Facile synthesis and self-assembly of amphiphilic polydimethylsiloxane with poly(ethylene glycol) moieties via thiol-ene click reaction

Yong Xia, Hongtao Yao, Zhihui Miao, Yun Ma, Meifang Cui, Liqiang Yan, Huanhuan Ling and Zhengjian Qi*
College of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 211189, PR China. E-mail: qizhengjian@seu.edu.cn; Tel: +86 13605186011

Received 29th May 2015 , Accepted 5th June 2015

First published on 5th June 2015


Abstract

We demonstrate here a facile and efficient synthesis of polysiloxane-based amphiphilic copolymers via thiol-ene click chemistry. The properties of PEG-b-PDMS-b-PEG (T-PPG) and PDMS-g-PEG (S-PPG20 and S-PPG100) amphiphilic copolymers were studied in detail by a combination of 1H NMR, FT-IR, gel permeation chromatography, and thermogravimetric analysis. In comparison with the traditional hydrosilylation method which requires the noble metal catalyst platinum, the newly designed thiol-ene protocol produces polysiloxane-based amphiphilic copolymers with only anti-Markovnikov addition products under benign conditions. The resulting copolymers have lower critical aggregation concentration (CAC), and dynamic light scattering (DLS) results revealed that the obtained amphiphilic copolymers can self-assemble into nanoparticles (128 nm to 198 nm) in aqueous solutions with a narrow size distribution (PDI is less than 0.24).


Introduction

Amphiphilic copolymers capable of smart self-assembly into diverse nanostructures have aroused significant interest in many application areas such as nanocarriers,1,2 nanoreactors,3,4 and drug delivery and controlled release systems.5–8 Among them, polydimethylsiloxane block/graft polyethylene glycol (PDMS-b-PEG or PDMS-g-PEG), which is one of the multitudinous amphiphilic copolymers, has been the focus of research scientists for its wealth of advantageous physical properties brought by siloxanes. PDMS are generally recognized as unique valuable polymers with various distinctive properties, such as low surface energy, low glass transition temperature, hydrophobicity, excellent flexible Si–O–Si bonds, high gas permeability, excellent thermal stability, and biological compatibility.9–11 PEG, which is a well-known nontoxic, flexible, and excellent water-soluble polymer, is widely used in pharmaceutical, cosmetic, food processing and other industries.12–15 Because of covalent bonding of these two segments, the block or graft copolymers combining synergistically the features and characteristics of both PDMS and PEG, can endow the corresponding copolymers with amphiphilic property, optical transparency, good thermal and mechanical stabilities, etc.

A large variety of polysiloxane-based amphiphilic copolymers have been investigated to study their structure–property relationships. In 1981, Galin synthesized a series of linear triblock dimethylsiloxane–ethylene oxide PDMS–PEO–PDMS copolymers, and studied the structural and thermodynamic properties.16 Subsequently, Grainger and his colleagues synthesized a series of poly(dimethylsiloxane)–poly(ethylene oxide)–heparin (PDMS–PEO–Hep) triblock copolymers. The surface characterization, the compositional differences between surface and bulk, and bioactivity had been explored in detail.17–19 Wegner made a thorough inquiry into the phase behavior of photo-cross-linkable ethylene oxide (PEO)–dimethylsiloxane (PDMS) triblock copolymers PEO–PDMS–PEO in aqueous solutions, and found the triblock copolymer/water system could form cubic I1, hexagonal H1, and lamellar Lα phases depending on its compositions.20 Kickelbick synthesized a series of short-chain PDMS-b-PEO diblock copolymers, and observed a spontaneous vesicle formation in water, the electron microscopy studies showed that the copolymers were inclined to aggregate into vesicles and lamellar structures.21,22 Furthermore, functionalized polysiloxane-based amphiphilic copolymers have been widely applied as targeted-drug carriers,23 bioreactors,24–26 and gas separation membranes.27,28

Most of the above-mentioned polysiloxane-based amphiphilic copolymers were prepared by hydrosilylation of polymethylhydrosiloxanes with vinyl-terminated hydrophilic segments using Pt complex catalysts (Fig. 1). However, this traditional method has some disadvantages: noble metal platinum is very expensive and meanwhile is difficult to be removed during the purification procedure, which would limit its application in biomedicine; also, the reactions usually require anhydrous and anaerobic environment; what is more, the hydrosilylation reaction usually results in coexistence of Markovnikov and anti-Markovnikov addition products,29 which might complicate the structure–property relationships of the amphiphilic copolymers.


image file: c5ra10150f-f1.tif
Fig. 1 Preparation methods of polysiloxane-based amphiphilic copolymers report previously and in this manuscript.

Recently, because of its efficiency and fidelity such as modular, wide in scope, very high-yield, only inoffensive byproduct click chemistry has attracted increased attention in the preparation of silicone materials.30–34 Herein, we present a facile thiol-ene click chemistry method to prepare PEG-b-PDMS-b-PEG and PDMS-g-PEG amphiphilic copolymers with well-defined structures under benign conditions, and study their thermodynamics and properties in aqueous solutions. Our goal is not only to synthesize a triblock copolymer PEG-b-PDMS-b-PEG and comb-like copolymer PDMS-g-PEG but also to demonstrate the successful use of “thiol-ene” in macromolecules conjugation and study the aqueous solution behaviors of the amphiphilic copolymers.

Experimental section

Materials

Poly(ethylene glycol) methyl ether (1000 g mol−1), thioglycolic acid (TGA, 98%) 2,2-dimethoxy-2-phenylacetophenone (DMPA), were purchased from Aladdin (China) and used as received. Octamethylcycloterasiloxane (D4), tetramethyltetravinylcyclotetrasiloxane (D4Vi), 1,3-divinyl-1,1,3,3-tetramethyl-disiloxane (MMVi), hexamethyldisiloxane (MM) and tetramethylammonium hydroxide ((CH3)4NOH) were purchased from J&K Chemical and used without any further purification. Tetrahydrofuran (THF), diethyl ether, and toluene were of analytical grade. In the current work, the synthesis of precursor was carried out under a dry nitrogen atmosphere, whereas the thiol-ene reaction was carried out under ambient conditions. A UV lamp (20 mW cm−2, λ = 365 nm; LP-40A; LUYOR Corporation) was used to irradiate the samples to perform the photo-induced reactions.

Synthesis of vinyl-functional polysiloxanes (PDMS-Vi and sPDMS-Vi)

Vinyl-terminated polysiloxane (PDMS-Vi) and polymethylvinylsiloxane (sPDMS-Vi) were synthesized according to the previous literature.35

D4 (25.0 g, mol), MMVi (0.94 g, mmol), and 0.0125 g tetramethylammonium hydroxide were added to a three-neck flask with a stir bar and condenser under dry argon atmosphere. The mixture was stirred for 5 h at 90 °C and then heated to 150 °C to eliminate tetramethylammonium hydroxide. PDMS-Vi was obtained as a colorless liquid after the low molecular-weight products were removed under vacuum at 180 °C. Yield: 93%, 1H NMR (400 MHz, CDCl3, ppm): δ = 0.02 to 0.19 (m, –CH3), 5.71 to 6.21 (m, –CH[double bond, length as m-dash]CH2). GPC-result, Mn: 5274, PDI: 1.28.

D4 (15.0 g, mol), D4Vi (10.0 g, mol), and 0.25 g tetramethylammonium hydroxide were added to a three-neck flask with a stir bar and condenser under dry argon atmosphere. The mixture was stirred for 0.5 h at 90 °C to obtain a preformed polymer. MM (0.81 g, mmol) was then added to the three-neck flask by constant-pressure funnel. The mixture was stirred for another 5 h at 90 °C and then heated to 150 °C to remove the tetramethylammonium hydroxide. sPDMS-Vi was obtained as a colorless liquid after the low molecular-weight products were eliminated under vacuum at 180 °C. Yield: 91%. 1H NMR (300 MHz, CDCl3, ppm): δ = 0.07 to 0.15 (m, –CH3), 5.75 to 6.07 (m, –CH[double bond, length as m-dash]CH2). GPC-result, Mn: 7536, PDI: 1.32.

Synthesis of thiol-terminated polyethylene glycol (mPEG-SH)

Thiol-terminated polyethylene glycol was synthesized according to the classical esterification reaction. Poly(ethylene glycol) methyl ether (20 g, 0.02 mol) and thioglycolic acid (9.2 g, 0.1 mol) are dissolved in 100 mL of toluene. The reaction was carried out by an azeotropic distillation followed by a gentle reflux for one night. After removing the solvent under vacuum, the residue is purified by dissolution in dichloromethane and precipitation in cold ether for three times. The resulting product is finally dried under vacuum at room temperature. Yield: 88%, 1H NMR (300 MHz, CDCl3, ppm): δ = 2.0 (t, –SH), 3.26 (d, –CH2–SH), 3.34 (s, CH3O–), 3.61 (m, –OCH2CH2O–), 4.26 (t, –CH2–OCO–). GPC-result, Mn: 1098, PDI: 1.11.

Synthesis of PEG-b-PDMS-b-PEG (T-PPG) and PDMS-g-PEG (S-PPG) copolymers

The structure and synthetic route are shown in the Scheme 1. The triblock copolymer (T-PPG) was synthesized by thiol-ene click chemistry as follow: 1.3 g vinyl-terminated polysiloxane (PDMS-Vi), 1.2 g thiol-terminated polyethylene glycol (mPEG-SH) and 0.06 g DMPA were dissolved in glass vessels containing a dry THF solvent (3 mL). The vessels were placed under UV light irradiation and stirred gently for 30 min, then the solution was placed in a dialysis bag (cutoff Mn: 3.5 kDa) and dialyzed against water for 3 days to remove residual mPEG-SH. The solution outside the bag was replaced with fresh water every 4 h and finally, the mixture in the dialysis bag were dried to give final product. Yield: 98%, 1H NMR (300 MHz, CDCl3, ppm): δ = 0.02 to 0.19 (m, –CH3), 0.90 (t, –SiCH2CH2–), 2.70 (t, –SiCH2CH2–), 3.26 (d, –S–CH2COO–), 3.37 (s, CH3O–), 3.64 (m, –OCH2CH2O–), 4.27 (t, –COO–CH2–). GPC-result, Mn: 6599, PDI: 1.34. PDMS-g-PEG (S-PPG) copolymers were obtained by a similar procedure. S-PPG20 (the mole ratio of thiol and vinyl is 0.2). Yield: 97%, 1H NMR (300 MHz, CDCl3, ppm): δ = 0.04 to 0.28 (m, –CH3), 0.91 (t, –SiCH2CH2–), 2.71 (t, –SiCH2CH2–), 3.37 (d, –S–CH2COO–), 3.55 (s, CH3O–), 3.69 (m, –OCH2CH2O–), 4.26 (t, –COO–CH2–), 5.74 to 6.05 (m, –CH[double bond, length as m-dash]CH2). GPC-result, Mn: 10[thin space (1/6-em)]857, PDI: 1.35. S-PPG100 (the mole ratio of thiol and vinyl is 1.0). Yield: 96%, 1H NMR (600 MHz, CDCl3, ppm): δ = 0.04 to 0.17 (m, –CH3), 0.91 (t, –SiCH2CH2–), 2.73 (t, –SiCH2CH2–), 3.27 (d, –S–CH2COO–), 3.40 (s, CH3O–), 3.65 (m, –OCH2CH2O–), 4.33 (t, –COO–CH2–). GPC-result, Mn: 14[thin space (1/6-em)]445, PDI: 1.31.
image file: c5ra10150f-s1.tif
Scheme 1 Syntheses of polymers and copolymers.

Characterizations

1H-Nuclear Magnetic Resonance (1H NMR) spectroscopy were recorded on a Bruker Avance 300, 400, or 600 MHz at 25 °C using deuterated chloroform (CDCl3) as solvent and without the interior label. All chemical shifts are reported in ppm (δ). Fourier Transform Infrared Spectroscopy (FT-IR) spectra were recorded using a Bruker TENSOR27 infrared spectrophotometer with KBr pellet technique within the 4000 cm−1 to 400 cm−1 region. Gel permeation chromatography (GPC) measurements were carried out on PL-GPC220. THF was used as the eluent at a low flow rate of 1.0 mL min−1 at 40 °C and polystyrene standards as the references. Thermogravimetric analysis (TGA) was performed using a STARe System (Mettler Toledo) with a heating rate of 20 °C min−1 from 50 °C to 850 °C under N2. TEM images were taken using a JEOL 2100 high-resolution TEM and Philips (CM 200, 80 kV). A tiny drop of sample was deposited on a carbon coated copper grid containing 400 meshes.

Critical aggregation concentration (CAC) measurements

The CAC of the copolymers in ultrapure water was determined by fluorescence spectroscopy using pyrene as a hydrophobic fluorescent probe.36,37 Briefly, a pyrene solution (6.2 × 10−6 M in acetone, 1 mL) was added to different vials, and the solvent was evaporated. Then, 10 mL of aqueous solutions containing different concentrations of copolymer were added to the vials. The final concentration of pyrene in each vial was 6.2 × 10−7 M. The concentrations of polymer micelles varied from 1.0 × 10−4 g L−1 to 1.0 g L−1. Fluorescence measurements were performed on a FluoroLog 3-TCSPC (Horiba Jobin Yvon Inc.) equipped with a xenon light source (UXL-150S, Ushio, Japan). The emission and excitation slit widths were 2 nm and 5 nm, respectively. The samples were excited at 330 nm and emission spectra were recorded from 345 to 500 nm. The emission fluorescence values I372 (I1) and I384 (I3), at 372 and 384 nm, respectively, were used for subsequent calculations. The CAC was determined by plotting the I384/I372 (I3/I1) ratio against the polymer concentration. The CAC was taken as the intersection of regression lines calculated from the linear portions of the plot.

Dynamic light scattering (DLS)

The measurements were performed in the 1 g L−1 polymer solution using a Brookhaven BI-200SM instrument equipped with a 4 mW He–Ne laser (λ = 532 nm) at an angle of 90°, an avalanche photodiode detector with high quantum efficiency, and an ALV/LSE-5003 multiple τ digital correlator electronics system. The micelle copolymer solutions were prepared by direct dissolution of copolymers in ultrapure water, and were filtered through 0.45 μm PTFE microfilters 24 hours before measurements. The sizes of the particles were determined using the intensity-weighted distribution of particle sizes.

Results and discussion

Characterization of the amphiphilic copolymers

The three copolymers were synthesized by coupling via click chemistry of a Si–CH[double bond, length as m-dash]CH2 end-capped or side-capped polysiloxane with a thiol-terminated polyethylene glycol (Scheme 1). The PDMS segment was prepared via anionic ring-opening polymerization (AROP), and the classical esterification reaction for thiol-terminated polyethylene glycol. The FT-IR spectra for T-PPG, S-PPG20, and S-PPG100 are shown in Fig. 2, the corresponding spectra for PDMS-Vi, sPDMS-Vi, and mPEG-SH are shown in Fig. 1S. The peaks observed at 3055 cm−1 and 1598 cm−1 in the curve of sPDMS-Vi are the ν(C[double bond, length as m-dash]C–H) and ν(C[double bond, length as m-dash]C) vibrations respectively. The curve of mPEG-SH shows st(S–H) vibration at 2559 cm−1. The ν(C[double bond, length as m-dash]C–H), ν(S–H), and ν(C[double bond, length as m-dash]C) vibrations disappeared and ν(C[double bond, length as m-dash]O) vibration is observed at 1741 cm−1 in the curve of S-PPG100, which indicated the occurrence of the thiol-ene reaction and the reaction was complete. The integral area of the peak at 1741 cm−1 in S-PPG100, S-PPG20, and T-PPG diminishes gradually, which confirms the polyether content of the copolymers gradually reduce. The peaks at 1106 cm−1 and 1010 cm−1 in the curves of the three copolymers are the ν(C–O–C) and ν(Si–O) vibrations respectively. The relative size of integral area further confirms S-PPG100 has the highest content of polyether. It should be noted that small peaks at 3055 cm−1 and 1598 cm−1 are due to the retained CH2[double bond, length as m-dash]CH group in S-PPG20, which is in agreement with the incomplete substitution of PDMS observed by 1H NMR (enlarged figure is shown in Fig. 1S), but the integral area of the peaks diminishes obviously compared with before thiol-ene reaction. The full conversion of thiol-ene reaction of T-PPG is confirmed through 1H NMR spectra with the disappearance of a vinyl peaks (–Si–CH[double bond, length as m-dash]CH2) at 5.71 ppm to 6.21 ppm and the appearance of –Si–CH2 – (0.90 ppm) and –Si–CH2 CH2 – (2.70 ppm), as shown in Fig. 3a. The same results are observed for S-PPG100, and there are residue vinyl peaks (5.74 ppm to 6.05 ppm) in S-PPG20 (Fig. 3b). The data of 1H NMR spectra is in good agreement with the result of the FT-IR spectra.
image file: c5ra10150f-f2.tif
Fig. 2 Infrared spectra of S-PPG100, S-PPG20, and T-PPG copolymers.

image file: c5ra10150f-f3.tif
Fig. 3 1H NMR spectra of PDMS-Vi, sPDMS-Vi, mPEG-SH, S-PPG100, S-PPG20, and T-PPG (detail is shown in the Fig. 2S).

Self-assembly of copolymers in aqueous solutions

The amphiphilic block/graft copolymer consists of a hydrophilic PEG segment and a hydrophobic PDMS segment. CAC is one of the important parameters for investigating the formation of micelles and assessing the stability of the resulting micelles. CAC values of S-PPG100, S-PPG20, and T-PPG copolymers are determined by fluorescence technique using pyrene as a hydrophobic probe, which are widely used in the other similar materials and corresponding results are shown in Table 1S. The fluorescence spectrum of pyrene exhibits five peaks, and the ratio of intensities of the first and third peaks (I3/I1) correlates with the polarity of the probe microenvironment. When pyrene molecule accesses from polar environment to nonpolar environment, the values of I3/I1 have a point mutation. Above the CAC, pyrene molecules enter into the hydrophobic environment of the core thereby experiencing a different local polarity.38 The pyrene fluorescence intensity ratios (I384/I372) are plotted against the logarithm of copolymer concentration. Below a certain concentration, I3/I1 is almost constant. Above this concentration, I3/I1 increases with the increase of log[thin space (1/6-em)]C and finally reaches a plateau. The fluorescence emission spectra of pyrene in the presence of S-PPG20 at various concentrations are shown in Fig. 4a. The intensity ratio of I3/I1 versus log[thin space (1/6-em)]C of the S-PPG20 copolymer in the pyrene emission spectra is shown in Fig. 4b. From this plot, the CAC of S-PPG20 was determined to be approximately 8.1 × 10−3 g L−1 through the intersection of two straight lines. The CAC of S-PPG100 and T-PPG were also obtained by the same method and shown in Table 1 and Fig. 3S. The CAC values of the three copolymers reduced as the proportion of PEG segment increased, which is opposite to the expected order. In a generally way, surfactants with higher content of the hydrophobic segments will result in stronger interactions between hydrophobic chains, leading to a more stable structure, and therefore to a lower CAC value. While the polysiloxane-based copolymers studied in the current work, the trend is the opposite. The reason for this phenomenon is that what we are obtaining is not micelle formation but formation of vesicles and lamellar. The PDMS segments of the copolymers used in this work are rather bulky, rendering micelle formation unfavorable and favoring the formation of a lamellar phase already at low concentration. The reverse order of CAC values found in the measurements most likely reflects the ease or complexity of packing into vesicles and lamellar. Thus, the order of the CAC values reflects the copolymer geometry, not the hydrophobicity, which is the critical factor that governs the CMC values of ordinary surfactants. This trend is in good agreement with reported results in the literature.21,22,39,40 Furthermore, the starting PDMS and PEG precursors with different concentrations have almost the same I3/I1 ratio in aqueous solutions, which confirms there is an aggregate effect instead of the purely proximity effect (Fig. 4S).
image file: c5ra10150f-f4.tif
Fig. 4 Emission spectra of pyrene as a function of S-PPG20 concentration in water (a), and variation of the intensity ratio (I3/I1) as a function of S-PPG20 concentration (b), the dotted line shows the CAC value.
Table 1 The related data of copolymers
Copolymers GPC Method of fluorescent probe DLS
Mn (g mol−1) Mw/Mn CAC (g L−1) Size (nm) PDI
T-PPG 6599 1.34 (1.2 ± 0.02) × 10−2 198 ± 2 0.19 ± 0.02
S-PPG20 10[thin space (1/6-em)]857 1.35 (8.1 ± 0.01) × 10−3 146 ± 1 0.21 ± 0.01
S-PPG100 14[thin space (1/6-em)]445 1.31 (6.8 ± 0.04) × 10−3 128 ± 4 0.23 ± 0.02


To study the self-assembly nanoparticle formation, the particle size was studied using dynamic light scattering, and the results are shown in Fig. 5. DLS results showed that all of the three copolymers exhibited unimodal size distribution with the mean diameters ranging from 128 to 198 nm and a narrow size distribution (PDI is less than 0.24), which is agreement with reported results of similar structure of the copolymer. The size of particle reduced with an increase in the proportion of hydrophilic part, so the size of the copolymer particle could be adjusted by changing the proportion of the hydrophilic part of the copolymer. The T-PPG copolymer has the largest diameter up to 198 nm, which might be ascribed to the microaggregation of T-PPG nanoparticles. Compared with S-PPG100 and S-PPG20, T-PPG contains more PDMS content and is more hydrophobic, which might lead to the tendency of aggregation of T-PPG nanoparticles. The particle size obtained from TEM micrograph are smaller than those obtained by DLS because TEM micrographs show the micelle with the corona shrinkage after evaporation of water, while DLS gives the size of swollen nanoparticles in aqueous solution (shown in Fig. 5S). It is interesting to note that there are some rod-like structures in T-PPG copolymer. We are concentrating on optimizing the assembly conditions to obtain the desired micellar structures, which could be used as special functional materials.


image file: c5ra10150f-f5.tif
Fig. 5 Size distribution of nanoparticles formed by S-PPG100, S-PPG20, and T-PPG determined by DLS at 25 °C in aqueous solutions. Copolymer concentration is 1.0 mg mL−1.

Thermogravimetric analysis

The thermal behavior of the resulting copolymers is evaluated through TGA analysis, and the TGA curves are presented in Fig. 6. The TGA data shows that all the three copolymers exhibit excellent thermal stability, and the degradation temperatures (Td) are in the range of 290–340 °C under nitrogen, the presence of thioether bonds does not affect the thermal stability of the copolymers. The thermal stability increased with the increase of the PDMS content, in the order of T-PPG > S-PPG20 > S-PPG100 of the copolymers as it can be seen from Fig. 6. The increased thermal stability of the copolymers with increased PDMS content is attributed to the fact that the PDMS polymers are known to have high thermal stability. The mPEG curve exhibit a one-step decomposition, while the TGA weight loss curve and first-derivative curve for T-PPG copolymer with the largest PDMS content indicate the presence of two distinct decompositions. The first is consistent with the PEG segment of the copolymer, while the second is due to the PDMS segment decomposing.
image file: c5ra10150f-f6.tif
Fig. 6 TGA curves of T-PPG, S-PPG20, S-PPG100, and mPEG (in N2).

Conclusions

In summary, we developed PEG-b-PDMS-b-PEG (T-PPG) and PDMS-g-PEG (S-PPG20 and S-PPG100) amphiphilic copolymers by a newly designed thiol-ene click chemistry protocol. The results of 1H NMR, FT-IR, and gel permeation chromatography indicate the well-defined structures of the copolymers. The obtained polysiloxane-based amphiphilic copolymers have lower critical aggregation concentration (CAC), and could directly self-assemble into the stable uniform-sized nanoparticles in aqueous solutions, whose aggregative diameters are closely related with polysiloxane content. Thermal analysis revealed that all the three copolymers exhibit excellent thermal stability, and the degradation temperatures (Td) are in the range of 290–340 °C under nitrogen. Because of these novel characteristics such as facile synthesis, amphiphilicity, and ability to self-assemble directly into polymer nanoparticle in aqueous solution, the copolymers are believed to find wide applications in a lot of research fields, especially in biomedical engineering.

Acknowledgements

The author wish to acknowledge the financial supports from Jiangsu Province Transformation of Scientific and Technological Achievements Program (BA 2014123) and the Fundamental Research Funds for the Central Universities (CXLX13_106).

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Footnote

Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra10150f

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