Thermoresponsive microgel decorated with silica nanoparticles in shell: Biomimetic synthesis and drug release application

Colloids and Surfaces A: Physicochem. Eng. Aspects 356 (2010) 32–39

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Thermoresponsive microgel decorated with silica nanoparticles in shell: Biomimetic synthesis and drug release application Shigan Chai, Jinzhi Zhang, Tingting Yang, Jianjun Yuan ∗ , Shiyuan Cheng ∗ Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, Faculty of Materials Sciences and Engineering, Hubei University, 430062 Wuhan, China

a r t i c l e

i n f o

Article history: Received 7 September 2009 Received in revised form 14 December 2009 Accepted 17 December 2009 Available online 24 December 2009 Keywords: Bio-inspired synthesis Silica nanoparticles Microgel Drug release

a b s t r a c t We report designing and using a thermoresponsive microgel, poly(N-isopropylacrylamide-co-2(dimethylamino) ethyl methacrylate, methyl chloride quaternized) (poly(NIPAM-co-DMC)) as a colloidal and biomimetic template for silica deposition, producing a microgel decorated with particulate silica in shell. Poly(NIPAM-co-DMC) microgel was synthesized by surfactant-free emulsion polymerization, showing a lower critical solution temperature (LCST) of about 34 ◦ C estimated by dynamic light scattering (DLS) measurements. The silicification selectively occurred in the shell domain of microgel, due to that the DMC segments enriched in microgel shell are catalysis-active for silica deposition under ambient conditions. DLS studies did not show significant size change of hybrid microgel-silica particles with temperatures from 20 to 50 ◦ C, indicating the remarkable suppression of LCST of precursor microgel due to silica deposition. We further found that the silica deposition could be well controlled by simply adjusting the level of silica source and the time for silica deposition. The higher level of TMOS amount and longer time for silica deposition produced the silica-microgel particles with much denser and thicker silica-rich shell. Moreover, the drug-delivery behaviors of poly(NIPAM-co-DMC) microgel and hybrid microgel-silica particles were studied by selecting aspirin as a model drug. The preliminary data indicate that the drug release has been remarkably retarded after silica deposition on the shell of microgel. © 2009 Elsevier B.V. All rights reserved.

1. Introduction Mineralization of inorganic nanoparticles into polymer microgels has attracted intensive interests due to that these hybrid organic–inorganic particles could be used as advanced drug/gene delivery, highly efficient catalysts, chemical and biosensing, and so forth [1]. For example, Kumacheva and co-workers [2] reported using polymer microgel templates for the controlled synthesis of semiconductor, metal and magnetic nanoparticles. Alternatively, Armes group [3] reported the synthesis of microgel-based hybrid nanoparticles by conducting an in situ emulsion polymerization using a suitable cross-linker in the presence of silica nanoparticles. However, the controllable position of inorganic nanoparticles in the different regions of microgel still remains a challenge. Recently, Rubio-Retama et al. [4] reported a method of preparing hybrid material based on poly(N-isopropylacrylamide) (polyNIPAM) microgels covered with ␥-Fe2 O3 nanoparticles of 6-nm size, rendering materials which are both magnetically and thermally responsive. Suzuki et al. [5] described the synthesis of ther-

∗ Corresponding authors. Fax: +86 27 88663043. E-mail addresses: [email protected] (J. Yuan), [email protected] (S. Cheng). 0927-7757/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.colsurfa.2009.12.026

moresponsive hybrid core/shell microgels containing localized Au nanoparticles. Biosilicification occurs in water under ambient conditions, producing exquisite hierarchical structures and multiple morphologies with precise nanoscale control [6]. Recently, templated deposition of silica under ambient conditions has been exploited to achieve more precise control over the nanoscale morphology and structure of silica. For example, core–shell or hollow silica spheres [7–10], silica nanofibers and nanotube [11–17], hexagonal silica plates [18] and silica micropatterns [19] could be achieved by using designed polyamine-based organic templates. Recently, there is increasing interest in exploiting the biotechnological and biomedical applications of biomimetic silicas due to the benign conditions for silica rapid formation and potential control over the silica nanostructure [20–28]. Most of work focus on the immobilization of enzymes/proteins [20–28] or cell [28]. For example, Luckarift and co-workers [20] demonstrated that butyrylcholinesterase could be entrapped during the precipitation of silica nanospheres. The immobilized enzyme was substantially more stable than the free enzyme and retained all of its activity. However, there are very few studies describing the biomimetic silicas for drug delivery application [29,30]. Corma and co-workers reported biomimetic synthesis of microporous and mesoporous materials and their application for controlled release of chemicals (pheromones) [29].

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that the aspirin release was retarded after microgel was silicified in shell. 2. Materials and methods 2.1. Materials N-isopropylacrylamide (NIPAM) was purchased from Shanghai Wujing Chemical and Engineering Co. Ltd. (China), and it was recrystallized from benzene and cyclohexane for three times. The methyl chloride quaternized form of 2-(dimethylamino)ethyl methacrylate (DMC) was purchased from Xinyu Chemicals Co. Ltd. (China); Tetramethyl orthosilicate (TMOS) were purchased from Wuhan University Silicone New Material Co. Ltd., and it was used without further purification. Other chemicals were used as received. Deionized water was used in all experiments. 2.2. Preparation of poly(NIPAM-co-DMC) microgel by surfactant-free emulsion polymerization

Fig. 1. Schematic illustration of the bio-inspired silicification in the shell domain of thermoresponsive poly(NIPAM-co-DMC) microgel. The microgel was synthesized by surfactant-free emulsion polymerization, allowing that the DMC segments were mainly located in the shell domain of microgel, which serves as catalytically active component for silica deposition. The silicification reaction was performed by using tetramethyl orthosilicate (TMOS) as a silica precursor under ambient conditions.

Emulsion polymerization techniques have made big progress in the controlled synthesis of latex particles with tunable composition, morphology and size [31], however these designer colloidal particles are seldom used for biomimetic silica deposition [32]. In a recent publication [32], we first reported using poly(acrylamide-co-2-(dimethylamino) ethyl methacrylate, methyl chloride quaternized) (poly(AM-co-DMC)) cationic microgels as a porous colloidal template for biomimetic in situ silica mineralization, allowing the well-controlled synthesis of submicrometer-sized hybrid microgel-silica particles. Compared to polypeptide vesicle templates [11], PEI nanofibers [14], and cationic polyamine micelles [7], these microgel templates can be readily synthesized on a large scale, with reasonable size control and relatively facile functionalization. Studies on the sliced samples indicated that the silica deposition occurred in the whole of microgel due to that the DMC segments active for biomimetic silicification are uniformly distributed in the whole microgel. Thus, it is difficult to selectively silicifying the shell domain of microgel to produce the hybrid particles with polymer core and silica-enriched shell, by using poly(AM-co-DMC) microgel prepared by reverse emulsion copolymerization. Recent studies indicated that polymer nanoparticles with silica-enriched shell are important for achieving improved performance as drug delivery, such as offering a slower release rate of the entrapped molecules over a much longer period of time [33]. Herein, we report designing and using a novel thermoresponsive poly(NIPAM-co-DMC) microgel as a colloidal and biomimetic template for silica deposition, leading to the synthesis of hybrid microgel decorated with silica nanoparticles in the shell domain (as shown in Fig. 1). Different to poly(AM-co-DMC) microgel, poly(NIPAM-co-DMC) microgel was synthesized by using surfactant-free emulsion polymerization [34], which allows us to control the DMC segments to be selectively rich in the shell domain of microgel. The poly(NIPAM-co-DMC) microgel and the DMC segments in microgel shell serve as template and bio-inspired catalysis for silica deposition under ambient conditions, respectively. Furthermore, the hybrid microgel-silica particles were exploited to use as a novel carrier for drug release. The preliminary results indicated

The poly(NIPAM-co-DMC) microgel with approximately 10% cross-linking degree was prepared by surfactant-free emulsion polymerization. The experiment was carried out in a 250-mL four-neck flask equipped with a poly(tetra-fluoroethylene) anchorshaped stirrer, condenser, a thermometer and nitrogen inlet and outlet. The pH of solution of NIPAM (2 g), MBA (0.2 g), DMC (0.02 g) and deionized water (90 mL) was adjusted to 4. The solution was stirred at 700 rpm for 30 min under nitrogen atmosphere before the temperature was raised up to 70 ◦ C, and then the initiator V50 (0.02 g) dissolved in water (8 mL) was added. After 2 min, opalescence appeared, the stirring speed was slowed to 140 rpm to prevent fluctuation and the polymerization reaction was continued for 5 h. After polymerization, the microgel was purified by dialyzing against water for one week. 2.3. Synthesis of hybrid microgel-silica core–shell particles The silicification of microgel was simply achieved by stirring a mixture of aqueous solution of microgel and TMOS for 30 min under 20 ◦ C at pH 7.2. Microgel-silica hybrid particles were obtained by washing with ethanol, followed by three centrifugationredispersion cycles at 15,000 rpm for 30 min. Redispersal of the sedimented particles was achieved with the aid of an ultrasonic bath. After purification, the wet microgel-silica particles can be easily redispersed in either water or alcohols with the aid of an ultrasonic bath, indicating that good colloidal stability was maintained even after silica deposition. 2.4. Drug loading and release The loading of drug aspirin into microgel and microgel-silica hybrid particles was achieved by dispersing 0.02 g samples into 2 mL aqueous solution of aspirin (4.0 wt%) at room temperature for one week. The particles loaded with aspirin were isolated and washed by centrifugation at 15,000 rpm to remove the free aspirin. The aspirin-loaded samples were dispersed in 10 mL deionized water and then transferred into dialysis bag for release studies. The release experiments were conducted at 40 ◦ C in body fluid. Aliquots were removed at specified time intervals, replaced with the same volume of fresh medium, and the absorbance was measured at 295 nm with UV–vis instrument. 2.5. Characterization FT-IR spectra were recorded in KBr disks using a PerkinElmer Spectrum one instrument. The average number of scans per

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Table 1 The synthesis conditions, compositions and properties of hybrid microgel-silica particlesa . Entries

TMOS (mL)

The mass ratios of microgel to TMOS

Reaction time (h)

SiO2 contents in hybrid particles (wt%)b

Diameters from TEM (nm)

Diameters from DLS at 20 ◦ C (nm)

Zeta potentials at pH 7.0 (mV)c

Microgel 1 2 3 4 5 6 7

– 0.1 0.4 0.8 0.4 0.4 0.4 0.4

– 1:2.5 1:10 1:20 1:10 1:10 1:10 1:10

– 0.5 0.5 0.5 2 6 12 2

– 23.1 30.0 42.5 34.3 70.2 72.6 45.1

207 223 239 214 257 197 202 183

442 372 398 – – – – –

2.76 0.75 −6.30 – −10.5 −14.7 – –

a The silica depositions were performed by using 2.0 mL of 2 wt% aqueous dispersion of microgel at pH 7.2. The silicification reaction temperature is 20 ◦ C for entries 1–6 and 40 ◦ C for entry 7. b As estimated by TGA analysis. c As determined by zeta potential measurements.

spectrum was 128 and the spectral resolution was 4 cm−1 . Thermogravimetric measurements were performed on a Perkin-Elmer Diamond TG/DTA instrument at a heating rate of 20 ◦ C per min. TEM studies were conducted on a Tecnai G20 microscope (FEI Corp. USA) operating at 200 kV. The elemental compositions of hybrid particles were also analyzed by energy-dispersive X-ray spectrometry (EDX, GEN-ESIS2000 XMS 30T, EDAX Corp. USA). X-ray photoelectron spectroscopy was performed on a XSAM800 spectrometer. A Malvern Zetasizer NanoZS instrument operating at a laser wavelength of 633 nm and a fixed detector angle of 173◦ was used for DLS measurements on highly dilute aqueous particles dispersions. Aqueous electrophoresis measurements were performed in 1 mM NaCl solution using Malvern Zetasizer NanoZS instrument. The solution pH was adjusted using NaOH or HCl. UV–vis measurements were operated on an instrument of Lambda 17 at the wavelength of 190–350 nm. 3. Results and discussion It has been well-documented that hydrophilic co-monomers could be well incorporated into the shell domain of latex particles by using surfactant-free emulsion polymerization techniques [34,35]. For example, our group has demonstrated that acrylic acid group could be densely functionalized on shell domain of monodisperse poly(styrene-co-methyl methacrylate) latex by this polymerization method [35]. Here, we use DMC as cationic co-monomer to synthesize microgel of poly(NIPAM-co-DMC) by performing surfactant-free emulsion polymerization using MBA as cross-linker and V50 as initiator. Microgel particle formation was assumed to occur through homogeneous nucleation [34]. DMC segments incorporated into the microgels serves as hydrophilic component to colloidally stabilize the primary particles, thus leading to the formation of microgel particles with DMC segments enriched in the expanded shell layer of microgel (as shown in Fig. 1). This suggestion is supported by the report from Fu and coworkers based on the H NMR studies on PNIPAM microgel prepared using dimethylaminoethylmethacrylate (un-quaternized DMC) as co-monomer [34]. Thus, it is obvious that, compared to poly(AMco-DMC) microgel with DMC segments uniformly distributed in whole microgel particle [32], the current microgel of poly(NIPAMco-DMC) represent a novel colloidal object for biomimetic silica deposition with DMC segments selectively located in microgel shell domain. The shape and size of synthesized microgel was studied by TEM observation. As shown in Fig. 2a, the microgel showed spherical shape and good monodispersity. The number-average diameter is 207 ± 9 nm by analyzing more than 100 particles (see Table 1). DLS studies on dilute microgel dispersions in water at 20 ◦ C indicated an intensity-average diameter of around 442 nm (Table 1).

The difference between the DLS and TEM diameters was assumed to be mainly due to the swollen dimensions of microgel in aqueous solution (compared to the high-vacuum conditions required for electron microscopy). In addition, the DLS studies on aqueous dispersions of microgel under different temperatures indicated a lower critical solution temperature (LCST) of about 34 ◦ C. This is slightly higher than that from normal linear polyNIPAM with a LCST of 32 ◦ C [36] due to the cross-linking structure of microgel. 3.1. Silica deposition in the shell domain of microgel The silicification was performed by stirring a mixture of 2.0 mL of 2.0 wt% aqueous solution of microgel and 0.1 mL TMOS for 30 min at 20 ◦ C and pH 7.2 (entry 1 in Table 1). DLS study on the silicified microgel indicated an intensity-average diameter of around 372 nm in water at 20 ◦ C. To examine the LCST of obtained hybrid microgel-silica particle, the intensity-average diameters of silicified microgel (entry 1 in Table 1) were further studied by DLS at temperatures ranging from 20 to 50 ◦ C. We found that microgel-silica did not show significant change of diameters with temperatures, indicating that the LCST of precursor microgel has been remarkably suppressed due to the silica deposition. This could be possibly attributed to the fixation of precursor microgel dimension due to the cross-linking of microgel shell from silicification reaction [7]. We are currently trying to find more sensitive method to detect the special thermoresponsive property of PNIAM network in silicified microgel. Also, it is possible to adjust the thermoresponsive behaviors of microgel-silica by using microgel with different cross-linking degree and DMC contents. We would like to address these possibilities in our future publications. The nanostructure and morphology of microgel-silica hybrid particles were further studied by TEM observation. As shown in Fig. 2b, the hybrid particles have a number-average diameter of about 223 ± 8 nm, similar to the size of microgel before silica deposition. We found that silica selectively deposited in the shell region of microgel (Fig. 2b and c), due to that the DMC segments are selectively enriched in the shell. Furthermore, we found that there was no evidence for non-templated silica, suggesting that silica deposition occurred exclusively within the microgel shell region. Thermogravimetric analyses suggested that the hybrid microgelsilica particles (as shown in Fig. 2b) were silica-poor. The mean silica content is about 23.1% by mass. A typical high-magnification TEM image of the microgel-silica hybrid particle, as shown in Fig. 2c, indicates that the silica has particulate morphology with the diameter ranging from 5 to 10 nm. This is interesting; since silica formed by biomimetic approaches using micelle [7] or nanofiber [14] templates, usually have relatively continuous silica shells or walls. We assume that the porous nature of swollen surface region of poly(NIPAM-co-DMC) microgels contribute to the formation of

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Fig. 2. Representative TEM images of (a) poly(NIPAM-co-DMC) microgel particles, (b) microgel-silica hybrid nanoparticles prepared by stirring a mixture of 2.0 mL of 2.0 wt% aqueous solution of microgel and 0.1 mL TMOS for 30 min at 20 ◦ C (entry 1 in Table 1), (c) is an individual hybrid microgel-silica particle in (b).

silica nanoparticles. This is similar to the case of using poly(AM-coDMC) microgel as template for synthesis of porous hybrid particles [32]. In addition, we found that several times of ultrasonic treatment of these microgel-silica particles did not show detectable loss of the 5–10 nm nanoparticles in the microgel shell by TEM observation, indicating that these small silica nanoparticles are not simply physically adsorbed in the shell network of microgel. We assume that small nanoparticles were chemically incorporated in the microgel shell region, due to that the PDMC-mediated silicification should produce a hybrid structure of silica-copolymer [32,37]. The hybrid silica-microgel particles were further studied by FTIR, EDX and XPS. FT-IR studies confirmed the silica formation. As shown in Fig. 3a, the bands at 1080, 950, 800 and 470 cm−1 due to silica and the band at 1726 cm−1 due to the copolymer were observed for the hybrid microgel-silica particles. After calcinations at 600 ◦ C, the characteristic band at 1726 cm−1 due to the copolymer completely disappeared, while all the bands due to the thermally-stable silica were still observed. EDX was employed to confirm the coexistence of copolymer (microgel) and silica within individual hybrid particles. As shown in Fig. 3b, analysis of a randomly-selected particle produced a Si signal due to the silica component and N signal due to the copolymer, indicating that the microgel was successfully silicified. To examine the silica distribution in silicified microgel, EDX was performed by focusing the electron beam on the different positions of an individual microgelsilica particle. We found that the rates of Si/O in shell and core regions of hybrid particles are about 1.23 and 0.87, respectively. Relatively higher Si/O ratio in shell region suggested that the hybrid particles have a silica-rich shell. This is in agreement with the observation of TEM (see Fig. 2b). Fig. 4 shows X-ray photoelectron survey spectrum recorded for the silicified microgel. The observation of signals of Si2s and Si2p further confirmed the presence of silica on the surface of hybrid microgel. Moreover, signals due to C1s and N1s were also observed, indicating that the silicified microgel has a polymer-silica hybrid surface. Calculation from XPS data indicated that the silica content of hybrid microgel surface is about 55.0% in mass. In comparison, the bulk silica content calculated from TGA is only 23.1% in mass (see Table 1). This further confirmed that the silicified microgel has a silica-rich shell.

particles from high level of TMOS leads to the increased shell thickness of silica-copolymer. When further increasing the TMOS level to 0.8 mL, as shown in Fig. 5b, the silica-copolymer hybrid shell became much thicker, compared to those obtained with lower level of TMOS (Figs. 2b and 5a). Thermogravimetric analyses also supported such improved silica deposition by raising the amounts of silica source. As summarized in Table 1, the hybrid microgel-silica particles obtained from 0.1, 0.4 and 0.8 mL TMOS have the mean silica contents of 23.1, 30.0 and 42.5% in mass, respectively.

3.2. Controlled deposition of silica We further found that the silica deposition in the microgel shell domain could be well controlled by simply adjusting the mass ratios of polymer to TMOS and the time for silica deposition. Fig. 5a shows a typical TEM image of microgel-silica hybrid particles synthesized by using 0.4 mL TMOS (entry 2 in Table 1). Compared to the particles prepared from 0.1 mL TMOS (Fig. 2b), the hybrid

Fig. 3. FT-IR spectrum (a) and EDX spectrum (b) of microgel-silica hybrid particles showed in Fig. 2b.

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Fig. 4. XPS spectrum of microgel-silica hybrid nanoparticles. The synthesis conditions are identical to those of Fig. 2b.

mass for microgel-silica hybrid particles synthesized at 30 min, 2 h and 6 h, respectively. Obviously, 6 h silicification led to the formation of hybrid particles with silica-rich composition. To confirm the silica deposition behavior after 6 h, the silicification was further performed at 12 h. As shown in Fig. 5f, the nearly same hybrid particles as that from 6 h (Fig. 5d) were obtained with a numberaverage diameter of about 202 nm. The hybrid particles showed a mean silica contents in mass of about 72.6%, estimated by thermogravimetric analyses, indicating that there is not significant silica deposition after 6 h reaction. To further examine the core–shell structure of microgel-silica hybrid particles, cross-sectional TEM analysis was conducted. The sample shown in Fig. 5b was selected as representative hybrid particles. As shown in Fig. 6, the microgel-silica particles show obvious core–shell structure with a shell thickness of around 20 nm. This cross-sectional TEM study indicated that the silicification mainly occurred in shell domain of the microgel due to that DMC segments are rich in shell domain of microgel, which are catalysis-active for hydrolysis and polycondensation of TMOS. 3.3. Silicification reaction at 40 ◦ C

To address the time effect for silica deposition on the nanostructure and compositions of microgel-silica particles, the silicifications were also performed at 2 h (Fig. 5c, entry 4 in Table 1), 6 h (Fig. 5d, entry 5 in Table 1) and 12 h (Fig. 5f, entry 6 in Table 1) by keeping the TMOS amount to be 0.4 mL. As shown in Fig. 5c, the hybrid particles synthesized from 2 h demonstrated a much denser and thicker silica-rich shell, compared to that from 30 min (Fig. 5a). It is interesting that the silica deposition occurred in the whole microgel when the silicification reaction was carried out for 6 h (see Fig. 5d). The hybrid particles showed good spherical shape with a number-average diameter of around 197 nm. The calcinations of such hybrid particles at 600 ◦ C for 6 h produced the pure silica nanoparticles (Fig. 5e). The thermogravimetric analyses further confirmed the increased silica deposition with longer silicification time. The mean silica contents are about 30.0, 34.3 and 70.2% by

The silicification was also performed at 40 ◦ C, a temperature higher than the LCST of the microgel (34 ◦ C), to evaluate the temperature effect to silica deposition. DLS studies indicated an intensity-average diameter of around 220 nm of poly(NIPAM-coDMC) microgel in water at 40 ◦ C. This is much smaller than that obtained at 20 ◦ C (442 nm), due to that the particles behavior shrinkage when temperature increases higher than LCST (34 ◦ C). The silicification reaction was carried out by stirring a mixture of 0.4 mL TMOS and 2.0 mL of 2 wt% aqueous dispersion of microgel at 40 ◦ C for 2 h (entry 7 in Table 1). TEM studies revealed that spherical particles with a number-averaged diameter of 183 nm were obtained (as shown in Fig. 7a and b), indicating that silica deposition could be also successfully taken place at 40 ◦ C by templating this shrunken microgel. At the same time, non-templated silica

Fig. 5. TEM images of microgel-silica hybrid particles with tunable nanostructures by adjusting the synthesis conditions. (a) and (b) were obtained with a silicification time of 30 min by using 0.4 mL (entry 2 in Table 1) and 0.8 mL TMOS (entry 3 in Table 1), respectively; (c), (d) and (f) were prepared with the silica deposition times of 2 h (entry 4 in Table 1), 6 h (entry 5 in Table 1) and 12 h (entry 6 in Table 1), respectively. (e) is TEM image from the calcinations of (d) at 600 ◦ C for 6 h. All silicifications were performed by using a 2.0 mL of 2.0 wt% aqueous solution of microgel at 20 ◦ C.

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Fig. 6. TEM image of sliced sample of microgel-silica hybrid particles prepared by stirring a mixture of 2.0 mL of 2.0 wt% aqueous solution of microgel and 0.4 mL TMOS at 20 ◦ C for 2 h (entry 4 in Table 1).

deposition was also observed due to the high-temperature silicification. As shown in Fig. 7a, a large number of particulate silicas with diameters of about 20–50 nm coexisted with microgel-templated particles. High-magnification image indicates that these small silicas are not uniform and irregular (Fig. 7b). In contrast, the silica deposition at 20 ◦ C for all cases studied (entries 1–6 in Table 1) demonstrated that silicification reaction exclusively occurs on the microgel template. Therefore, the reaction temperature is one of important factors for achieving controlled silica deposition. 3.4. Zeta potentials Aqueous electrophoresis measurements were performed to study the surface zeta potential of the hybrid microgel-silica particles. As shown in Table 1, poly(NIPAM-co-DMC) microgel show positive zeta potential at pH 7.0 due to the cationic character of the quaternized DMC units. After silica deposition, the hybrid microgelsilica particles generally exhibited the decreased zeta potentials, compared to that of microgel template. This latter behavior indicated that the microgel was coated with an overlayer of silica, since aqueous colloidal silica sols typically exhibit negative zeta potentials over a wide pH range [7]. Moreover, we found that the zeta potentials could be controlled by simply adjusting the silica con-

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Fig. 8. Release curves of aspirin from poly(NIPAM-co-DMC) microgel and microgelsilica hybrid particles (Fig. 5c, entry 4 in Table 1) at 40 ◦ C.

tents in hybrid microgel-silica particles. As shown in Table 1, when silica contents of hybrid particles increased from 23.1% to 30.0%, to 34.3%, to 70.2% in mass, the zeta potentials decreased from 0.75 to −6.3, to −10.5 and to −14.7 mV, respectively. 3.5. Drug delivery The precise materials design is important for highperformance controlled drug release [38]. Recently, silica-based organic/inorganic hybrid drug-delivery systems have been of great interest because of their tunable nanostructure, chemical composition and good biocompatibility [39–48]. For example, mesoporous silica@PNIPAM has been designed for cellar imaging [44] and smart uptake and release of drug [45–48]. However, there are few reports describing the usage of hybrid polymer-silica particles from bimimetic silicification for controlled drug release [49–51]. Here, we attempt to use our novel hybrid microgel-silica particles for controlled drug release. Different to conventional silica formation occurring under relatively hash conditions (i.e. high temperature or extreme pH) [39–48], our silica deposition was performed under very mild conditions (in water, nearly neutral pH and room temperature) due to the presence of polyamine in the shell of microgel. The particles shown in Fig. 5c (entry 4 in Table 1) was selected as a representative sample for preliminary drug release study. In addition, the microgel without silica depo-

Fig. 7. TEM images of microgel-silica hybrid particles prepared at 40 ◦ C, (a) is a low-magnification image and (b) is a high-magnification image. The silicification was performed by stirring a mixture of 2.0 mL of 2.0 wt% aqueous solution of microgel and 0.4 mL TMOS for 2 h at 40 ◦ C (entry 7 in Table 1).

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sition was also used for comparison. Microgel and microgel-silica particles showed the drug aspirin loading of 45.4% and 41.5%, respectively. Fig. 8 shows the release profile of aspirin at 40 ◦ C. We found that the microgel released aspirin very fast for initial 5 h, and the release was not significant after 5 h. In contrast, microgel-silica hybrid particles show remarkable slow release of aspirin, and the release could be kept for more than 24 h. Obviously, the silica-rich shell of hybrid particles was successfully designed as a barrier for aspirin release. The further control of drug release by adjusting the microgel parameters and silicification conditions is currently under progress in our group. 4. Conclusion A thermoresponsive poly(NIPAM-co-DMC) microgel from surfactant-free emulsion polymerization has been successfully used as colloidal and biomimetic template for in situ silica mineralization in aqueous solution at 20 ◦ C, leading to microgel-silica hybrid particles with silica-rich shell. There was no evidence for non-templated silica, indicating that silica deposition was confined within the microgel shell domain, as expected. TEM, EDX and XPS studies confirmed that the silicified microgel has silica-rich hybrid shell, and the deposited silica has a particulate morphology. The silica deposition could be controlled by simply tuning the reaction conditions, such as time and silica source amounts. Finally, hybrid microgel-silica particles were used as novel drug release system, and preliminary results indicated that the release rate of hybrid particles was remarkably retarded due to the presence of silica-rich shell. Acknowledgments This work was financially supported by National Natural Science Foundation of China (50703006) and Wuhan Chenguang Project (200750731275) and key Project of Education Department of Hubei Province (Z200710001). We would like to thank the reviewers for their insightful and fruitful comments. References [1] M. Das, H. Zhang, E. Kumacheva, Microgels: old materials with new applications, Annu. Rev. Mater. Res. 36 (2006) 117–142. [2] J.G. Zhang, S.Q. Xu, E. Kumacheva, Polymer microgels: reactors for semiconductor, metal, and magnetic nanoparticles, J. Am. Chem. Soc. 126 (2004) 7908–7914. [3] S. Fujii, E.S. Read, B.P. Binks, S.P. Armes, Stimulus-responsive emulsifiers based on nanocomposite microgel particles, Adv. Mater. 17 (2005) 1014–1018. [4] J. Rubio-Retama, N.E. Zafeiropoulos, C. Serafinelli, R. Rojas-Reyna, B. Voit, E.L. Cabarcos, M. Stamm, Synthesis and characterization of thermosensitive PNIPAM microgels covered with superparamagnetic ␥-Fe2 O3 nanoparticles, Langmuir 23 (2007) 10280–10285. [5] D. Suzuki, J.G. McGrath, H. Kawaguchi, L.A. Lyon, Colloidal crystals of thermosensitive, core/shell hybrid microgels, J. Phys. Chem. C 111 (2007) 5667–5672. [6] H.C. Schroder, X.H. Wang, W.G. Tremel, H. Ushijima, W.E.G. Muller, Biofabrication of biosilica-glass by living organisms, Nat. Prod. Rep. 25 (2008) 455–474. [7] J.J. Yuan, O.O. Mykhaylyk, A.J. Ryan, S.P. Armes, Cross-linking of cationic block copolymer micelles by silica deposition, J. Am. Chem. Soc. 129 (2007) 1717–1723. [8] J. Yang, J.U. Lind, W.C. Trogler, Synthesis of hollow silica and titania nanospheres, Chem. Mater. 20 (2008) 2875–2877. [9] D.J. Belton, S.V. Patwardhan, V.V. Annenkov, E.N. Danilovtseva, C.C. Perry, From biosilicification to tailored materials: optimizing hydrophobic domains and resistance to protonation of polyamines, Proc. Natl. Acad. Sci. 105 (2008) 5963–5968. [10] H. El Rassy, E. Belamie, J. Livage, T. Coradin, Onion phases as biomimetic confined media for silica nanoparticle growth, Langmuir 21 (2005) 8584–8587. [11] J.-S. Jan, S. Lee, C.S. Carr, D.F. Shantz, Biomimetic synthesis of inorganic nanospheres, Chem. Mater. 17 (2005) 4310–4317. [12] S.C. Holmstrom, P.J.S. King, M.G. Ryadnov, M.F. Butler, S. Mann, D.N. Woolfson, Templating silica nanostructures on rationally designed self-assembled peptide fibers, Langmuir 24 (2008) 11778–11783. [13] C. Zollfrank, H. Scheel, P. Greil, Regioselectively ordered silica nanotubes by molecular templating, Adv. Mater. 19 (2007) 984–987.

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