Preparation and Characterization of Narrowly Distributed Nanogels

Department of Chemistry, Nankai University, Tianjin 300071, P.R.C., and Department of Chemistry, Jiaying University, Meizhou, Guangdong 514015, P.R.C...
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Preparation and Characterization of Narrowly Distributed Nanogels with Temperature-Responsive Core and pH-Responsive Shell Xin Li,†,‡ Ju Zuo,*,† Yanling Guo,† and Xinghai Yuan‡ Department of Chemistry, Nankai University, Tianjin 300071, P.R.C., and Department of Chemistry, Jiaying University, Meizhou, Guangdong 514015, P.R.C. Received July 3, 2004; Revised Manuscript Received October 21, 2004

ABSTRACT: Narrowly distributed spherical core-shell nanogels were prepared by a two-step aqueous dispersion polymerization. Core particles composed of cross-linked temperature-responsive poly(Nisopropylacrylamide) (PNIPAM) were synthesized via aqueous dispersion polymerization and then used as nuclei for subsequent shell addition of pH-responsive poly(4-vinylpyridine) (P4VP). The morphology and structure of the core-shell particles were confirmed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM), and the size distribution was determined by dynamic laser light scattering (DLLS). Temperature- and pH-induced volume phase transitions of the latex particles were also investigated by DLLS. The results show that the P4VP shell does not significantly perturb the temperature-induced volume phase transition of the parent core whether P4VP is ionized or not, and the deswelling behavior differs significantly from that of other polyelectrolyte gels within which the ionic groups are randomly distributed.

1. Introduction Much attention has been directed in recent years at environmentally responsive hydrogels due to their potential applications in numerous field, including drug delivery,1,2 chemical separations,3,4 chemical transducer,5,6 enzyme and cell immobilization.7,8 The most widely studied responsive hydrogels are those composed of temperature-responsive poly(alkylacrylamides), specifically poly(N-isopropylacrylamide), PNIPAM, which undergo a dramatic reversible volume change at 31 °C.9-16 Early study has mainly focused on macroscopic gels/bulk gels, and many significant results have been obtained. Microgels, however, have recently attracted increasing attention because of the fast dynamics in swelling or collapsing process. Tanaka et al.17,18 have demonstrated that the time taken to swell or collapse is approximately in proportion to the square of a linear dimension of the gel, so the volume change for microgels is much faster than that for the macroscopic gels/bulk gels with the same chemical structure. As a result, for microgels, the swelling or collapsing equilibrium can be reached in minutes instead of in hours, and it is hence convenient to accurately investigate the swelling or collapsing process by laser light scatting. On the other hand, a detailed understanding of this process will also be a great help to true applications of PNIPAM-based gels. The swelling or collapsing of temperature-responsive latex microgel particles dispersed in water is an intraparticle phenomenon, but as well-known, interparticle aggregation also take place during the collapse transition. For various potential applications, it is important to prevent the particles from aggregating upon an increase in temperature. Usually, a pH-ionizable monomer is introduced into PNIPAM microgel networks by †

Nankai University. Jiaying University. * To whom correspondence should be addressed: e-mail: [email protected]. ‡

randomly copolymerization; as a consequence, the incorporated pH-ionizable components will not only prevent the aggregation due to the electrostatic repulsion but also provide pH sensitivity. However, the randomly introduced ionic groups will also result in an adverse effect, i.e., the transition temperature of the gels will rise significantly to a high level far above physiological temperature when these groups are ionized,19,20 and in some cases, the strong electrostatic repulsion will even smear out the temperature-induced transition.21 This effect greatly limits the application, e.g., in controlled drug delivery. Nevertheless, it is expected that the temperatureinduced transition will not be affected if the introduced ionic groups are not randomly distributed within the PNIPAM microgels but only locally distributed in the peripheral regions of the particles. For this purpose, we prepared a novel colloidal nanostructure microgel with a temperature-responsive PNIPAM core and a pHresponsive poly(4-vinylpyridine) shell using a two-step aqueous dispersion polymerization. To the best of our knowledge, it appears for the first time that core-shell particles may be prepared by this novel synthetic method with two different water-soluble monomers. The produced core-shell latex particles could offer some advantages such as fast swelling dynamics and increasing stability upon heating as compared to the corresponding PNIPAM microgels. Moreover, the pH-responsive P4VP shell does not perturb the temperature sensitivity of the PNIPAM core, including the position, magnitude, and range of this volume phase transition (VPT) temperature. 2. Experimental Section Materials. N-Isopropylacrylamide (NIPAM, from Aldrich, analytical grade) was recrystallized three times in a benzene/ n-hexane mixture. N,N′-Methylenebis(acrylamide) (BIS, from Aldrich, analytical grade) as cross-linker and cationic surfactant dodecyltrimethylammonium chloride (DTAC, analytical grade) as dispersant were purified by recrystallization from

10.1021/ma048658a CCC: $27.50 © 2004 American Chemical Society Published on Web 12/02/2004

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methanol, respectively. 4-Vinylpyridine (4VP, from Aldrich, analytical grade) was used without further purification. 2,2′Azobis(2-amidinopropane) dihydrochloride (AAPH, from Aldrich, analytical grade) as cationic initiator was recrystallized three times in redistilled water. Preparation of Core-Shell Microgels. The core-shell microgel particles were prepared by two-step aqueous dispersion polymerization. The core particles polymerization was conducted in a 100 mL four-necked glass flask equipped with a reflux condenser, a thermometer, a Teflon paddle stirrer, a nitrogen bubbling inlet, and outlet. NIPAM (0.65 g), DTAC (0.03 g), and BIS (5 mol % of NIPAM) predissolved in 60 mL of redistilled water were first charged into the flask; after the solution was stirred for 1 h at 70 °C under nitrogen purge, 0.030 g of AAPH dissolved in 5 mL of redistilled water was introduced to start the polymerization. The reaction was carried out at 70 °C and with a stirrer speed of 350 rpm for 6 h under a nitrogen atmosphere to produce cross-linked PNIPAM core particles. Then the core particles served as nuclei in the following stage of polymerization (shell addition). Prior to shell addition, the core particles were purified by dialysis against frequent changes of redistilled water for 2 weeks at room temperature. In the shell synthesis, 20 mL of latex of the desired seed particles (the seed latex is at a concentration of ca. 0.01 g/mL), 4VP (0.02 g), DTAC (0.025 g), BIS (10 mol % of 4VP), and 25 mL of redistilled water were placed into the reaction flask. The solution was kept at 70 °C under a stream of nitrogen for 1 h. Polymerization was then initiated by the addition of AAPH (0.01 g) and was again carried out for 2 h under the same apparatus and reaction conditions as for core preparation. The core-shell particles were also purified by dialysis before characterizing. Morphology and Structure Characterization of the Core-Shell Particles. The morphology and structure of the core-shell particles were determined by SEM and TEM. SEM was performed on a Hitachi S3500N microscope at 20 kV. For samples preparation, the dialyzed microgel solution was fixed on a microscope slide and dried in air, and then the dried samples were sprayed with a 3 nm thin gold layer. TEM observation was performed on a Philips EM400ST microscopy operating at an acceleration voltage of 80 kV. The specimen was prepared as follows. One drop of dilute latex was cast on a copper EM grid covered with a thin carbon film and dried at ambient temperature, and then staining was carried out by depositing a drop of 0.1 wt % phosphotungstic acid aqueous solution onto the surface of sample-loaded grid. Three minutes later the solution was blotted with a filter paper, and the sample was then washed with water and dried in air. To better visualize the core-shell structure, ultrathin cross sections were observed by TEM (JEOL JEM-2010) at an accelerating voltage of 200 kV, after sample staining with ruthenium tetraoxide (RuO4) vapor for 20 min. DLLS Measurement. Dynamic laser light scattering (DLLS) experiments were performed on a laser light scattering spectrometer (BI-200SM) equipped with a digital correlator (BI-9000AT) at 514.5 nm. In DLLS measurements, the Laplace inversion of a measured intensity-intensity time correlation function G(2)(t,q) in the self-beating mode can lead to a linewidth distribution G(Γ). For a pure diffusive relation, G(Γ) can be transferred into a translational diffusion coefficient distribution G(D) as D ) Γ/q2 at C f 0 and θ f 0 or a hydrodynamic diameter distribution f (Dh) via the Stokes-Einstein equation

Dh ) kBT/(3πηD)

(1)

where kB, T, and η are the Boltzmann constant, the absolute temperature, and the solvent viscosity, respectively. Here 2 Γ/qθf0 or D° of the nanogels at given concentration is calculated by extrapolating q2 to 0, and then the hydrodynamic diameter D0h or the hydrodynamic diameter distribution f (Dh) of the nanogels at given concentration is further calculated from eq 1.

Figure 1. SEM images of the core-shell particles.

Figure 2. TEM photograph of the core-shell particles which were selectively stained by phosphotungstic acid.

3. Results and Discussion 3.1. Morphology and Structure Characterization and Formation Mechanism of the Core-Shell Particles. SEM images of the resultant core-shell particles are shown in Figure 1. The nanogel particles appear to be concentric spheres, revealing a similar structure to that of core-shell particles, and the particle size distributions are quite narrow. Figure 2 shows the TEM images of the same core-shell particles. The images clearly reveal a two-layered spherical structure, in which every individual core is surrounded with a dark shell. Here the P4VP shell is selectively contrasted by phosphotungstic acid so that it is easy to differentiate the core and shell domains.22 The result shows the suitability of the two-step aqueous dispersion polymerization for preparation of core-shell composite particles. To better visualize the core-shell structure, the ultrathin cross section of the core-shell particles which were stained with RuO4 vapor for 20 min was observed on TEM. Herein RuO4 preferentially stains the P4VP component, thus rendering them more electron dense under the transmission electron microscope. It is obviously seen in Figure 3 that there exists a thin shell layer located in the periphery of the core domain. This result shows again that core-shell particles can be approached by this two-step aqueous dispersion polymerization. To interpret these results, a mechanism concerning this two-stage synthetic method for the core-shell particles is proposed. In the first stage, i.e., synthesis of core particles, PNIPAM nanogel latex particles are formed mainly by homogeneous nucleation because the monomers employed (NIPAM and BIS, herein BIS can be treated as a special monomer) are water-soluble, and the concentration of the surfactant DTAC is strictly controlled below its critical micelle concentration (cmc).23,24 During this stage, water-soluble initiators first commence its thermal decomposition to generate primary radicals, and then the growing radicals precipitate to form particles until their chain length reach

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Figure 3. TEM photograph of ultrathin cross section of the core-shell particles. The P4VP component was preferentially stained by RuO4 vapor for 20 min.

a critical value. The colloidal stability of the primary particles and the subsequent latex particles is achieved by both DTAC and the surface charges stemming from the decomposed fragments of initiator AAPH. In the second stage for shell addition, initiation will occur in water instead of in the inside of the seed particles because both kinds of shell monomers (4VP, BIS) and initiator AAPH are all water-soluble. Nevertheless, two factors will greatly limit the nucleation of new particles in aqueous phase and result in preferential growth of the existing seed particles. First, before shell addition, surfactants in the seed latex have been previously removed by dialysis so that most of newly added surfactants (the concentration is still below its cmc) in the stage of shell addition will adsorb onto the PNIPAM core particles to enhance the colloidal stability at reaction temperature. Thus, surfactants remaining in water will be very rare. Second, after initiation, the primary radicals generated grow to form oligomeric radicals; as these oligomeric radicals reach a certain critical chain length, they become insoluble and thermodynamically unstable in water. Because of low surfactant concentration, these individual oligomeric radicals are impossible to form stable colloidal particles by absorbing sufficient surfactants. Therefore, there is only an alternative for these oligomeric radicals, namely attaching themselves onto the existing seed particles driven by hydrophobic interaction and propagating in the peripheral region of seed particles. As a consequence, core-shell particles are formed. The mechanism for core-shell particles formation may be pictured with the aid of Figure 4.

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However, it should be noted that slight interpenetration may occur in the interface between the core and shell. During core particles preparation, BIS is consumed more quickly than is the NIPAM. Therefore, the cross-link density of core particles decreases when moving outward to the particle periphery and lead to a radial cross-link density gradient, so the PNIPAM chain near the periphery is much looser.23,25 Accordingly, P4VP oligomeric radicals formed can enter the relatively loose peripheral region of the core particles, and locally interpenetrated networks are formed. This local interpenetration does not strongly change the core-shell structure but really affect the deswelling behavior, and this influence is discussed in the deswelling measurement. 3.2. Narrow Size Distribution of the Core-Shell Particles. Figure 5 shows the angular dependence of the translational diffusion coefficient distributions G(Γ/ q2) of the PNIPAM core (a) and core-shell latex particles (b), where C ∼ 1 × 10-5g/mL, T ) 25 °C, and pH ) 3.0. The peaks essentially appear at Γ/q2 ∼ 5.08 × 10-8 for PNIPAM core nanogels even at three different scattering angels (θ ) 60°, 90°, 110°). A similar result was also observed for core-shell sample with the peaks at Γ/q2 ∼ 2.95 × 10-8. The peaks are related to the translational diffusion of the nanogels in water, from which the hydrodynamic diameter distribution f (Dh) can be calculated by using the Stokes-Einstein equation Dh ) kBT/(3πηD), where D ) Γ/q2 and the scattering wave vector q ) (4πn/λ0) sin(θ/2). For symmetrical spherical particles (as shown in SEM and TEM images), this angular independence indicates a narrow size distribution of the samples. This result agrees well with that from SEM. Figure 6 shows a narrow size distribution of the core and core-shell nanogels with the average hydrodynamic diameter 〈Dh〉 at 95.0 ( 3 and 160.5 ( 4 nm, respectively, both of which were measured at C ∼ 1 × 10-5g/ mL, T ) 25 °C, and pH ) 3.0. An increase in the average hydrodynamic diameter of the core-shell particles by 65.5 nm relative to the parent core indicates that shell monomers have indeed been added to the core particles, as supported by the TEM and ultrathin cross-section data. The narrow size distributions for both batches of particles also suggest that the nucleation of new particles during shell addition is negligible.

Figure 4. Schematic representation for formation mechanism of the core-shell particles. Stage A: surfactant molecules remaining in water are very rare because most of them have adsorbed onto hydrophobic PNIPAM core particles to enhance the colloidal stability at reaction temperature. Stage B: initiation occur in water due to water solubility of 4VP, BIS, and AAPH. Stage C: hydrophobic oligomeric radicals adsorb onto core particles to propagate and form core-shell particles.

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Figure 5. Translational diffusion coefficient distributions G(Γ/q2)of the core (a) and core-shell (b) particles in water at different scattering angles, where T ) 25 °C, pH ) 3.0, and C ∼ 1 × 10-5 g/mL.

Figure 6. Hydrodynamic diameter distributions of core and core-shell particles measured at C ∼ 1 × 10-5 g/mL, pH ) 3.0, and T ) 25 °C.

Figure 7. Deswelling curves for core and core-shell (c-s) particles at pH ) 3.0 and 11.0.

3.3. Temperature and pH Sensitivity of the Core-Shell Particles. Figure 7 shows the deswelling behavior of the core and core-shell particles at pH 3.0 and 11.0. All the curves clearly exhibit a sharp VPT upon raising temperature to the vicinity of 31 °C. It is well-known that a low critical solution temperature (LCST) at 31 °C is characteristic of an unperturbed PNIPAM gels. To our interest, there is almost no shift in LCST for core-shell particles at both pH 3.0 and 11.0 in contrast to the parent core, which suggests that shell components nearly do not perturb VPT of the core whether the shell components are ionized or not (4VP components are ionized at pH 3.0). The results significantly differ from other polyelectrolyte gels within which the ionic groups are randomly distributed. Snowden19 reported a poly(NIPAM-co-4VP) microgel with a wider range of VPT temperature from 30 to 60 °C when 4VP units are protonated under acidic conditions (cf. Figure 7 of ref 19). A combination of a broadening VPT and a reduction in the magnitude of the deswelling was also reported for a poly(NIPAM-co-AAc) gels when AAc units are deprotonated under alkaline conditions (cf. Figure 3 of ref 20 and Figure 3 of ref 21).20,21 The perturbation of the ionic groups on VPT is attributed to both Cou-

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lombic repulsion between charged groups and added osmotic pressure (Donnan effect) from incorporated counterions, which dominate over the attractive hydrophobic interaction; therefore, the collapse of the PNIPAM subchains within the polyelectrolyte gels is limited even at a temperature above LCST. For the present coreshell particles, even if the 4VP components are ionized at pH 3.0, the sharpness and position of the VPT still remain the same as those of the PNIPAM core particles. An interpretation is proposed as follows: for high crosslink density of the shell, the P4VP chains are limited in the periphery of core particles; thus, the temperatureinduced hydrophobic interaction of PNIPAM chains in the core cannot be significantly perturbed by charged 4VP units, i.e., the driving force that acts to shrink the PNIPAM network has not been changed, and therefore the unperturbed VPT are maintained. Figure 7 also reveals that at the same temperature the particle size of the core-shell particles increase significantly when changing pH from 11.0 to 3.0, while hydrodynamic diameter of the core particles at pH 11.0 and 3.0 differ very slightly. The results may be well understood by considering the difference in structure and chemical composition of the core and core-shell nanogels. The core particles are composed of temperature-responsive and pH innocent material, i.e., PNIPAM, upon which a pH-responsive component P4VP is added to form the core-shell particles. At low temperature and low pH, both PNIPAM core and P4VP shell are soluble in water. When raising temperature above LCST, waterunfriendly hydrophobic PNIPAM subchains aggregate and the core domains collapse. Because of the interpenetration of two materials in the interface between the core and shell, the shrunk core will attract the shell and thus result in a decrease in the overall size of the core-shell particles. Besides temperature, pH will also affect the size and swelling ability of the particles. At low pH, P4VP is protonated and soluble in water; when raising pH higher than 4.8,26 the polymer is deprotonated and relatively hydrophobic, and the particle size decreases. As described above, a selective response of the core-shell particles can be obtained by changing either temperature or pH, i.e., the response of PNIPAM core and P4VP shell, respectively. It is worth noting that the temperature-induced VPT is continuous for both core and core-shell particles. The results may be explained as follows. During core latex preparation, the cross-linker BIS is statistically incorporated faster than NIPAM monomers, leading to a radial distribution of cross-linking density.23,25 Microscopically, the swelling or collapsing of a nanogel can be visualized as the expansion or contraction of the subchains between two neighboring cross-linking points inside the networks.10,12 Because of cross-linker heterogeneity within individual nanogel, the length of subchains varies. As temperature increases, a longer subchain will undergo VPT before a shorter subchain; thus, different parts of the gel networks undergo VPT at different temperature. As a result, a macroscopically continuous VPT with a broad transition temperature range was observed. Figure 8 shows the temperature and pH dependence of the swelling ratio 〈Dh〉/〈Dh〉* of the core-shell particles, where 〈Dh〉* is the average hydrodynamic diameter of the core-shell particles at the collapsing limit monitored at T ) 44.2 °C and pH ) 11.0. The 〈Dh〉/〈Dh〉* reach a maximum at T ) 25.0 °C and pH ) 3.0 which

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Nankai University and Tianjin University Joint Academy is gratefully acknowledged. References and Notes

Figure 8. Temperature and pH dependence of the swelling ratio 〈Dh〉/〈Dh〉* of the core-shell particles obtained at pH 3.0 and 11.0, where 〈Dh〉* is the average hydrodynamic diameter of the core-shell particles at the collapsing limit.

increase by 2.5-fold compared to the collapsing limit. Noting that hydrodynamic volume 〈Vh〉 ) (4π/3)(Dh/2)3, thus a 2.5-fold increase in the particle diameter corresponds to about a 15-fold increase in volume. Under the identical temperature, the value of 〈Dh〉/〈Dh〉* is apparently higher at pH ) 3.0 than that at pH ) 11.0, which indicates the collapsing of the P4VP shell under alkaline conditions. 4. Conclusions Narrowly distributed colloidal nanogels with temperature-responsive core and pH-responsive shell have been successfully prepared by a two-step aqueous dispersion polymerization. SEM and TEM were employed for characterization of the morphology and structure of the nanogels. The deswelling behavior investigated by DLLS shows that the temperature sensitivity of the PNIPAM core is not significantly affected by addition of the pH-responsive P4VP shell; the temperature-induced VPT of the core-shell particles still occur in the vicinity of the physiological temperature which implies a potential applications in controlled release. Together, the present work may extend the scope of preparing colloidal nanogels with more complex structure from aqueous dispersion polymerization. Acknowledgment. The financial support by the National Natural Science Foundation of China (20174019) and the Chinese Education Ministry Foundation for

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