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Preparation and characterization of pH-sensitive hydrogel microspheres based on atom transfer radical polymerization.

INTRODUCTION

Hydrogels are hydrophilic polymeric networks which can be swollen in water and maintain their dimensional stability [1-3]. Because of the similarity between the highly hydrated three-dimensional networks and the hydrated body tissues, hydrogels have been widely used in biomedical fields [4-6], Recently, the combination of microscale technologies and hydrogels has resulted in the emergence of microscale hydrogels (microgels) with widespread applications [7-9]. For example, the side effects of drugs can be reduced if the drug is targeted to the site of action using microspheres [10]. Just as hydrogels, microgels/ nanogels are 3D biocompatible materials with high water content [11]. And their sizes can be tuned from submicrons to tens of nanometers and their surface-to-volume ratios are much larger than that of the macrogels. The responsive time to environmental stimuli is proportional to the square of a linear dimension of the hydrogels, therefore, the hydrogel microspheres respond more quickly to environmental stimuli. Furthermore, microgel particles can be packed in columns or form crystalline colloidal arrays in relatively concentrated suspensions [12, 13]. Several techniques for manufacturing microspheres have been developed, such as electrospray drying [14, 15], solvent evaporation [16-18], emulsion crosslinking [19, 20], ionic gelation technique [21], direct dispersion method [22], microfluidic channels [23], supercritical carbon dioxide [24], coacervation method [25], and free radical emulsion polymerization [26]. One of the most common methods for the fabrication of well-defined hydrogel microspheres is to use inverse emulsion polymerization of hydrophilic water-soluble monomers in the presence of crosslinkers. During polymerization process, it is a mechanism of conventional free radical polymerization (CFRP) that is usually involved. Since atom transfer radical polymerization (ATRP) was reported by the groups of Matyjszewski and Sawamotoin [27], much effort has been given to apply ATRP in inverse emulsion polymerization. Compared with CFRP, ATRP is a controlled/living radical polymerization technique and can fabricate polymer chains with equal length and incorporate monomers and crosslinkers in a regular fashion. However, ATRP proceeds rapidly in aqueous media, so it is difficult to control over the molecular weight, molecular weight distribution, and structure of the resulting polymer in water. Afterward, Siegwart et al. proposed a novel technique, that is, activator generated electron transfer-atom transfer radical polymerization (AGET-ATRP), in which Cu(I) is provided by a redox reaction of a Cu(II) complex and a reducing agent. This technique has resulted in energetic investigation of emulsion polymerization based on ATRP. There is a crucial difference between nanogels prepared by ATRP and those prepared by CFRP [28], For example, the colloidal particles prepared by ATRP preserve a high degree of halide end functionality which enables further chain extension; in a reducing environment, the crosslinked nanogels can degrade to individual polymeric chains with relatively narrow molecular weight distribution [29, 30], In addition, the ATRP-nanogels swell larger than CFRP-nanogels do in various solvents [31]. More recently, increasing interest has been devoted to the exploration of stimuli sensitive polymeric particles that are also called smart or intelligent materials which can be used, due to their unique physical and chemical properties, in biomedical applications such as controlled drug delivery, separation, catalysis [32], Of these microspheres, pH-responsive microspheres are frequently studied, as pH values in different tissues and cellular compartments vary tremendously. For example, many pathological processes in tumor tissue and intracellular endosome/lysosome go with local pH decrease by 1-2.5 pH units compared with that (pH 7.4) of blood and normal tissues [33], Therefore, various pH-responsive microspheres have been developed for drug delivery. However, some aspects of microspheres must be considered such as the ability for pH-regulated drug delivery, minimizing side-effects, and improving therapeutic efficacy of conventional drugs.

In this article, pH-sensitive hydrogel microspheres are fabricated by copolymerization of hydroxyethyl methacrylate (FIEMA) and a pH-sensitive comonomer, 4-vinylpyridine, with poly(ethylene glycol) dimethylacrylate (PEGMA) as a crosslinker. It is known that poly(4-vinylpyridine)(P4VP) is a cationic polyelectrolyte which is pH-sensitive. When the pH of its solution is greater than 5, P4VP is hydrophobic in its deprotonated state; however, when the pH is lower than 5, P4VP is protonated and soluble [34]. Moreover, 4-VP can be chemically modified to prepare a charged particle with tunable alkyl chain length and structure by the reaction with various quartemization agents because of the nucleophilicity of the nitrogen atoms on the pyridine ring [35, 36]. Additionally, these nitrogen atoms have great chelating tendency for metal ions such as Cu, Ni, and Co [37], Therefore, p(4-VP) and p(4-VP)-based materials can be used in many fields, such as actuators, chromophore forming, bactericidal materials. Conversely, HEMA is a water-soluble monomer. Poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels have potential application in biomedical fields due to water content similar to living tissue, inertness to biological processes, resistance to degradation, permeability to metabolites, and resistance to absorption by the body. They can be incorporated into different parts of polymers to enhance the functionality of the materials [38, 39]. Further, polyethylene glycols (PEGs) and their analogues oligoethylene glycols have been well investigated for various material applications due to their unique properties, including biocompatibility, low toxicity, good solubility, low degrees of protein adsorption, and cell adhesion. Therefore, PEGMA was chosen as crosslinker herein. In addition, daidzein (DAI), a natural isoflavone found in Leguminosae [40], was used as a model drug and related release mechanism was investigated.

MATERIALS AND METHODS

PEGMA (average Mn 750), 4-VP and HEMA were purchased from Sigma-Aldrich Trading Co. (Shanghai, China). Oligo(ethylene oxide) monomethyl ether methacrylate (average Mn 1900, PEO1900-OH) was obtained from Alfa Aesar (Tianjing) Chemical Co., Copper(II) bromide (Cu[Br.sub.2], 99%), L-ascorbic acid (AscA, 99%) were purchased from Shanghai Jingchun Chemical Co., China. Tris[(2-pyridyl)methyl]amine (TPMA) was prepared as described elsewhere [41]. A water-soluble macroinitiator, PEO-functionalized 2-bromoisobutyrate (PEO1900Br), was synthesized by the reaction of PEO1900-OH and 2bromoisobutyryl bromide (98%) in toluene with triethylamine as acid-binding agent as described elsewhere [42]. DAI (98%) was obtained from energy-chemical Co., China.

Formation of Microspheres by Inverse Emulsion Polymerization

A series of microspheres were prepared by AGET ATRP of 4VP, HEMA, and PEGMA in inverse emulsion under different conditions. Reaction time (2, 4, 6, 8, and 10 h), reaction temperature (35[degrees]C, 40[degrees]C, 45[degrees]C, 50[degrees]C, 55[degrees]C, 60[degrees]C), the amount of crosslinker (0.12, 0.18, 0.24, 0.36, and 0.72 g), and stirring rate (800, 1000, 1200,1400, and 1600 r/min) were optimized by one-factor experiment. A typical procedure for the preparation of microspheres with the feeding molar ratio of 4:1 (HEMA to 4-VP) is described below. HEMA (0.999 g, 7.68 mmol), 4-VP (0.202 g, 1.92 mmol), PEO1900-Br (98.4 mg, 0.048 mmol), TPMA (6.96 mg, 0.024 mmol), Cu[Br.sub.2] (5.36 mg, 0.024 mmol), and water (3.1 mL) were mixed in a 50-mL-round-bottom flask at room temperature. The resulting clear solution was mixed with a solution of Span 80 (2.15 g) and OP-10 (0.18g) in paraffin liquid (32 mL), and the mixture was stirred and emulsified by high-shearing dispersion emulsifying machine (FLUKO) for 3 min at room temperature to form a stable emulsion. Then dispersion was deoxygenated by vacuum-pumping and argon-filling. The flask was immersed in a water bath preheated to a preset temperature, and then an argon-purged aqueous solution of AscA (2.7476 mg, 0.0156 mmol) was added dropwise via syringe to activate the catalyst and start the polymerization. The polymerization was stopped after a period of time by exposing the reaction mixture to air. The emulsion was destroyed by addition of ethyl acetate. After the supernatant was removed, ethyl ether was added. The same procedure was repeated twice to completely remove soluble species in ethyl ether including unreacted monomers and surfactant. Finally, the microspheres were dried under vacuum to a constant mass.

Swelling Behavior

The swelling behavior of the dried microspheres was studied using a classic gravimetric method. Typically, 60 mg of the dry microgels was weighed precisely and put into centrifugal pipettes containing 6-mL buffer solutions with different pH, respectively. The weight of the swollen microspheres was recorded at 37[degrees]C at regular intervals after the excess surface water was carefully blotted using filter paper. Equilibrium swelling ratio (ESR) was calculated using the equation; ESR = ([M.sub.1] - [M.sub.0])/[M.sub.0], where [M.sub.0] represents the initial mass of dried gels and Mt the mass of the microgels after getting swelling equilibrium. To study recurrent response to pH change, the microspheres were alternately put into buffer solutions of pH = 2 and pH = 9.

Preparation of Drug-Carried Microspheres

DAI exhibits many beneficial effects on human health, but its clinical potential is limited by its low bioavailability, unfavorable metabolism, the low partition coefficient of oil/water, and uterine estrogenicity [40, 43]. Therefore, it is of significance to develop DAI-loaded carriers.

Herein, drug-carried microspheres were prepared by adding DAI in situ during polymerization, that is, drug was mixed with monomer, crosslinker, initiator, and then the mixture was added to the polymerization medium. To determine the amount of drug in microspheres, a known amount of the microspheres were crushed in an agate mortar with a pestle and then added into a prescribed amount of buffer solution of PBS. After making the drug in microspheres release fully by ultrasound and stirring, the concentration of the supernatant solution was quantified using UV-vis spectroscopy according to DAI standard curve. Loading capacity (LC%) and encapsulation efficiency (EE%) of drug were calculated through the below equations.

LC% = weightof drugin microspheres/weight of microspheres x 100 (1)

EE% = weight of drugin microspheres/weight of feed drug x 100 (2)

Drug Release Profile In Vitro

The drug release profile was evaluated by the dialysis bag method. About 50 mg of the microspheres was suspended in 5 mL of PBS (pH 7.4) and placed into a cellulose dialysis bag with the molecular weight cutoff of 8-14 kDa. The tied dialysis bag was incubated in 95 mL of PBS (pH 7.4) at 37[degrees]C in a shaker. At selected time intervals, 5 mL of the release medium was taken, and then an equal volume of fresh PBS was supplemented to maintain a constant volume. The amount of DAI released from the microspheres was determined by UV-vis spectrophotometer at 250 nm and calculated from a calibrated standard curve. It is necessary to avoid microsphere aggregation and to ensure homogeneous release among all microspheres. In vitro experiments were performed by triplets. The accumulative release percent Q (%) of DAI was calculated by the following equation.

Q = [M.sub.t]/[M.sub.[infinity]] X 100% (3)

where [M.sub.t] and [M.sub.[infinity]] represent the cumulative amount of drug released at time t and the initial amount of drug loaded, respectively.

Drug Release Kinetics

Generally, the release rate is affected by several factors, that is, structure and composition of matrix, and matrix-drug interactions, and so forth, in which diffusion is one of the most important factors. In order to explain the release mechanism of drug, different mathematical models have been given. The frequently used models include: zero-order kinetic model, first-order kinetic model, Higuchi kinetic model, Korsmeyer-peppas kinetic model, which are presented in Table 1, where Q is the accumulative release rate at time t, K is the kinetic constant. The release data was analyzed according to the models described above, k value of Higuchi model and n and k in Korsmeyer-Peppas model were calculated by means of linear regression analysis. The quality of prediction of each model was evaluated by correlation coefficients ([R.sup.2]). In Korsmeyer-peppas kinetic model, n is the diffusional exponent, which characterizes the mechanism of drug release and taking various values according to the geometry of the release device [44], For spherical shape matrices, values of n = 0.43 or less indicate the release mechanism corresponds to Fickian diffusion (Type I transport), which means drug release is controlled by diffusion of drug molecules resulting from a chemical potential. Values of n between 0.43 and 0.85 follow anomalous (non-Fickian) diffusion mechanism, in which drug release was influenced by both diffusion and swelling phenomena. When values are greater than 0.85 and less than 1, the release mechanism accords with Case II transport, where the swelling of polymer has an effect on the drug release. If n is greater than 1, super Case II transport diffusion mechanism is involved [45, 46]. Therefore, the release mechanism will be predictable according to the diffusional exponent.

Characterization

The FTIR spectra (KBr disc technique) were obtained using a WQF-510 spectrometer (Beijing Beifen-Ruili Analytical Instrument (Group) Co. China) at ambient temperature in the range of 4000-500 [cm.sup.-1] at a resolution of 2 [cm.sup.-1]. Thermal analyzer thermogravimetric analysis (TGA) was investigated using a Netzsch STA 409 PC/PG thermogravimetry analyzer, with a heating rate of 10 K/min from 20 to 600[degrees]C. Nitrogen was used as a purge gas with a flow rate of 30 mL/min. A Malvern Mastersizer 2000 particle-size analyzer (which uses a laser light scattering technique and dry feeder) was used to measure particle size and particle-size distribution.

Scanning electron microscopy (SEM) experiments were performed using a JEOL JSM-6390 scanning electron microscope. A few of the microspheres were spread in a sputter coater and covered by a thin gold film. The size, shape, surface characteristics of the blank microspheres, and the drug-loaded microspheres were recorded.

The X-ray diffraction (XRD) patterns of the powders of triturated microspheres and the corresponding copolymer without crosslinker were obtained with a powder diffractometer (Empyrean, PANalytical), using monochromated Cu K[alpha] radiation ([lambda] = 1.5406 [Angstrom]), operated at 40 kV and 40 mA with a scanning rate of 2[degrees]/min in the 20 range of 20[degrees]-80[degrees].

RESULTS AND DISCUSSION

Preliminary experiments indicated that the variables, such as monomer composition, reaction time, reaction temperature, crosslinker dosage, stirring speed, were the main factors that affect the particle size, size distribution. Thus, a one-factor experiment was used to optimize preparation conditions of microspheres. Size distribution, particle shape, and yield were used as main assessment indicators during optimizing conditions of preparing microspheres. The optimized conditions of preparing microspheres were presented in Table 2.

Under these conditions, pH-sensitive hydrogel microspheres were prepared with good spherical shape, and the average particle size of 10 [micro]m. Particle-size distribution curve and SEM are shown in Figs. 1 and 2.

FTIR Spectra of p(HEMA-co-4-VP) Microsplteres

FTIR spectra of p(HEMA-co-4-VP) microspheres with different feeding ratios are presented in Fig. 3. The broad peak around 3425 [cm.sup.-1] and the strong peak at 1726 [cm.sup.-1] are assigned to the O-H stretching mode and C=0 stretching mode in HEMA, respectively. The bands at 1604 and 1560 [cm.sup.-1] are attributed to C-N stretching mode in pyridine ring, and the bands at 1456 and 1417 [cm.sup.-1] are assigned to C-C stretching mode. It can be seen that the intensity of the peak at about 1726 [cm.sup.-1] becomes stronger and the intensity of the peak at about 1604 [cm.sup.-1] becomes weaker from curve a to curve d as the HEMA to 4-VP molar ratio augments.

It can be seen from Table 3, the largest drug LC and EE of drug can reach 5.12% and 35.13%, respectively. It also can be seen from SEM image (Fig. 4) that the product remained well spherical shaped after adding drug into polymerization system, and the surface presents little gibbosity, which may be DAI crystalline.

TGA Studies

The TGA is a powerful technique used to track in situ weight changes of the samples during heating process, thereby evaluating their thermal stability. The TGA thermograms of microspheres (a) and the corresponding copolymer of p(HEMA-co-4-VP) (b) are presented in Fig. 5. Both curves did not change under 100[degrees]C, indicating there is no physically absorbed water in the two samples. Further, the copolymer began to decompose at 100[degrees]C, the gradual weight loss was 4.5% between 100[degrees]C and 260[degrees]C, which may be attributed to the decomposition of the side hydroxyls in the copolymer. The weight loss of the microspheres did not happen until 260[degrees]C, which implies that the microspheres possess better thermal stability compared with the copolymer. Finally, weight loss of the copolymer was about 78% between 260[degrees]C and 421[degrees]C and that of the microspheres was 74% between the same temperature range, which may be due to the loss resulted from C--C bond cleavage. The residue weight percentages of the microspheres and the copolymer at 600[degrees]C are 14% and 9%, respectively.

XRD Data

Figure 6 illustrates the XRD patterns of the copolymer of p(HEMA-co-4-VP) (a) and the corresponding microspheres (b). The main feature of the two patterns is a broad band (around 18 and 19, respectively) lain on the left part of the diffraction patterns, which are similar and without sharp diffraction peaks, indicative of their noncrystalline nature. PEG is known to be a crystal polymer and has two characteristic diffraction peaks at 20 = 19[degrees]C and 23[degrees]C [47, 48]. The characteristic peaks of poly (ethylene glycol) dimethacrylate do not present in the XRD patterns of the microspheres, which indicates the crosslinker has been distributed in the microspheres evenly.

Swelling Behavior

The ESR of the hydrogel microspheres is highly dependent on pH value of the medium. As can be seen in Fig. 7 that the ESRs of the hydrogel microspheres decreased with the pH value of buffer solution increased from 2 to 10, which suggests the hydrogel microspheres possess pH-sensitivity. It was thought that pH-sensitivity of poly(4-VP) is due to the conversion between protonation and deprotonation states of the poly(4-VP) block. At low pH, the amine groups of the pyridyl rings will combine with protons to get ionized groups, which are more hydrophilic and then adsorb more water. In addition, electrostatic repulsion between adjacent ionized groups makes the chain expansion and exhibiting an extended conformation, leading to an increase in swelling ratios [49]. When pH is increased, a collapsed conformation forms due to deprotonation of the charged pyridinium segments. The deprotonation of poly(4-VP) not only promotes the removal of the surface charges but also leads to a dramatically transition of the swollen hydrophilic state into a collapsed hydrophobic state due to the disappearance of electrostatic repulsion between polymer chains.

Recurrent response is an important property of smart hydrogels when their application is considered, especially in actuators for drug release regulation. Fig. 8 presents the pH-stimulating swelling-deswelling kinetics of the hydrogel microspheres between pH = 2 and 9. The microspheres deswelled at pH = 9 and swelled at pH = 2, and the ESR of the hydrogel microspheres changed slightly after five cycles. This also indicates that the hydrogel microsphere possess reversible pH response properties.

Fig. 9 presents release curves of different microspheres in medium of pH = 7.4. The standard deviation at each time point, measured in triplicate, is less than 10%. The DAI release is faster in initial stage and then becomes slower. Moreover, release rates for different microspheres are different, the more content of 4-VP in microspheres, the faster release rate of DAI, which means release rates can be controlled by tuning the composition of microspheres.

Taking the microspheres of 4:1 for an example, linear regression analysis are done according to the aforementioned models, the results are displayed in Table 4

It can be seen that the best fitting is obtained with the Korsmeyer-Peppas model with correlation coefficients about 0.99 which indicates the validity of the fitting results. The corresponding n values equals to 0.48 > 0.43, suggesting that the main mechanism of DAI release is non-Fickian diffusion, in other words, the mechanism involves both diffusion and swelling.

In vitro release curves of microspheres at different pHs at 37[degrees]C are shown in Fig. 10. As is shown, the release rate is slower in pH =1.4 than that in pH = 7.4, which is different from swelling behavior of the microspheres. As is known to us, the release behavior of drug in hydrogel microspheres is closely related to several factors, that is, structure and composition of matrix, matrix-drug interactions, solubility of drug in water, in which diffusion is one of the most important factors. Diffusion is related to swelling and solubility of drug. The solubility of DAI in PBS of pH = 7.4 is larger than that in pH = 1.4, which outweighs the effect of swelling on drug release in different pHs, leading to the release profiles described here. If the release behavior of the microspheres is expected to accord with their swelling behavior under different pHs, proper monomers, or neutral model drug can be chosen.

The release data at pH = 1.4 and pH = 7.4 are also analyzed by linear regression analysis according to Korsmeyer-peppas model, the results are as follows: at pH = 2, lnQ = 0.4224 lnt - 1.77577, [R.sup.2] = 0.98392; at pH = 7.4, lnQ = 0.48907 lnt - 1.61958, [R.sup.2] = 0.93942. The diffusional exponents are both less than 0.5, so the release of DAI follows non-Fickian diffusion at pH = 2 or pH = 7.4.

CONCLUSIONS

Herein, pH-sensitive hydrogel microspheres were successfully prepared by ATRP in inverse emulsion. It was found that the as-prepared hydrogel microspheres presented with good spherical shape under the optimized conditions. The study on swelling behavior indicated that the swelling ratio of the hydrogel microspheres decreased with increasing pH value of the medium and the microspheres possessed reversible pH response properties. Different DAI-carried microspheres showed different release profiles and release rates could be controlled by tuning the composition of microspheres and pH of the medium. It was found Korsmeyer-Peppas model enables a more precise assignment of the diffusion mechanism during DAI release, which suggested an anomalous transport as a combination of diffusion and swelling. Further studies about the hydrogel microspheres will be performed in order to tune the drug release features according to specific therapeutic needs and increase the range of their applications in pharmaceutical and biomedical areas.

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Hong-Zheng Zhu, Li-Qin You, Hong-Liang Wei, Guo-Feng Wang, Hui-Juan Chu, Jing Zhu, Juan He

Department of Chemistry, School of Chemistry and Chemical Engineering, Henan University of Technology, Zhengzhou 450001, People's Republic of China

Correspondence to: H.-L. Wei; e-mail: weihl68@l26.com

Contract grant sponsor: Henan Province University Innovation Talents of Science and Technology Support Program; contract grant number: 20I2HAS TIT0I7; contract grant sponsor: the Science and Technology Department of Henan Province; contract grant numbers: 102102210131; 142300410011; contract grant sponsor: the Education Department of Henan Province; contract grant number: 20IOA430002; contract grant sponsor: Henan University of Technology; contract grant number: 20I2JCYJ07.

DOI 10.1002/pen.24168

TABLE 1. Frequently used mathematical models for analyzing the
data of drug-release.

Kinetic model          Equation

Zero order         Q = Kt
First order        ln(1-Q) = -Kt
Higuchi            Q = [Kt.sup.1/2]
Korsmeyer-peppas   Q = [Kt.sup.n]

TABLE 2. The optimized conditions for preparing p(HEMA-co-4VP)
hydrogel microspheres.

HEMA/4-VP              Temperature    Emulsifier dosage:
(mol/mol)   Time (h)   ([degrees]C)   Span 80/OP10 (g/g)

4:1            6            40            2.15/0.18

HEMA/4-VP   Crosslinker   Stirring rate
(mol/mol)   dosage (g)       (r/min)

4:1            0.36           1200

TABLE 3. LC% and EE% of microspheres with different monomer feed
ratios.

HEMA:4-VP(mol/mol)   Dosage (g)   LC%     EE%

1:1                     0.23      5.12   35.31
2:1                     0.23      4.50   31.88
4:1                     0.23      4.00   29.09

TABLE 4. The results of linear regression analysis.

Kinetic model      Equation by linear regression        k     [R.sup.2]

Zero order         Q = 0.0l286t + 0.21467            0.01286   0.88687
First order        ln(l -Q) = -0.02218t-0.22476      0.02218   0.94694
Higuchi            Q = [0.09548t.sup.l/2] + 0.07187  0.09548   0.97805
Korsmeyer-peppas   lnQ = 0.483611int-2.02818         0.48361   0.99031
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Author:Zhu, Hong-Zheng; You, Li-Qin; Wei, Hong-Liang; Wang, Guo-Feng; Chu, Hui-Juan; Zhu, Jing; He, Juan
Publication:Polymer Engineering and Science
Article Type:Report
Geographic Code:1USA
Date:Dec 1, 2015
Words:4962
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