Preparation of Thermoresponsive Polymer Nanogels of Oligo(Ethylene Glycol) Diacrylate-Methacrylic Acid and Their Property Characterization
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Stimuli-responsive polymers have received growing attention in recent years owing to their wide applications in diverse fields. A novel stimuli-responsive polymer, based on oligo(ethylene glycol) diacrylate (OEGDA) and methacrylic acid (MAA), P(OEGDA-MAA), is prepared by precipitation polymerization and is shown to have a LCST-type VPTT (volume phase transition temperature) at 33 °C in water and a UCST-type VPTT at 43 °C in ethanol, all at concentration of 1 mg/mL. Both VPTTs are strongly concentration and pH dependent, providing an easy way to tune the phase transition temperature. The polymer is characterized with regard to its composition and its morphology in water and in ethanol at different concentration. The two transitions are studied and interpreted based on the results. This work provides a novel way for the preparation of a new type of stimuli-responsive polymer with great potential for different applications, particularly those in biomedical areas because PEG-based stimuli-responsive polymers are known to be nontoxic and non-immunogenic.
KeywordsOligo(ethylene glycol) diacrylate Methacrylic acid Crosslinking Thermoresponsive Volume phase transition
Atom transfer radical polymerization
Dynamic light scattering
Lower critical solution temperature
Oligo(ethylene glycol) diacrylate
Poly(oligo(ethylene glycol) diacrylate-methacrylic acid)
Poly[(oligo(ethylene glycol) methyl ether methacrylate]
Reversible addition-fragmentation chain transfer polymerization
Hydrodynamic particle radius
Upper critical solution temperature
Volume phase transition temperature
Stimuli-responsive polymers are able to respond to external stimuli with considerable change in their physicochemical properties [1, 2, 3]. A great variety of their applications, including actuators, drug delivery, gene transfer, and materials separation, have been developed [4, 5, 6, 7] thanks to this responsiveness. Among the common external stimuli, such as temperature, pH, ionic strength, electric field, and ultrasound, polymers responsive to temperature change, namely thermosensitive polymers, have received great attention for decades [1, 2, 3, 4, 5, 6, 7, 8, 9], of which the polymers with a volume phase transition temperature (VPTT) or a lower critical solution temperature (LCST), for no-crosslinked soluble polymers, have been by far the most widely studied. This is particularly true for P(N-isopropylacrylamide), PNIPAM, a thermosensitive polymer extensively studied for its potential biomedical applications [2, 9, 10, 11, 12] due to its VPTT in water around 32 °C, close to the human body temperature.
It is well accepted that PNIPAM-based materials are of discernable hysteresis, have strong hydrogen-bonding interactions with proteins, and produce low-molecular weight amines during hydrolysis. All these properties have limited their applications in the biotechnology field . Recently, a new family of polymers (PEG) based on oligo(ethylene glycol) (OEG) with thermoresponsive properties has been developed [14, 15, 16, 17]. However, PEG in water is only thermoresponsive at elevated temperature and under pressure , which makes PEG unsuitable for many applications. To widen its applications as thermoresponsive materials, the common practice is to attach functional groups at one or both of its OEG terminals, making an OEG macromonomer, which is then polymerized through different processes, including for instance anionic , cationic , group transfer polymerization [21, 22]; conventional free radical polymerization ; a variety of free radical-based living polymerizations, including ATRP , RAFT [25, 26], and NMP ; and diverse other processes of polymerizations [28, 29]. It is now well known that VPTT or LCST of the OEG-based polymers can be adjusted by changing the experimental conditions of their syntheses, in order to change their structures, including for instance the molecular weight, the architecture and the length of EG segment, the ratio and the structure of the comonomers, and the nature of the end groups. All these have been well presented in recent reviews [1, 17].
It is notable that an absolute majority of the reported studies on OEG-based responsive polymers has been prepared with one end of the OEG monomer functionalized by (meth)acrylate while the other end is terminated by an ether. The polymers thus prepared are therefore consisted of a backbone of the (meth)acrylic segments with the OEG chains as the pendant groups, which makes the OEG polymer a comb-like chain. Another common feature for the OEG-based polymers reported up to date is that these polymers have been prepared mostly by polymerization of one single OEG macromonomer  or copolymerization of two or more OEG macromonomers of different OEG length or structure [14, 15, 16], not crosslinked in either case. In contrast to this background, a novel type of OEG-based polymer, P(OEGDA-MAA), is prepared in this work by copolymerization of oligo(ethylene glycol) diacrylate (OEGDA) with methacrylic acid (MAA), through precipitation polymerization in water. The polymer thus formed is therefore crosslinked because of the diacrylate structure and is shown to be thermoresponsive with a VPTT in water, which is similar to the commonly reported LCST-type phase transition, whereas in ethanol this polymer demonstrates a VPTT of UCST-type. Both VPTTs are closely concentration dependent. These phase transitions are characterized with regard to polymer composition and morphology in dispersion at different concentration. This work provides therefore a novel type of stimuli-responsive polymer with great potential for different applications, particularly in biomedical areas.
Oligo(ethylene glycol) diacrylate (OEGDA, Mn = 575) was purchased from Aladdin (Shanghai, China). Methacrylic acid (MAA) was from Tianjin Guangcheng Chemicals (Tianjin, China), with inhibitors removed by passing through basic Al2O3 (Sinopharm Chemical Regent Co. Ltd., Shanghai, China). Ammonium persulfate (APS) was supplied by Tianjin Hedong Hongyan Chemicals (Tianjin, China). The dialysis bags (MWCO 3500) were from Union Carbide Corporation (Shanghai, China).
Preparation of P(OEGDA-MAA)
The copolymer of OEGDA and MAA, P(OEGDA-MAA), was prepared by precipitation polymerization in water. For a typical process, MAA (0.1834 g, 2.11 mmol) and OEGDA (0.8166 g, 1.43 mmol, molar ratio of OEGDA/MAA = 40/60) were added into 500 mL of deionized water pre-located in a glass flask of 1 L capacity. After nitrogen purging to remove oxygen, APS solution (10 wt%, 300 μL) was added. The flask was quickly sealed off and located into a water bath at 70 °C to start the polymerization for 4 h usually. The clear content in the bottle quickly became turbid after initiation, indicating the precipitation of the polymer. At the end of the polymerization, the reaction system was cooled down to room temperature, and the turbid emulsion-like mixture turned into a clear polymer dispersion, to which a certain amount of NaCl solution (2 M) with pH at 1.0, pre-adjusted using hydrochloric acid, was added. The addition of NaCl solution provoked the precipitation of the polymer, which was collected by centrifugation at 10,000 rpm, redispersed in water, and finally dialyzed against deionized water at room temperature for 72 h to remove NaCl.
1H NMR analysis of the polymers was performed on a 400-MHz NMR spectrometer (Avance III, Bruker, Switzerland) using dimethyl sulfoxide-d6 (DMSO-d6) as the solvent. The morphology of the dried polymer was observed using a scanning electron microscope (SEM, FEI Quanta Feg-250, US). OEGDA content of the polymer was determined using potentiometric titration as previously described . A dispersion of the polymer in deionized water (1.0 mg/mL) was titrated to pH 11.5 with calibrated NaOH solution of about 0.1 M. pH of the dispersion was measured and recorded with a pH meter (Metrohm 808 Titrandio, Switzerland). The equivalence point was used to determine MAA content in the copolymer. VPTT of P(OEGDA-MAA) in a gastric dispersion (pH = 1.0, 150 mM NaCl) was measured as previously described . VPTT of P(OEGDA-MAA) in its ethanol dispersion was determined by following the transmittance of the dispersion by a light of 565 nm using a spectrophotometer (UV3101PC, Shimadzu, Japan). The polymer dispersion was first heated to 70 °C, above the transition temperature, equilibrated for 5 min, and followed by cooling down from 65 to 10 °C at an interval of 5 °C with also an equilibrium time of 5 min at each temperature. The transmittance versus temperature was recorded, and the temperature, at which 50% of the maximal transmittance was reached, was taken as the VPTT. The size and size distribution of P(OEGDA-MAA) hydrogels in ethanol and in water were measured by dynamic light scattering (DLS, Nano-ZS, Malvern Instruments, UK).
Results and Discussion
Composition Analysis of P(OEGDA-MAA)
Morphology of P(OEGDA-MAA)
As to the turbid mixture of P(OEGDA-MAA) in ethanol at room temperature, the sample was prepared in the same way, by dropping it on the sample support and the morphology observed under SEM. For the sample at 5 mg/mL concentration, it was found that the nanoparticles, observed in water as shown in Fig. 2a, disappeared (Fig. 2b). Instead, aggregated granules of the hydrogel polymer appeared, and the size of the granules was significantly larger than that of the particles obtained from their water dispersion (Fig. 2a). This is a strong indication that the deswelling was quite different for the two types of the dispersions.
It is most likely that the hydrogel polymer chains were more interpenetrated in ethanol above the high VPTT of UCST-type than they were in water below the low VPTT of LCST-type. This is very likely since ethanol is more similar to P(OEGDA-MAA) in the structure and hydrophilicity. By cooling down to room temperature, the original nanoparticles of the hydrogel polymers, formed in their synthesis and largely swelled above this UCST-type high VPTT, were stuck together and the granules or their aggregation were therefore observed. At a higher concentration (10 mg/mL, Fig. 2c) in ethanol, it seemed that the hydrogel polymer chains were further interpenetrated that a continuous hydrogel film was formed, with randomly dispersed small granules present.
Low VPTT of P(OEGDA-MAA) Hydrogel in Water
This polymer, P(OEGDA-MAA) as synthesized above, was thermoresponsive (Fig. 3), and the responsiveness was also closely dependent on pH. A VPTT of 33 °C was detected in water at concentration of 1 mg/mL and pH 1.0, and this VPTT shifted to a higher temperature at 42 °C at pH 3, an obvious increase with increased pH. With pH further increased to 5, the polymer did not show any change in the light transmittance, i.e., the VPTT disappeared. These observations suggest that the presence of hydrogen ions was necessary for the hydrogel polymer to be thermoresponsive, quite different from most of the OEG-based responsive materials prepared with monomers free of carboxylic acid, which remain responsive at pH = 7 or higher . It is known that a responsive polymer is solubilized, or swelled if crosslinked, at room temperature by different interactions between their chains and water molecules, i.e., their VPTT behavior can be regarded as the consequence of the competition between hydrophilic polymer-water interactions and hydrophobic polymer-polymer interactions [1, 2, 7, 16, 35]. Below this VPTT, the interactions between hydrophilic portion of the polymer and water are favored, water molecules are arranged around the polymer chains, establishing hydrogen bonds with the hydrophilic EG segments, leading to polymer solubilization if linear, and swelling when crosslinked, while above VPTT, this interaction of water-polymer is reduced, synchronously with increased interactions between the hydrophobic polymer themselves, leading to the dehydration of the polymer chains and their self-aggregation. For most of the OEG-based polymers without carboxylic moiety, there is no strong hydrogen bond donor in their chains but weak van der Waals interactions. The dependence of VPTT on pH is relatively moderate. However, the situation is dramatically changed when carboxylic groups are incorporated in the polymer chains, as in the present case for P(OEGDA-MAA). At low temperature (< VPTT) combined with low pH, below pKa (4.8) of the carboxylic acid [1, 3], the carboxylic groups are protonated and they may play the role of proton donor to the ether oxygen of the polymer to form hydrogen bonding, and such a complexation results in a sort of shrinkage of the hydrogel because the interaction of water molecules with the polymer chains is reduced this way, though the polymer chains remain hydrated and the polymer appears solubilized with high transmittance. At high pH, the carboxyl groups become ionized, leading to an electrostatic repulsion among the negatively charged polymer chains. This repulsion is much larger than all the interactions that can be achieved by the non-electrolyte polymer chains between themselves or with water, i.e., van der Waals and hydrogen bonding, and makes the polymer chains at their most extended state as possible: a full dissolution is achieved for the polymers not crosslinked, and the chains are largely extended with the polymer largely swelled for those chemically crosslinked . In Fig. 3 at pH 5, the disappearance of VPTT was the case where a large number of the polymer chains were ionized, which generated by consequence a repulsion between the polymer chains, making them remain swelled even at a higher temperature, without the collapsed state observed. At a lower pH (pH 3, for example), there were less ionized carboxylic groups on a same polymer chain, which was less extended at a given temperature; the interactions of non-electrolyte polymer chains, such as van der Waals and hydrogen bonding, were gaining more importance, and a delayed VPTT was therefore detected at a higher temperature. Obviously, the lower is the pH; the lower is the VPTT, just as observed in Fig. 3. In addition, this is true only for polymer chains which turn negatively charged at high pH. For the polymers which become cationic at high pH (those with amine groups for instance), the opposite is true: VPTT appears at higher pH, and it disappears at lower pH [3, 36].
Besides the responsiveness dependence on pH as seen in Fig. 3, the thermoresponsive behavior of the material is also closely related to ionic strength, concentration, and the rate of heating/cooling. It has been shown by different authors that VPTT of OEG-based polymers is rather insensitive to concentration [14, 37]. However, Wu et al. reported, in a study on a copolymer of 2-(2-methoxyethoxy)ethyl methacrylate with oligo(ethylene glycol) methyl ether methacrylate, that a slight difference was observed and assumingly attributed to a higher concentration (10 wt%) than in other studies . The influence of the polymer concentration on the VPTT was briefly investigated, with the concentration varied from 1.0 to 5.0 mg/mL (see Additional file 1: Figure S5). It was found that, in comparison with the VPTT observed at 33 °C for the hydrogel at concentration of 1.0 mg/mL, the VPTT was shifted to a lower temperature of 29 °C at concentration of 2.0 mg/mL, and to a further lower temperature of about 27 °C with the concentration increased to 5.0 mg/mL. This is simply owing to the concentration effect of the copolymer. In the present heating process, far below the VPTT, all or most of the polymer chains were independently and largely swelled in their dispersion; around VPTT, they started to aggregate, and after VPTT, all polymers were aggregated to form a heterogeneous suspension of the polymers in the solvent (water in the present case), leading to 0% light transmittance. VPTT is the indication of the time point where the polymer chains start to aggregate massively. It is easy to conceive that the polymer chains are easy to encounter each other to aggregate in a dispersion of higher concentration, and a shorter time is required to have a reduction in transmittance equivalent to that in a dilute dispersion.
VPTT of P(OEGDA-MAA) Hydrogel in Ethanol
In contrast to LCST-type VPTT, studies on the polymers with UCST or UCST-type VPTT have been reported at a much lessened extent . Polysulfobetaine  and poly(N-acrylolyglyciamide) [40, 41, 42] are the polymers reportedly with UCST in water, while polyacryamide  and poly(acetoacetoxyethyl methacrylate)  are reported to exhibit UCST in binary ethanol/water solvent mixture. Roth et al. demonstrated that poly[oligo(ethylene glycol) methyl ether methacrylate], (POEGMA), exhibited UCST in a large variety of aliphatic alcohols and that the UCST phase transition temperature was dependent on the structure, molecular weight, and the concentration of POEGMA, as well as the solvent, co-solvents . P(NIPAM) was also reported to exhibit UCST behavior in ethanol/water mixture .
Phase Transition Mechanism
A novel responsive polymer based on OEG, P(OEGDA-MAA), is prepared through precipitation copolymerization of OEGDA with MAA. The polymer prepared with 40 mol% of OEGDA was chemically crosslinked and showed a distinct LCST-type VPTT of 33 °C in water at pH 1.0 and concentration of 1.0 mg/mL. This VPTT was closely concentration and pH dependent. It shifted towards lower temperature with increased concentration, whereas a shift towards higher temperature was observed with increased pH, and the VPTT completely disappeared at pH 5. This same polymer exhibited also a UCST-type VPTT in ethanol at 43 °C, which was equally concentration dependent. The size evolution of the hydrogel particles versus temperature was measured for the two types of dispersions across their VPTT. For the LCST-type VPTT in water, a slight size increase was detected with increased temperature as long as the temperature was below this VPTT; and a dramatic size increase was observed once the temperature was increased to above this LCST-type VPTT. For the UCST-type VPTT in ethanol, the opposite was observed, i.e., a slight size increase with decreased temperature as long as the temperature was above this VPTT, and a dramatic size increase once the temperature was lowered below the UCST-type VPTT. These results suggest that the responsiveness of the polymer follows a two-step process, including a transition of polymer chain conformation from extended status to coil-form due to the dehydration of the hydrophilic chains from the largely swelled state, followed by an aggregation of the individual particles. This work provides therefore a novel type of candidate materials for potential applications in biomedical fields.
This research is financially supported by National Natural Science Foundation of China (Nos. 21304038, 51473066), Science & Technology Development Plans of Shandong Province (Nos. 2017GGX202009), and by Natural Science Foundation of Shandong Province, China (Nos. ZR2018BB049, ZR2018MB021).
Availability of Data and Materials
The datasets supporting the conclusions of this article are included within the article.
All authors participated in the design of the study. HYC performed most of the experiments, FHG carried out part of the experiments, and HYC did the draft of the manuscript. HYC, ZYC, and XZK participated in the data analysis and result interpretation. XZK finalized the manuscript. All authors read and approved this manuscript.
The authors declare that they have no competing interests.
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