showed an emission peak at 395 nm, with the excitation at 299.07 nm, which gradually decreased for a fixed concentration of CAP and changing concentration of Q[7] or iQ[7], in an aqueous solution. As seen in Fig. 4(A), the fluorescence intensity of the guest, CAP, gradually decreased as the ratio Q[7]/CAP increased, which is attributed to the formation of the supramolecular complex Q[7]-CAP. Moreover, when the molar ratio of CAP and Q[7] was close to 1:1, the fluorescence intensity of the system tended to be gentle. Meanwhile, when Q[7] was replaced by iQ[7], similar fluorescence spectra were observed, Fig. S2. Furthermore, the Job’s plot for the Q[7]-CAP system (Fig. 4B) clearly shows that the fluorescence spectra data fit well to the 1:1 stoichiometry of the host–guest inclusion complex, which is consistent with the data obtained from the ITC analysis.

Fluorescence spectra of CAP (4.0 × 10−5 M) (A) with increasing concentrations (0.0, 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0 equiv) of Q[7], and (B) the corresponding ΔF-NCAP/(NQ[7] + N CAP) curves.
Fig. 4 Fluorescence spectra of CAP (4.0 × 10−5 M) (A) with increasing concentrations (0.0, 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0 equiv) of Q[7], and (B) the corresponding ΔF-NCAP/(NQ[7] + N CAP) curves.

3.4

3.4 MALDI-TOF mass spectrometry

MALDI-TOF mass spectrometry (MS) provided further evidence for the interaction between Q[7] or iQ[7] and CAP. As shown in Fig. 5, major signals were observed at m/z = 1522.04 and 1522.98, corresponding to Q[7]-CAP (calculated for [(Q[7]-CAP + Na+]+, 1522.31) and iQ[7]-CAP (calculated for [(iQ[7]-CAP + Na+]+, 1522.31), respectively. These observations confirm the formation of the 1:1 inclusion complex, both in the Q[7]-CAP system and iQ[7]-CAP system, in an aqueous solution, which is in agreement with our findings by fluorescence spectroscopy and ITC.

MALDI-TOF mass spectrum of the complex Q[7]-CAP (A) and iQ[7]-CAP (B).
Fig. 5 MALDI-TOF mass spectrum of the complex Q[7]-CAP (A) and iQ[7]-CAP (B).

4

4 Conclusions

In the present study, two supramolecular drug complexes, namely Q[7]-CAP and iQ[7]-CAP, were investigated by a wide range of methods including NMR, fluorescence spectroscopy, MALDI-TOF MS and ITC. Obtained results revealed that the alkyl chain moiety of the guest, CAP, is inserted into the cavity of the hosts, Q[7] or iQ[7]. Our study represents an important strategy to manipulate the physicochemical properties of pharmaceutical agents, and supports the continuous exploration of cucurbit[n]urils, for their potential applications in pharmaceutical sciences.

Acknowledgements

We thank the Natural Science Foundation of China (21561007), the Innovation Program for High-level Talents of Guizhou Province (No. 2016-5657), the Major Program for Creative Research Groups of Guizhou Provincial Education Department (2017-028) and the Science and Technology Fund of Guizhou Province (No. 2016-1030) for financial support.

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Appendix A

Supplementary material

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.arabjc.2018.04.011.

Appendix A

Supplementary material

Supplementary data 1

Supplementary data 1


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