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First Self-Assembly of Dihydroxy Triterpenoid Maslinic Acid Yielding Vesicles Braja Gopal Bag,* Sk Nurul Hasan, Subrata Ghorai, and Saikat Kumar Panja Department of Chemistry and Chemical Technology, Vidyasagar University, Midnapore 721102, West Bengal, India
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S Supporting Information *
ABSTRACT: Maslinic acid, a naturally occurring dihydroxy triterpenoid having a 6-6-6-6-6 fused pentacyclic structure, is extractable from the fruits of olive (Olea europaea). As part of our ongoing investigations on the self-assembly of natural products, herein, we report the results of our detailed investigation on the self-assembly of maslinic acid in different liquids. The triterpenoid self-assembled in aqueous binary liquid mixtures yielding vesicles of nano to micrometer diameters. Detailed characterization of the self-assemblies was carried out by scanning electron microscopy, highresolution transmission electron microscopy, atomic force microscopy, optical microscopy, Fourier-transform infrared spectroscopy, and low-angle X-ray diffraction studies. The vesicular self-assemblies were capable of entrapping fluorophores including the chemotherapeutic anticancer drug doxorubicin. Triton X-100-triggered release of the encapsulated drug was also demonstrated via rupture of vesicles.
1. INTRODUCTION Triterpenoids, the 30C-containing plant metabolites, are one of the most interesting classes of natural products due to their structural diversities, functional group dispositions, and biosynthesis.1−5 Acyclic and monocyclic to fused pentacyclic triterpenoids offer varied rigid and flexible molecular backbones of nanometric dimensions.6 Moreover, the presence of several hydroxyl, carbonyl, and carboxyl functional groups with several centers of chirality in common makes them one of the most interesting classes of functional nanoentities. The presence of both nonpolar regions in the lypophilic triterpenoid backbone and polar regions in the functional groups makes them an interesting class of amphiphiles for the study of their self-assembly properties in different liquids, even without further derivatization. Plant metabolites with their inherent renewable nature have drawn a significant research interest in chemistry, biology, and materials science in the last decade because their utilizations in science and technology will aid in the development of a sustainable society.7−9 Since the first report of the spontaneous self-assembly of a naturally occurring triterpenoid betulinic acid yielding gels via the formation of fibrillar networks in the year 2011, self-assembly of several natural products has been reported, even without functional transformation.10−15 Suitable derivatization of the triterpenoids has yielded derivatives such as alkali metal salts,16,17 esters,18−20 and ketals21 also having interesting self-assembly properties in organic and aqueous organic binary liquid mixtures.10 Utilization of the selfassemblies has been reported for the generation of thermochromic materials, hybrid materials, recyclable heterogeneous catalysts, liquid crystals; entrapment of fluorophores © 2019 American Chemical Society
including anticancer drugs, drug carriers; and also for the removal of toxic chemicals, etc.22−30 Self-assembly of different classes of compounds such as sugars,31,32 proteins and peptides,33−35 steroids,36 fatty acids,37−39 sophorolipids,40,41 etc. has been reported.42 Although such studies have led to a better understanding of the molecular self-assembly process, predictability of the morphology of the self-assemblies for a given molecule in a liquid is still in its infancy.43−54 Maslinic acid 1, a 6-6-6-6-6 pentacyclic dihydroxy triterpenic acid, is extractable from the fruits of olive (Olea europaea) as a free acid (Figures 1 and 2). Antiangiogenic, antiproliferative, and anticancer activities of maslinic acid have been reported in different human cell lines.55−57 The structure of maslinic acid is identical to that of arjunolic and oleanolic acids (Figure S1) having identical molecular backbones. All of the three compounds have similar kind of functional groups, i.e., hydroxyl and carboxyl groups although the number of the hydroxyl groups varies. For example, arjunolic, maslinic, and oleanolic acids are trihydroxy, dihydroxy, and monohydroxy triterpenic acids, respectively. Arjunolic acid having three hydroxyl groups self-assembled in polar aqueous binary liquid mixtures yielding vesicular self-assemblies, whereas oleanolic acid having one hydroxyl group was ambidextrous in nature, forming mostly vesicular self-assembly along with a small percentage of fibrillar network in both organic and aqueous organic binary liquid mixtures.58,59 Realizing that minute variation in the triterpenoid skeleton and the number and kind Received: December 29, 2018 Accepted: March 8, 2019 Published: April 26, 2019 7684
DOI: 10.1021/acsomega.8b03667 ACS Omega 2019, 4, 7684−7690
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and S3). The large lyphophilic region provided by the rigid pentacyclic backbone with the polar groups lying at the two extreme ends makes it an unique amphiphile for the study of its self-assembly properties in different liquids. 2.1. Study of Self-Assembly Properties. The amphiphilic compound maslinic acid 1 was not soluble in water or common organic solvents such as chloroform and dichloromethane but soluble in polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), and ethanol. When a hot solution of 1 (2 mg) in DMSO (100 μL) contained in a vial (capacity 4 mL) was treated with water (50 μL) and the resulting mixture was allowed to cool at room temperature, cloudiness was observed visually after 1 h. A viscous suspension was formed as observed by tilting the vial after 12 h. Following this procedure, selfassembly was studied in ethanol−water, DMF−water, and THF−water mixtures and viscous suspensions were obtained in all of the binary liquid mixtures studied (Tables 1 and TS1).
Figure 1. Schematic representation of self-assembly of maslinic acid 1 extractable from the fruits of olive (Olea europaea) yielding vesicular self-assemblies and its use for the entrapment of fluorophores.
Table 1. Self-Assembly Studies of Maslinic Acid entry
medium(v/v)
conc. (mM)
statea
1 2 3 4 5
ethanol−H2O (4:1) DMSO−H2O (2:3) DMF−H2O (2:1) THF−H2O (1:1) H2O
35.5 28.6 28.2 26.5 ≥0.84
VS VS VS VS I
a
VS = viscous suspension, I = insoluble, concentrations are in mM. Table TS1 for a complete table.
Figure 2. Energy-minimized structure of maslinic acid: two molecules shown are H-bonded. The length of the molecule is 1.67 nm. In Hbonded dimeric structure, the length of the dimer is 2.62 nm.
2.2. Morphology of the Self-Assemblies. Morphological characteristics of the self-assemblies of 1 were studied by atomic force microscopy, scanning electron microscopy, transmission electron microscopy, optical microscopy, X-ray diffraction, and FTIR spectroscopy. Atomic force microscopy of the dried self-assemblies of 1 prepared from a colloidal suspension of 1 in DMF−water (6.8 mM, 2:1, v/v) indicated the formation of densely packed spherical self-assemblies of 187.6 nm average diameter (as calculated from the diameters of 228 spheres, Figure S4) and 46−134 nm in heights. The three-dimensional images (Figure 3a) clearly indicated the spherical shape of the self-assemblies. Similarly, AFM studies of dried self-assemblies prepared from 1 in THF−water (12.7 mM, 1:1 v/v) and DMSO−water (17 mM, 2:3 v/v) also indicated the formation of spherical selfassemblies shown in Figure 3b,e,c,f. The heights and radii of the respective spherical objects did not match due to deformation, indicating that the spherical self-assemblies were soft in nature. The self-assemblies of 1 prepared from the colloidal suspensions in DMF−water (13.9 mM, 2:1 v/v), THF− water (12.7 mM, 1:1 v/v), DMSO−water (8.5 mM, 2:3 v/v), and EtOH−water (4.45 mM, 4:1 v/v) were studied by scanning electron microscopy. Spherical self-assemblies were observed in all of the samples at low concentrations. In the DMF−water suspension (13.9 mM, 2:1 v/v), densely packed spherical self-assemblies were observed having a size range of 1.4−1.6 μm (Figure 4a,b). In the THF−water suspension (12.7 mM, 1:1 v/v), polydispersed spherical self-assemblies were observed with nano- to micrometer diameter having average size of 500 nm (Figures 4c,d and S5). Optical microscopy was carried out to investigate the morphology of self-assembled 1 in four different aqueous
of functional groups can have a profound effect on the selfassembly properties of a liquid and the resulting morphology of the self-assemblies,10 it occurred to us that maslinic acid 1 will be an interesting choice for the investigation of its selfassembly properties. Herein, we report the first self-assembly properties of maslinic acid in different liquids. The dihydroxy triterpenoid spontaneously self-assembled in aqueous binary liquid mixtures, yielding vesicles of nano- to micrometer diameters. Characterizations of the self-assemblies were carried out by scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), atomic force microscopy (AFM), optical microscopy, X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR) studies. The vesicular self-assemblies were capable of entrapping the chemotherapeutic anticancer drug doxorubicin (Figure 1). The entrapped drug could be released by the rupture of vesicles.
2. RESULTS AND DISCUSSION Maslinic acid 1 was extracted from olive fruit by solvent extraction technique and purified by chromatography and crystallization (see Experimental Section) as a white crystalline solid. The molecule has a 6-6-6-6-6 fused pentacyclic rigid backbone with two hydroxyl groups attached at the “A”-ring and a carboxyl group attached at the ring junction of the cisfused “D” and “E” rings. Energy minimization carried out by density functional theory (DFT) calculation and by molecular mechanics calculation using Allinger’s MMX algorithm revealed the length of the molecule as 1.67 nm (Figures S2 7685
DOI: 10.1021/acsomega.8b03667 ACS Omega 2019, 4, 7684−7690
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Figure 3. AFM images of dried self-assemblies of 1 prepared from (a, d) DMF−water (6.8 mM, 2:1, v/v); (b, e) THF−water (12.7 mM, 1:1 v/v); and (c, f) DMSO−water (17 mM, 2:3 v/v).
Figure 4. (a, b) SEM images of a dry self-assemblies prepared from 1 in DMF−water (13.9 mM, 2:1 v/v) and (c, d) field emission scanning electron microscope images of dry self-assemblies prepared from 1 in THF−water (12.7 mM, 1:1 v/v).
Figure 5. Optical microscopy images of self-assemblies prepared from 1 in (a) DMSO−water (28.2 mM, 2:3 v/v) and (b) THF−water (26.5 mM, 1:1 v/v).
organic binary liquids such as THF−H2O (1:1), DMSO−H2O (2:3), DMF−H2O (2:1), and ethanol−H2O (4:1) in native state. In DMSO−H2O (28.2 mM, 2:3 v/v), distinct spherical self-assemblies were observed with average size of 3.20 μm (Figures 5a and S8). In THF−H2O (26.5 mM, 1:1 v/v), densely packed spherical self-assemblies with average size 340 nm were observed (Figures 5b and S8). A similar type of densely packed spherical self-assemblies was also observed in both DMF−H2O (28.2 mM, 2:1 v/v) and ethanol−H2O (35.5 mM, 4:1 v/v) with uniform size (Figure S8). The spherical shapes observed by AFM and SEM in the dried self-assemblies of 1 were also observed in their native state in the colloidal suspensions by optical microscopy, although at a larger length scale. To gain further insight into the morphology of the selfassemblies, HRTEM studies were carried out with the dried self-assemblies of 1 prepared from the colloidal suspensions in DMF−water (3.51 mM, 2:1 v/v). Vesicular self-assemblies of 20−30 nm diameter with distinct peripheries were observed (Figures 6b and S6). The membrane thickness of the vesicles obtained from HRTEM is 2.62 nm. With the length of the H-
Figure 6. (a) Schematic representation of the formation of bilayer vesicles, (b, c) HRTEM images of self-assemblies prepared from 1 in DMF−water (3.51 mM, 2:1 v/v). 7686
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bonded maslinic acid dimer being 2.62 nm (Figure 2), a bilayer vesicular structure is proposed (Figure 6a). The bilayer membrane morphology was also supported by low-angle Xray diffraction studies carried out with dried self-assemblies of 1 in DMF−water (56.4 mM, 2:1 v/v) and EtOH−water (74.1 mM, 4:1 v/v) (discussed later). Sharp peaks observed at 2θ = 3.37° for both the samples correspond to a d spacing of 2.62 nm (Figure S7), which matched the length of the H-bonded dimeric structure. Noncovalent interactions such as H-bonding from the “O− H” and “COOH” groups and lypophilic interactions from the triterpenoid backbone might play a significant role in addition to the solvophobic interactions during the self-assembly process. To investigate the role of H-bonding, FTIR studies were carried out with the dried self-assemblies obtained from DMF−water and DMSO−water, and the stretching frequencies were compared to the neat powder (recorded in attenuated total reflectance mode). The stretching frequency of the “−O−H” group in the neat powder appearing at 3388 cm−1 shifted to lower frequencies appearing at 3352 and 3349 cm−1 for the dried self-assemblies prepared from DMF−water and DMSO−water, respectively. But the stretching frequency of the “−CO” group in the neat powder and dried selfassemblies did not change significantly. Thus, the lowering of the −O−H stretching frequencies was due to intermolecular H-bonding among the O−H groups (Figure S9) inside the self-assemblies. The mechanism of the formation of bilayer vesicle was supported by low-angle X-ray diffraction studies of selfassembled 1 prepared from the colloidal suspensions in DMF−water (56.4 mM, 2:1 v/v) and EtOH−water (74.1 mM, 4:1 v/v). The diffraction data in the range of 2θ = 2−10° were recorded and their diffraction patterns were compared (Table TS2). Observation of several sharp peaks in the dried self-assemblies of 1 prepared from its suspension in EtOH− water is indicative of more ordered self-assemblies in EtOH− water than that observed in DMF−water. The peaks at the d spacings of 2.85, 2.62, 2.49, and 1.01 nm were common in both the samples, indicating that identical morphs were present in the samples studied. The critical vesicular concentrations of maslinic acid in DMSO−water (2:3 v/v) and DMF−water (2:1 v/v) determined by using pyrene as a fluorescence probe were 60 and 90 μm, respectively.60 2.3. Entrapment Study of Fluorophores Including Anticancer Drug Doxorubicin. Investigations on the delivery of drugs via biocompatible nanocarriers to a targeted site inside physiology has been one of the most significant areas of research to reduce the side effects in chemotherapy.61−64 Evidence for the formation of microsized vesicular self-assemblies of maslinic acid 1 in DMSO−water (28.2 mM, 2:3 v/v) (Figure S8) prompted us to investigate the entrapment of guest molecules inside the vesicular selfassemblies. Initially, we examined the entrapment of the cationic fluorophore rhodamine B (Rho-B) and the anionic fluorophore 5,6-carboxyfluorescein (CF). Interestingly, the vesicular self-assemblies were capable of entrapping both cationic and anionic fluorophores. For instance, when a hot solution of maslinic acid in DMSO−water (17 mM, 2:3 v/v) containing Rho-B (0.17 mM) was cooled at room temperature and examined by epifluorescence microscopy, bright fluorescence from the vesicular self-assemblies indicated the entrapment of fluorophores inside the vesicles (Figure 7a). Similarly, the anionic dye 5,6-carboxyfluorescein (CF) (0.17
Figure 7. Fluorescent micrographs of self-assembled 1 in DMSO− water (2:3 v/v): (a) self-assembled 1 (17 mM) containing rhodamine B (0.17 mM), (b) self-assembled 1 (17.4 mM) containing carboxyfluorescein (0.17 mM), and (c, d) self-assembled 1 (10.5 mM) containing doxorubicin (0.10 mM) exposed under both green and blue emission light.
mM) was also entrapped inside the vesicular self-assemblies in DMSO−water (17.4 mM, 2:3 v/v) as observed by epifluorescence microscopy (Figure 7b). Inspired by these results, we examined the entrapment of the anticancer drug doxorubicin by following the above procedure with a hot solution of 1 (10.5 mM) in DMSO−water (2:3 v/v) containing doxorubicin (0.04 mL, 0.10 mM). Reddish fluorescence observed from the inner portion of the vesicular self-assemblies indicated the entrapment of the chemotherapeutic drug inside vesicular self-assemblies (Figure 7c,d). Entrapment of fluorophores by the vesicular selfassemblies is also supported by fluorescence emission studies, as shown in Figure 8a. The fluorescence emission intensity decreases dramatically on entrapment of doxorubicin inside the self-assemblies within 2 h (Figure 8a,i). This decrease in fluorescence emission intensity is due to the quenching of excited state of the fluorophores after entrapment inside the vesicular self-assemblies. 2.4. Release Studies of the Entrapped Anticancer Drug Doxorubicin. Triton X-100, a nonionic surfactant, has been widely used for the disruption of membrane structure. Protein and other cellular organelles can be extracted via the lysis of cells using Triton X-100.65,66 Whether doxorubicin can be released from the doxorubicin-loaded vesicular selfassemblies of maslinic acid, Triton X-100 (0.04 mM) was added to the mixture and epifluorescence microscopy was carried out at different time intervals. Lysis of the spherical selfassemblies was observed confirming (i) the vesicular nature of the spherical assemblies, (ii) the entrapment ability of the selfassemblies, and (iii) surfactant-triggered release of entrapped drug molecules (Figure 8c).
3. CONCLUSIONS In conclusion, the first formation of vesicular self-assemblies of maslinic acid in aqueous binary liquid mixtures has been reported. According to our knowledge, this is also the first report on the formation of vesicular self-assemblies of a naturally occurring 6-6-6-6-6 pentacyclic dihydroxy triterpenic acid. Molecular modeling studies carried out by DFT and molecular mechanics method, optical and electron micrographs, and X-ray diffraction studies supported the bilayer 7687
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4.2. Study of Self-Assembly Properties. For selfassembly studies, crystalline maslinic acid 1 was weighed (2−5 mg) in a vial (1 cm i.d.) and dissolved in an organic liquid (usually 50−200 μL) by heating with magnetic stirring to obtain a clear solution. The solution was tightly sealed and cooled down at room temperature and observed visually after 12 h. For the study of self-assembly properties in aqueous binary liquid mixtures, the hot clear solution was treated with water (usually 20−100 mL) and then heated with stirring over a hot plate to obtain a clear solution. Then, the resulting mixture was kept at room temperature and observed after 12 h. 4.3. Entrapment Study of Fluorophores Including Anticancer Drug Doxorubicin. Entrapment of fluorophores rhodamine B (0.17 mM) and CF (0.17 mM) inside the selfassemblies of maslinic acid was carried out in DMSO−water (17 mM, 2:3 v/v) following an optimized procedure.22 A similar procedure was followed for entrapment of doxorubicin (0.04 mL, 0.10 mM) into the vesicular self-assemblies obtained from 1 in DMSO−water (10.5 mM, 2:3 v/v) system.
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ASSOCIATED CONTENT
* Supporting Information S
Figure 8. Entrapment and subsequent release of doxorubicin in DMSO−water (2:3) from the vesicular self-assemblies: (a) fluorescence emission spectra (λmax(ex.) 480 nm) of free and entrapped doxorubicin inside the vesicular structure of 1 (4.23 mM) at different time intervals: (i) free doxorubicin (0.04 mM), (ii) after 2 h, and (iii) after 24 h of encapsulation. (b) Fluorescent images of self-assembled 1 (4.23 mM) containing doxorubicin (0.04 mM). (c) Fluorescence emission spectra of the Triton X-100-triggered release of entrapped doxorubicin at different time intervals: (i) 36 h, (ii) 30 h, (iii) 15 h, (iv) 3 h, (v) 1 h. (d) Fluorescent images of the Triton X-100 (0.04 mM)-triggered release of encapsulated doxorubicin from the vesicular structure of 1 under green emission light.
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b03667. Energy-minimized structure of maslinic acid 1 (Figures S2 and S3); sample preparation; results of self-assembly studies (Table TS1); characterization of self-assemblies (Figures S4−S9); characterization of 1 by 1H NMR, 13C NMR, and HRMS studies (Figures S10−S12) (PDF)
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AUTHOR INFORMATION
Corresponding Author
vesicular structure. Both cationic and anionic fluorophores including the anticancer drug doxorubicin were entrapped inside the vesicles. Slow release of the entrapped drug doxorubicin has been demonstrated paving the way for targeted drug-delivery applications.
*E-mail:
[email protected].
4. EXPERIMENTAL SECTION 4.1. Isolation of Maslinic Acid 1. Finely powdered fruits of olive (35 g) were soaked in ethyl acetate (80 mL) in a 250 mL conical flask and stirred for 24 h. The extract was filtered, volatiles were removed, and the yellowish solid material (1.36 g) was purified twice by column chromatography (Si-gel, 100− 200 mesh, 1.2 × 12 cm2) using 20−50% ethyl acetate− dichloromethane as the mobile phase. The product was obtained as a white crystalline solid (0.018 g, 1.32% yield). Mp = 250−252 °C. Rf: 0.61 eluted in 50% ethyl acetate− dichloromethane. FTIR (cm−1): 3388 (B, −OH), 2936 (S, C−H), 1692 (S, −CC−, asymmetric), 1461 (S, −C C−, symmetric), 1457 (S), 1387 (S), and 1049 (S). 1H NMR [400 MHz, DMSO-d6−CDCl3 (4:1)] δ: 5.15 (1H, t), 2.71 (1H, d, 7.2 Hz), 2.79 (1H, m), 2.51−1.12 (m, terpenoid protons, 20H), 1.06 (3H, s), 0.91 (3H, s), 0.88 (3H, s), 0.85 (3H, s), 0.83 (3H, s), 0.69 (6H, s) (Figure S10). 13 C NMR [100 MHz, DMSO-d6−CDCl3 (4:1)] δ: 179.4, 148.4, 121.6, 82.9, 67.9, 55.2, 47.5, 46.8, 46.7, 46.0, 41.7, 41.1, 39.3, 39.2, 38.0, 33.8, 33.2, 32.6, 32.4, 30.7, 28.9, 27.5, 25.9, 23.7, 22.9, 22.5, 18.3, 17.2, 17.1, 16.6 (Figure S11). HRMS (EI) m/z 495.3446, M+ [C30H48O4Na] requires 495.3450 (Figure S12).
ACKNOWLEDGMENTS SERB, India (ref EMR/2016/001123), and India Srilanka project (DST/INT/SL/P25/2016) are acknowledged for financial support. S.N.H. and S.K.P aknowledge UGC and S.G. acknowledges CSIR for research fellowships.
ORCID
Braja Gopal Bag: 0000-0002-0058-7900 Notes
The authors declare no competing financial interest.
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REFERENCES
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DOI: 10.1021/acsomega.8b03667 ACS Omega 2019, 4, 7684−7690
