Supramolecular Micelles Constructed by Crown Ether-Based

Aug 6, 2012 - A Water-Soluble Cyclotriveratrylene-Based Supra-amphiphile: Synthesis, pH-Responsive Self-Assembly in Water, and Its Application in ...
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Supramolecular Micelles Constructed by Crown Ether-Based Molecular Recognition Xiaofan Ji, Jinying Li, Jianzhuang Chen, Xiaodong Chi, Kelong Zhu, Xuzhou Yan, Mingming Zhang, and Feihe Huang* Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China S Supporting Information *

ABSTRACT: A novel supramolecular amphiphilic polymer constructed by crown ether-based molecular recognition has been fabricated and demonstrated to self-assemble into core−shell supramolecular micelles in water. The reversible transition between assembled and disassembled structures can be achieved by changing the pH. This transition was used to realize the controlled release of small molecules. The supramolecular micelle was characterized by various techniques including conductivity, transmission electron microscopy (TEM), dynamic laser light scattering (DLS), and fluorescence titration. TEM images showed dark gray spherical aggregates, and the mean size of the micelles was 50 nm in diameter and of uniformly dispersed size, in good agreement with the DLS results. The release of hydrophobic molecules from the micelles was realized by adding acid (aqueous HCl), weakening the host−guest interactions and leading to disassembly of the supramolecular micelles. noncovalent interactions, such as hydrogen bonding,6 metal− ligand coordination,7 and host−guest interactions,8 have been utilized to prepare supra-amphiphiles. However, considering that the introduction of metal ions may lead to an ion imbalance in the body and the interactions of complementary hydrogen-bonding ligands may be severely destroyed in water,9 host−guest interactions could be better to prepare supraamphiphiles. Up to now, supramolecular hosts, such as cyclodextrins,8a,b cucurbiturils,8c−e and calixarenes,8f,g have served as junctions for supra-amphiphiles, while crown ethers, the first generation of artificial macrocyclic hosts,10 have never been utilized mainly due to the weakness of crown ether-based molecular recognition in water. Consequently, it is challenging to fabricate aqueous supra-amphiphiles driven by crown etherbased molecular recognition between hydrophilic and hydrophobic segments. In our recent work, we prepared a heteroditopic A−B monomer containing a bis(m-phenylene)-32-crown-10 (BMP32C10) host unit with two COO− groups and its complementary viologen dication guest moiety, which can selfassemble to form a linear supramolecular polymer at high concentration in aqueous media.10n The enhanced crown etherbased molecular recognition in aqueous media is due to the introduction of electrostatic attractions as was also demonstrated by other research groups for other crown ether-based host−guest systems.11 Herein we report a supramolecular micelle constructed by crown ether-based molecular recog-

1. INTRODUCTION Supramolecular micelles have received considerable attention from the scientific community because of their applications in drug delivery, controlled release, materials science, and so on.1 These applications owe to the unique core−shell structures constructed by spontaneous organization of amphiphiles that are formed by noncovalent interactions.1a,b The spontaneous organization of amphiphiles is due to the decrease of the free energy of the hydrophilic−hydrophobic interface: the hydrophobic segments gather in the core and the hydrophilic blocks are in contact with water to form the shell.1c,e Moreover, the hydrophilic and hydrophobic segments are connected by noncovalent interactions, which endow supramolecular micelles with stimuli-responsiveness, thereby functioning as hydrophobic molecule-loaded nanocapsules.2 Meanwhile, this distinctive property may be a profit for therapeutics because the amphiphilic nature makes supramolecular micelles suitable carriers for some drugs which are difficult to delivere into a tissue or an organ due to their poor solubility, limited stability, and toxicity.3 Then the release of hydrophobic molecules from micelles is achieved through external or internal stimuli, such as light,4a,b enzymatic degradation,4c or change in pH.4d,f Among these stimuli, pH change may be more suitable for biological applications because some intracellular compartments and tumors are more acidic than blood and normal tissues,4d which makes supramolecular micelles automatically release the hydrophobic molecules to the appointed sites due to their acidic environments. In contrast to the covalently linked amphiphiles, amphiphiles based on noncovalent interactions, namely supra-amphiphiles, have been found to respond to stimuli more easily.5 Various © 2012 American Chemical Society

Received: June 7, 2012 Revised: July 28, 2012 Published: August 6, 2012 6457

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Scheme 1. Cartoon Representation of the Formation of Supramolecular Micelles via the Self-Assembly of Supra-Amphiphiles Driven by Crown Ether-Based Molecular Recognition in Water and Chemical Structures of Model Compounds 3 and 4

Figure 1. 1H NMR spectrum (400 MHz, CDCl3, 298 K) of 1. NMR spectra were collected on a Bruker AVANCE DMX-500 spectrometer or a Varian Unity INOVA-400 spectrometer with TMS as the internal standard. Low-resolution electrospray ionization (LRESI) mass spectra were obtained on a Bruker Esquire 3000 plus mass spectrometer (Bruker-Franzen Analytik GmbH Bremen, Germany) equipped with an ESI interface and an ion trap analyzer. High-resolution electrospray ionization (HRESI) mass spectra were obtained on a Bruker 7-T FT-ICR mass spectrometer equipped with an electrospray source (Billerica, MA). The melting points were collected on a SHPSIC WRS-2 automatic melting point apparatus. Transmission electron microscopy investigations were carried out on a JEM-1200EX instrument. Molecular weights and molecular weight distributions were determined by gel permeation chromatography (GPC) with a Waters 1515 pump and Waters 1515 differential refractive index detector (set

nition with the capability of pH-responsive self-assembly/ disassembly in water (Scheme 1). We used poly(ethylene oxide) (PEO) as the hydrophilic moiety due to its high hydration level and good solubility in water.12 Hydrophilic PEO 1 terminated with a BMP32C10 host containing two COO− groups and a hydrophobic viologen dication derivative 2 containing a decyl group were used to prepare supra-amphiphiles (Scheme 1).

2. EXPERIMENTAL SECTION Materials and Methods. All reagents were commercially available and used as supplied without further purification. Compounds 7,S1 6,S2 5,S3 and 10S4 were prepared according to the published procedures. The other solvents were employed as purchased. 6458

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Scheme 2. Synthetic Routes for 1, 2, and 3

at 30 °C). It used a series of three linear Styragel columns (HT2, HT4, and HT5) at an oven temperature of 45 °C. The eluent was THF at a flow rate of 1.0 mL/min. A series of low-polydispersity polystyrene standards were employed for the GPC calibration. Dynamic light scattering (DLS) was carried out on a Malvern Nanosizer S instrument at room temperature. The fluorescence titration experiments were conducted on a RF5301 spectrofluorophotometer (Shimadzu Corp., Japan). FT-IR spectra were recorded on a NEXUS 47FT-IR spectrometer. Differential scanning calorimetry thermograms (DSC). DSC measurements were conducted on a DSC TA-60WS thermal analysis system (Shimadzu, Japan). Samples were first heated from −60 to 150 °C at a heating rate of 10 °C/min under a nitrogen atmosphere, followed by cooling to −60 °C at the rate of 10 °C/min after stopping at 150 °C for 3 min, and finally heating to 150 °C at the rate of 10 °C/ min. Compound 1. A mixture of 6 (310 mg, 0.435 mmol), 5 (581 mg, 0.232 mmol), CuSO4·5H2O (11.2 mg, 0.0440 mol), and ascorbic acid (15.3 mg, 0.0880 mol) was added to DMF/H2O (10 mL/1 mL) under the protection of N2, and the solution was stirred at 80 °C for 2 days. The solvents were removed by evaporation, and the residue was dissolved in THF and passed through a neutral alumina column to remove residual salts. After concentration and precipitation into an excess of diethyl ether, the product was obtained as a white solid (585 mg, 75%; Tm = 3.54 °C, Tg = 42.5 °C; Mn,GPC = 3.20 kDa, Mw,GPC = 3.30 kDa, PDI = 1.03). The 1H NMR spectrum of compound 1 is shown in Figure 1. 1H NMR (400 MHz, CDCl3, 298 K) δ (ppm): 8.69 (s, 1H), 7.89 (s, 1H), 6.34 (s, 1H), 6.09 (s, 2H), 5.88 (s, 1H), 5.04 (s, 2H), 4.55 (t, J = 4.9 Hz, 2H), 4.18 (m, 4H), 3.96−3.88 (m, 10H), 3.81−3.42 (252H, PhOCH2CH2O− and −OCHH2CH2O−). Compound 2. Compound 7 (484 mg, 1.00 mmol) was dissolved in H2O (10 mL), and an excess of NH4PF6 was added until no further precipitation occurred. The mixture was filtered. After vacuum drying the product was obtained as a brown solid (604 mg, 98%); mp: 196.5−198.2 °C. The 1H NMR spectrum of compound 2 is shown in Figure S1. 1H NMR (400 MHz, CD3CN, 298 K) δ (ppm): 8.93−8.88 (m, 4H), 8.38 (d, J = 5.3 Hz, 4H), 4.67 (m, 2H), 4.60 (t, J = 7.5 Hz, 2H), 1.64 (t, J = 7.2 Hz, 3H), 1.36−1.28 (m, 16H), 0.88 (t, J = 6.4 Hz, 3H). The 13C NMR spectrum of 2 is shown in Figure S2. 13C NMR (125 MHz, CD3CN, 298 K) δ (ppm): 149.62, 145.19, 145.04, 144.97, 126.85, 117.10, 61.82, 57.40, 30.61, 28.85, 28.72, 28.68, 28.29, 25.22,

22.08, 15.24, 13.09. LRESIMS is shown in Figure S3: m/z 470.9 [M − PF6]+ (100%). HRESIMS: m/z calcd for [M − PF6]+ C22H34F6N2P+, 471.2358; found 471.2353, error −1.1 ppm. Compound 3. A mixture of 10 (0.620 g, 1.10 mmol) and NH3·H2O (50 mL, 14 M) was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure, and the residue was dried in vacuum. The product was obtained as a yellow solid (0.61 g, 98%); mp: 75.4−76.8 °C. The 1H NMR spectrum of compound 3 is shown in Figure S4. 1H NMR (400 MHz, D2O, 298 K) δ (ppm): 7.49 (s, 1H), 6.99 (t, J = 8.2 Hz, 1H), 6.38 (d, J = 9.9 Hz, 2H), 6.32 (t, J = 2.4 Hz, 1H), 6.29 (s, 1H), 3.88 (m, 8H), 3.66 (m, 8H), 3.53 (m, 16H). The 13C NMR spectrum of 3 is shown in Figure S5. 13C NMR (125 MHz, D2O, 298 K) δ (ppm): 173.32, 159.32, 158.83, 131.61, 130.59, 119.07, 118.90, 107.77, 101.30, 98.88, 69.87, 69.79, 69.74, 69.66, 69.00, 68.95, 68.34, 67.31, 38.28, 38.13, 38.11, 37.94, 37.77, 37.60. LRESIMS is shown in Figure S6: m/z 623.6 [M − 2NH4 + H]− (100%). HRESIMS: m/z calcd for [M − 2NH4 + H]− C30H39O14−, 623.2351; found 623.2353, error 0.3 ppm. Preparation of Polymeric Micelles and the Encapsulation of Nile Red. Both 1 (78.0 mg, 20.0 mmol) and 2 (12.3 mg, 20.0 mmol) were dissolved in DMF (5 mL) at room temperature. After that, the solution was added dropwise into 15 mL of deionized water under stirring with a magnetic bar. Then the micellar solution was dialyzed against deionized water for 24 h (MWCO = 2000), during which the water was renewed every 4 h. The volume of the solution was increased to 40 mL with the addition of deionized water for further experiments. Nile Red was dissolved in the above micellar solution in an equal molar amount; then the suspension was sonicated for 30 min at room temperature. pH-mediated release of encapsulated Nile Red: An excitation wavelength of 550 nm and an emission wavelength of 660 nm were observed. The initial fluorescence intensity (F0) of the micellar solution without encapsuled Nile Red was measured using the fluorescence spectrometer. Then the fluorescence intensity (Fn) of the micellar solution with encapsuled Nile Red at the same concentration (5.0 × 10−4 M) was measured as a function of pH. The fluorescence intensity (F7) of the micellar solution with encapsuled Nile Red was measured at pH = 7.0, followed by adding small drops of HCl (38%) with the change of pH from 7.0 to 5.0, 4.0, and 3.0. The release percentage was calculated using the formula 6459

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release percentage (%) = (F7 − Fn)/(F7 − F0) × 100

3. RESULTS AND DISCUSSION The synthetic route for the preparation of the supramolecular amphiphilic polymer is shown in Scheme 2. In the synthesis of Table 1. Molecular Weight (kDa) Analysis of 5 and 1 5 1

Mn

Mw

Mp

Mz

Mz+1

PDI

3.20 3.90

3.30 4.10

3.31 4.04

3.40 4.33

3.50 4.62

1.03 1.05

Figure 4. Conductivity (κ) versus the concentration of the supramolecular amphiphilic polymer 1⊃2 in water.

Figure 2. FT-IR spectra of (a) 5 and (b) 1.

Figure 5. (a) TEM images of micelles formed by the self-assembly of the supra-amphiphiles at a concentration of 5.0 × 10−4 M in water (pH = 7.0). (b) Enlarged image of (a). (c) After adding a small drop of aqueous HCl solution to a (pH = 3.0). (d) After adding a small drop of aqueous NaOH solution to (c) (pH = 7.5).

Figure 3. GPC data (kDa) of (a) 5 and (b) 1. The weak peak at higher molecular region may be induced by certain weak interactions between polymer 1 in THF.

the hydrophilic block 1, the azide-terminated PEO (i.e., PEON3) was reacted with a water-soluble crown ether, a BMP32C10 derivative containing two COO− groups and an alkyne unit, to produce the targeted hydrophilic segment by click chemistry. The difference in molecular weight between the resultant polymer (Mn = 3.90 kDa, PDI = 1.05) and the starting azide-terminated PEO (Mn = 3.20 kDa, PDI = 1.03) was in coincidence with the molecular weight of the BMP32C10 derivative according to gel permeation chromatographic (GPC) measurements (Table 1). Further evidence of the formation of the targeted polymer was provided by FTIR and NMR analyses. The characteristic IR band of the azide at 2090 cm−1 disappeared in the spectrum of the resultant polymer (Figure 2). Calculations based on the integrations of the 1H

Figure 6. (a) Size distribution of the hydrophilic block 1 at the concentration of 5.0 × 10−4 M in water. (b) Size distribution of the supra-amphiphile 1⊃2 solution at the same concentration in water.

NMR peaks (Figure 1) indicated that the resultant polymer contained about 55 structural units per polymer chain, which was consistent with the result from GPC. The appearance of a 6460

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Figure 7. (a) Size distribution of 1 in aqueous solution at 5.0 × 10−4 M. (b) Size distribution of the supramolecular amphiphilic 1⊃2 solution at the same concentration. (c) After adding a small drop of aqueous HCl solution to (b) with a change of pH from 7.0 to 3.0. (d) After adding a small drop of aqueous NaOH solution to (c) with a change of pH from 3.0 to 7.5. (e) After adding a small drop of aqueous HCl solution to (d) with a change of pH from 7.5 to 3.0. (f) After adding a small drop of aqueous NaOH solution to (e) with a change of pH from 3.0 to 7.5.

signal for the triazole proton indicated the success of the click reaction. Compounds 3 and 4 were used as model compounds to investigate the host−guest complexation between 1 and 2 in water (see Supporting Information for the study on another host−guest pair). When an equimolar (4.00 mM) water solution of 3 and 4 was made, a yellow color appeared as a result of charge-transfer interactions between the electron-rich aromatic rings of 3 and electron-poor pyridinium rings of 4. A Job plot (Figure S9) based on UV−vis spectroscopy absorbance data in water demonstrated that the complexation of 3 with 4 was of 1:1 stoichiometry. The association constant (Ka) value was 1.5 (±0.1) × 103 M−1, which was determined by probing the charge-transfer band of the complex by UV−vis spectroscopy and employing a titration method (Figure S10). The proton NMR spectra (D2O, 5.0 mM) of 3, 4, and an equimolar mixture of 3 and 4 were examined (Figure S8). Upfield shifts were observed for pyridinium protons H6 and H7 of 4 after complexation. Aromatic protons H1−H5 of 3 shifted upfield after mixing, indicating crown ether/viologen complexation in water, similar to those in organic solvents.13 Therefore, by utilizing the electrostatic attraction-enhanced host−guest interactions, the negatively charged crown ether host unit of 1 binds the viologen dication guest moiety of 2 to form a supraamphiphile, and further this supra-amphiphile self-assembles to form stable dispersed supramolecular micelles with the decyl group as the core and PEO as the shell in water. (The compound 2 does not self-assemble into micellar aggregates due to the hydrophobicity of PF6−.) Furthermore, as demonstrated previously by us,10n the host−guest complexation between the negatively charged BMP32C10 unit and the paraquat moiety can be controlled by adding acid and base, giving pH responsiveness to the supramolecular micelles (Scheme 1). Conductivity measurements as a function of the amphiphilic polymer concentration were carried out (Figure 4) to determine the CMC of the supramolecular amphiphilic polymer 1⊃2.14 There are two linear segments in the curve

Figure 8. Fluorescence emission spectra of Nile Red (λexc = 550 nm) encapsulated in a 5.0 × 10−4 M micellar solution at different pH values compared with that of the micellar solution without Nile Red at pH 7.0 and at the same concentration.

Figure 9. Release percentage of Nile Red from the micellar solution as a function of pH.

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and a sudden reduction of the slope, implying the CMC is ∼7.5 × 10−5 M. To test the nature of the aggregates, transmission electron microscopy (TEM) and dynamic light scattering (DLS) studies were carried out.3a TEM images showed dark gray spherical aggregates, and the mean size of the micelles was 50 nm in diameter and uniformly dispersed (Figure 5a,b),3b in good agreement with the DLS results (Figure 6b). Thus, the big aggregates were believed to originate from the self-assembly of the supra-amphiphiles in water. The COO− groups can be converted into the neutral carboxylic acid groups by adding acid, weakening the complexation between the BMP32C10 unit and the viologen moiety and destroying the micellar structure. The reversible transition between assembled and disassembled structures can be achieved by this change of pH. TEM and DLS were used to investigate the effect of pH on the aggregation behavior according to the size of the amphiphilic polymer in solution (Figures 5 and 7). The DLS results indicated that the hydrophilic segment, PEO terminated with a BMP32C10 containing two COO− groups, exists with a size of 8−10 nm (Figure 6a), while the size of an equimolar mixture of hydrophilic and hydrophobic blocks was about 50 nm (Figure 6b). As shown in Figures 5 and 7, a small drop of aqueous HCl was added to the neutral micellar solution, inducing a dramatic decrease of the size from 50 nm in diameter to 10 nm (pH = 3.0). Meanwhile, the spherical aggregates with uniformly dispersed size were destroyed (Figure 5c). After HCl was added, the counteranions of salt 2 were partly changed to chloride anions. Therefore, some of salt 2 molecules were transformed to amphiphilic molecules, which can self-assemble to form the rodlike structure shown in Figure 5c. Continuous addition of small drops of aqueous NaOH solution resulted in a recovered aggregate size (Figures 5d and 7), indicating the reassembly of the amphiphilic polymer. Moreover, this reversible transition could be repeated by further additions of acid and base which brought about similar changes (Figure 8). Therefore, the micelles formed by supra-amphiphiles can be utilized to encapsulate hydrophobic guest molecules into their hydrophobic cores at neutral condition and later release the guest molecules in response to a decrease in pH. To study the encapsulation and controlled release abilities of the supramolecular micelles, a fluorescence titration experiment was carried out. It is well-known that Nile Red is insoluble and does not fluoresce in water, but its aqueous solution starts to fluoresce once it is encapsulated into micelles.15 Nile Red as a hydrophobic fluorescent guest was encapsulated into our supramolecular micelles at a concentration of 5.0 × 10−4 M. The emission spectrum of the micellar solution without Nile Red under the same conditions is also shown in Figure 8 for comparison. There is only the emission band of supraamphiphiles at 590 nm in the emission spectrum of the micellar solution without Nile Red, while for the micellar solution fluorescence emission centered at 660 nm (excited at 550 nm) was observed, indicating the encapsulation of the hydrophobic Nile Red into the hydrophobic core of the micelles. Furthermore, considering that the self-assembly of supra-amphiphiles is pH-responsive, release of Nile Red from the micelles was realized by adding acid (aqueous HCl), weakening the host−guest interactions and leading to disassembly of the supramolecular micelles. As shown in Figures 8 and 9, the fluorescence intensity of Nile Red centered at 660 nm reduced gradually as the pH decreased from 7.0 to

3.0, suggesting that the release of Nile Red from the micelles was pH-dependent, in agreement with the results of DLS and TEM.

4. CONCLUSIONS In conclusion, the first supra-amphiphile constructed by crown ether-based molecular recognition was synthesized and demonstrated to self-assemble into core−shell supramolecular micelles in water. The reversible transition between assembled and disassembled structures can be achieved by a change of pH. More importantly, the results demonstrated the pH-responsive release of hydrophobic guest molecules from the interior of supramolecular aggregates, making it possible to use these supramolecular micelles in controlled drug delivery and biotherapeutics.

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ASSOCIATED CONTENT

S Supporting Information *

Characterizations, UV−vis data, and other materials. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Fax +86-571-8795-3189; e-mail [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (20834004, 91027006, and 21125417), the Fundamental Research Funds for the Central Universities (2012QNA3013), Program for New Century Excellent Talents in University, and Zhejiang Provincial Natural Science Foundation of China (R4100009).

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REFERENCES

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dx.doi.org/10.1021/ma301162s | Macromolecules 2012, 45, 6457−6463