ARTICLE pubs.acs.org/Langmuir
pH/Temperature-Responsive Behavior of Amphiphilic Block Copolymer Micelles Prepared Using Two Different Methods Jun Mao, Shuqin Bo,* and Xiangling Ji* State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, People's Republic of China
bS Supporting Information ABSTRACT: The pH- and temperature-responsive behavior of amphiphilic block copolymer poly(L-lactide)-b-poly(2-(dimethylamino)ethyl methacrylate) (PLLA-b-PDMAEMA) in aqueous solutions is investigated using static and dynamic light scattering. Electrostatic force, hydrophobic interaction, and hydrogen bonding coexist in the system. Micelles with different structures are prepared using water addition (WA) and direct dissolution (DD) methods. The aggregation from loose micelles into large micellar clusters is observed above the transition temperature under basic conditions. Only micellar clusters from the DD method could disaggregate when temperature was decreased to 24.3 C after heating. The behavior of the micelles prepared with the DD method indicates that only the outer parts of the PLLA-b-PDMAEMA chains in the corona are solvated.
’ INTRODUCTION Stimuli-responsive amphiphilic block copolymers have attracted much attention in the past decades. This is due to their wide range of interesting and novel properties as well as applications in the biomedical field, such as being drug and gene carriers.1,2 Most of these applications are based on the micelle form because micelles have (1) high stability in aqueous solutions at low concentration, (2) small sizes that facilitate longterm circulation in the blood,3 and (3) the ability to respond to a combination of environmental stimuli4,5 (pH, temperature, ionic strength, etc.). These advantages make stimuli-responsive amphiphilic block copolymers ideal candidates to mimic the features of natural macromolecules, such as proteins and nucleic acids.6 Block copolymers are known to form spherical micelles in selective solvents at low concentration, with compact cores of insoluble blocks surrounded by a corona of soluble blocks.7 Numerous studies have been performed to establish the relationship between micelles and parameters such as intrinsic and environmental parameters.8,9 The intrinsic and key parameters controlling the characteristics of micelles10 are the degree of polymerization of the polymer blocks (N) and the FloryHuggins interaction parameter (χ). Such characteristics include the core radius (Rc), micelle radius (Rm), and the aggregation number (Z). Thus, the formation of micelles can be understood using thermodynamics; micelles can form spontaneously with a control of entropy and enthalpy. On the other hand, environmental parameters can be used to control the self-assembly process and morphological change kinetically. This includes concentration of the block copolymers, solvent selection, and salt concentrations.1113 The driving force can be different noncovalent interactions, including hydrophobic interaction, hydrogen bondings, and metal coordination or electrostatic interactions. r 2011 American Chemical Society
The intrinsic parameters are settled once the block copolymers have been synthesized. Using environmental parameters is more important and powerful to control micelle behavior kinetically and to meet the need of different applications. The chosen preparation route may affect the formation of micelles. Generally, micelles can be prepared using two methods. In the first method, the copolymer is dissolved in a cosolvent at the molecular level and is subsequently diluted with a selective solvent. In the second method, the block copolymer is directly dispersed in selective solvents.10 Selb and Gallot14 first reported a systematic investigation on micelle formation of polyelectrolyte block copolymers in aqueous solutions. They noted the low solubility of most polymers when directly dissolved in water.14,15 Since then, using a cosolvent (THF, DMF, acetone) has become common practice to dissolve block copolymers, followed by dilution into aqueous solutions to obtain stable micelles.16 Thus, few studies discussed the influence of the preparation routes on micelle formation.15,17,18 However, in some cases, polymers may be directly dissolved in water using short hydrophobic blocks.19 The behavior of micelles can be affected by environmental conditions, such as pH, temperature, solvent quality, and so on.2022 Micelles sometimes form larger aggregates, called “micellar clusters”. For example, Xu et al.23 reported a larger aggregate of polystyrene-b-poly(ethylene oxide) (PS-b-PEO) chains in aqueous solution, which was interpreted as loose micellar clusters. The clustering of long PEO chains was thought to account for the formation of micellar clusters. Lombardo Received: November 6, 2010 Revised: May 9, 2011 Published: May 18, 2011 7385
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et al.24 found similar micellar clusters in poly(dimethylsiloxane)b-poly(ethylene oxide) (PDMS-b-PEO) systems. The clusters were attributed to the partial interpenetration of PEO chains between different micelles. However, among the numerous investigations on micellar behavior and applications, only few systematic studies report on stimuli-sensitive micelles (particularly on micellar clusters) that respond to dual- or multi-stimuli. Recently, we prepared one kind of block-type polyelectrolyte, hydrophilichydrophobic block copolymers (Figure 1), with poly(L-lactide) (PLLA) as the short segment and hydrophobic component while poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) was the long segment and hydrophilic component. PDMAEMA has a pKa of ∼7.4 and shows pH-dependent lower critical solution temperature (LCST) behavior in aqueous solution.25,26 Below the critical temperature, PDMAEMA behaves as a hydrophilic polymer. When heated above the critical temperature, the polymer dehydrates, the chains shrink and tend to precipitate. Thus, the polymer plays both pH- and temperature-sensitive roles in the corona. Dubois27 and Hadjichristidis3 reported the synthesis of PLLA/PDLA-b-PDMAEMA block copolymers with short PDMAEMA segment. Hadjichristidis et al. investigated the aggregation behavior of diblock copolymers by dynamic light scattering (DLS), and zeta-potential at 25 C in aqueous solutions of pH e pKa of PDMAEMA (pH = 5.0, 6.5, and 7.4). In the present study, micelles were prepared using two different methods. Static light scattering (SLS) and DLS were performed to investigate micellar behavior during a heating-and-cooling cycle at both acidic and basic pH (pH = 6.2, 7.4, 8.3, and 8.6). The micellar formation process of these copolymers will help in understanding the origin of micellar clusters.
’ EXPERIMENTAL SECTION Materials. The diblock copolymer PLLA-b-PDMAEMA was synthesized by combining ring-opening polymerization (ROP) of LLA and atom transfer radical polymerization (ATRP) of DMAEMA using a dual-initiator 2-hydroxylethyl 2-bromoisobutyrate (HEBIB), as previously described.28 Molecular weight and polydispersity index were determined by gel permeation chromatographymultiangle LLS (GPCMALLS). The copolymer composition was determined using 1H NMR spectroscopy. Table 128 summarizes the molecular weight and block composition data. Preparation of Micelle Solutions with Different pH Values. Two different methods were used to prepare the micelles. The first method is called water addition (WA). In brief, 10 mg of the diblock
copolymer PLLA-b-PDMAEMA O8 was dissolved in 4 mL of THF, dropped slowly into 10 mL of ultrapure water (18.2 MΩ cm1), and stirred for 24 h. The THF was then extracted in reduced pressure at room temperature. Afterward, 90 mL of ultrapure water was poured into the 10 mL of solution to “freeze” the micelle. The final 100 mL of solution was passed through 0.8 μm syringe filter to obtain 0.1 g L1 of stock solution and stored under lower temperature before further use. The second method is the direct dissolution (DD) method. For example, 10 mg of O8 was dissolved in 4 mL of THF. The solution was placed in a dialysis tube (molecular weight cutoff: 14 000 g 3 mol1) and subjected to dialysis against 1000 mL of ultrapure water (18.2 MΩ cm1) for 24 h. The solution was then lyophilized to obtain a white solid. A total of 10 mg of the white solid was added into 10 mL of ultrapure water and stirred for 24 h at room temperature. Then, 90 mL of ultrapure water was poured into 10 mL of solution to “freeze” the micelle. The final 100 mL of solution was passed through 0.8 μm syringe filter to get 0.1 g L1 of stock solution and stored under lower temperature before further use. To prepare the micelle solution with a certain pH value, 0.3 mL of phosphate buffer solution (filtered with 0.2 μm syringe filter before use) was added into 1.0 mL of the foregoing stock solution. The phosphate buffer has strong capacity even when diluted 10-fold; its pH value changes for less than 0.1. Thus, the pH value of the final micelle solution can be considered the same as that of the phosphate buffer. The phosphate buffer solution was prepared with four pH values (6.2, 7.4, 8.3, and 8.6). The ionic strength of the buffer solutions was adjusted to 0.2 M by adding sodium chloride. Finally, the micelle solutions with different pH values, constant concentration of 7.7 102 g L1, and constant ionic strength of 46 mM were used in all LLS experiments. LLS. A commercial LLS spectrometer (ALV CGS-3), equipped with a multi-τ digital time correlation (ALV7000) and a cylindrical 22 mW HeNe laser (λ0 = 632.8 nm, Uniphase) as light source, was used. In static LLS,29 the apparent weight-average molar mass (Mw) and zaverage root-mean-square radius of gyration (ÆRgæ) of particles in a dilute solution by Zimm plot can be obtained from the angular dependence of excess absolute time-averaged scattered light intensity known as the Rayleigh ratio Rvv(q). For large aggregates, Mw and ÆRgæ were obtained using the Guinier plot.30 The range of scattering angle θ used in the present study was from 20 to 60, with a step of 2. In dynamic LLS, all measurements were performed at a fixed scattering angle of 20. The average hydrodynamic radius Rh and size distributions (μ2/Γ2) of the micelles were obtained by cumulant analysis29 of the experimental correlation function; the data are summarized in the Supporting Information. The temperature of the scattering vial was controlled by a thermostatic water bath (JULABO F12-ED) with precise temperature of (0.02 C. Each temperature was kept for at least an hour to reach equilibrium before measurement.
’ RESULTS AND DISCUSSION
Figure 1. Structure of the PLLA-b-PDMAEMA diblock copolymer.
Micellization Equilibrium. For the WA method, the copolymer was first dissolved in the common solvent THF. The hydrodynamic radius of O8 (Figure 2) in THF is 9.5 nm, indicating the absence of large aggregates. The solution was subsequently diluted with water. For the DD method, the
Table 1. Characterization Results of the PLLA-b-PDMAEMA Diblock Copolymer28
a
copolymer ID
Mn (g mol-1)
O8
86 800 1
Dp of LLA blocka
Dp of DMAEMA blocka
Mw/Mnb
cmcc (g L1)
80
516
1.11
5.0 102
b
Dp of both blocks was calculated by the H NMR spectrum. Molecular weight and polydispersity were determined by the GPC-MALLS system with THF as the mobile phase. c The critical micelle concentration (cmc) value was estimated using the fluorescence probe method. 7386
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Figure 2. Hydrodynamic radius of O8 in THF.
lyophilized solid was directly dissolved in water to form aggregates. DLS was used to determine the hydrodynamic radius (Rh) of the micelles in pure water (without the addition of buffer). The Rh of micelles prepared by DD method is 130.0 nm (the size distribution μ2/Γ2 = 0.10), whereas that of WA method is 97.8 nm (μ2/Γ2 = 0.07). Therefore, WA and DD lead to the same case; that is, the copolymer can form micelles in water with hydrophobic PLLA core and hydrophilic PDMAEMA corona. However, the formation of these micelles is under kinetic control. Water is an extremely strong precipitant for PLLA. Thus, the hydrophobic crystalline core (the crystallization temperature range for our PLLA block is 120170 C as determined from differential scanning calorimetry) is compact and is kinetically “frozen” when preparing the micelles in aqueous solutions. This is the same as block copolymer micelles with a high glass transition temperature core such as PS or PMMA.15,17,18 Whether these structures are determined by the method of preparation is a matter of concern. The theoretical length was calculated assuming that block copolymer chains are fully stretched. The contour length of the block copolymer chain is estimated to be ∼149 nm by L = Nl, where the length per unit is l = 0.25 nm and N is the total number of units.31 Either WA or DD led to the same case when the experimental sizes determined by DLS and the theoretical length were compared. Despite the hydration effect, the polymer chains take a stretched conformation in the solution. This is because the experimental sizes approach the theoretical lengths. Similar results were obtained by Rakhmatullina et al.32 when they investigated poly(n-butyl methacrylate) (PBMA)-b-PDMAEMA block copolymer micelles in water. DLS experiments show that copolymers form much larger aggregates when directly dissolved in water than when first dissolved in THF and subsequently diluted with water. Other researchers have observed similar behavior in PS- or PMMAbased systems in aqueous solution.15,17,18 Stejskal et al.33 attributed the behavior to the microphase separation of block copolymers in solid state. In the present case, PLLA is a crystalline polymer, similar to high glass transition temperature hydrophobic PS or PMMA. When selective solvents are used for the dissolution of block copolymers, the solid-state morphology may be partly preserved in the solution. This is because the solvent (i.e., water) cannot dissolve the phase-separated glassy or crystalline polymer. Water cannot easily penetrate PLLA domains, and the copolymer forms aggregates with structures reflecting the
Figure 3. Temperature dependence of average radius of gyration (ÆRgæ) and hydrodynamic radius (ÆRhæ) of micelles prepared using the WA method at different pH in one heating-and-cooling cycle.
morphology of the solid copolymer. Further, the zeta-potential of the micelles prepared by WA method is 50.9 mV, whereas that prepared by DD method is 33.5 mV. Compared with the DD method, micelles from the WA method are more stable. During the WA preparation, the long PDMAEMA chains in the corona are fully solvated because all THF molecules were replaced by water molecules. However, zeta-potential results indicate that possibly not all the PDMAEMA chains could be swollen by water molecules during DD preparation. Only part of the chains is solvated due to the limited mobility of the PDMAEMA chains. Thus, the method of preparation affects micelle formation. pH/Temperature-Responsive Behavior during the Heating Process. Both SLS and DLS experiments were performed to understand further the relationship between the preparation methods and micellar behavior in aqueous solution. This tracks the change of Rg and Rh in response to pH and temperature. Figures 3 and 4 show the results during a heating-and-cooling cycle. Focus is first given on the heating process. The following three cases are observed (in this section, as the similar trend of Rg and Rh values is discussed, only the change of Rh is described). To facilitate the description, micelles prepared by the WA and DD methods are abbreviated as Micelle-WA and Micelle-DD, respectively. First, at pH = 6.2, the Rh of MicelleWA was 93.0 nm at 24.2 C and 93.0 nm at 46.3 C. The Rh of Micelle-DD was 128.3 nm at 24.2 C and 134.7 nm at 46.3 C. The Rh values showed little change during the heating process. At pH = 7.4 (i.e., pKa value), from 24.2 to 46.3 C, the Rh of Micelle-WA changed from 97.8 to 88.3 nm, whereas that of Micelle-DD changed from 132.1 to 118.1 nm. Their Rh values slightly decreased as the temperature rose. However, at pH = 8.3 and at 24.2 C, the Rh of Micelle-WA and Micelle-DD aggregated from 82.4 and 103.3 nm, respectively, to several hundred nanometers of large structures above a transition temperature below 46.3 C. The situation at pH = 8.6 is almost the same as that at pH = 8.3. Second, the pH at 8.6 is more basic than that at 8.3. Thus, the transition temperature for MicelleWA and Micelle-DD are 30.4 and 35.7 C, respectively. These are lower than those at pH 8.3 (34.2 C for Micelle-WA and 39.6 C for Micelle-DD). Third, before aggregation at 24.2 C, from pH = 6.2 to 8.6, the Rh of Micelle-WA was respectively 7387
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Figure 4. Temperature dependence of average radius of gyration (ÆRgæ) and hydrodynamic radius (ÆRhæ) of micelles prepared using the DD method at different pH in one heating-and-cooling cycle.
93.0, 97.8, 82.4, and 88.4 nm, whereas that of Micelle-DD was respectively 128.3, 132.1, 103.3, and 106.5 nm. The Rh at pH e 7.4 is larger than that at pH > 7.4. Thus, Micelle-WA and Micelle-DD show significant pH and temperature dual-responsive behavior in the aqueous solution. Normally, the free energy of a micelle (Emicelle) is mainly determined by the force balance among three factors:8,10 (1) interfacial energy of the core/shell interface (Einterface1), (2) stretching energy of the core-forming blocks (Ecore), and (3) repulsion among coronal chains (Ecorona). In the present system, the interfacial energy of the corona/solvent interface (Einterface2) should be considered. For the as-prepared spherical micelles, the PDMAEMA corona acted as a shell to protect the PLLA core from the aqueous solution. The stability of micelles is mainly affected by the corona. Thus, Ecorona and Einterface2 became dominant factors to total free energy Emicelle in the system. The PDMAEMA corona has a pKa of 7.4. Thus, at pH = 6.2 and 7.4, Ecorona and Einterface2 behave as electrostatic repulsion and hydrogen bonding, respectively; at pH = 8.3 and 8.6, when raising temperature above the transition temperature, they both behave as hydrophobic interactions. If the electrostatic repulsion (including inter- and intrachain of PDMAEMA molecules and intermicelles) is weakened, such as changing pH from acidic to basic, Rg and Rh decrease. The size of micelles becomes smaller. If the hydrogen bonding (between PDMAEMA chains and water molecules) is weakened, such as raising the temperature at pH = 8.3 and 8.6, PDMAEMA chains from the same and neighboring micelles become more and more hydrophobic. This increases Einterface2. The micelles with higher free energy are unstable in the solution. The strong hydrophobic interactions act as a driving force. Micelles stack tightly together to minimize free energy, leading to the aggregation and formation of large micellar clusters. During the heating process, higher pH causes a higher degree of neutralization, higher Einterface2, and earlier micellar aggregation. However, in an acidic environment, electrostatic repulsion and hydrogen bonding cannot be weakened, and the micelles keep their isolated state. For the case at pH = 7.4, which is an intermediate state, hydrogen bonding may not be weakened when the temperature is increased. However, the size of micelles starts to contract due to the increased hydrophobicity of PDMAEMA chains and the decreased electrostatic repulsion between them.
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Meanwhile, Micelle-WA and Micelle-DD had significantly different behaviors during the heating process, especially under the basic environment. The situation at pH = 8.3 is described as follows. First, Micelle-WA starts to aggregate earlier than MicelleDD. In addition, the transition temperature of Micelle-WA at 34.2 C is much lower than that of Micelle-DD at 39.6 C. PDMAEMA is a type I thermosensitive polymer. This type of polymer follows the classical FloryHuggins miscibility behavior; the LCST shifts toward lower temperature upon increasing polymer molar mass.26,34 Ni35 recently studied the effect of the composition of the monomer unit on the LCST of the diblock copolymers PEEP-b-PDMAEMA; they found that LCST of block copolymers decreased when the molecular weight of PDMAEMA increased, while the molecular weight of PEEP block was roughly constant. Thus, Micelle-WA in aqueous solution exhibits longer PDMAEMA chains than Micelle-DD. This confirms the hypothesis that only part of the PDMAEMA chains of Micelle-DD are solvated. Second, at the transition temperature, Figure 4c shows a sharp and quick transition to large micellar clusters. In Figure 3c, the transition seems to be a relatively slower process. Studies36 on the popular LCST polymer PNIPAM show that a single chain collapses quickly from coil to compact globule. The current situation is different from the “free” single chain. The long PDMAEMA chains (see Table 1) are densely tethered to a curved surface and cannot easily stretch or collapse like free chains. The transition process from single a micelle to compact micelle clusters possibly involves two steps: (1) the PDMAEMA chains become hydrophobic to repel water molecules from inside to outside and (2) micelles aggregation and interpenetration of PDMAEMA chains. For Micelle-WA with very long PDMAEMA chains, step 1 makes the coming out of water molecules more difficult. Moreover, the hydrogen bonding between PDMAEMA chains and water molecules would prevent micelle aggregation if the chains were not hydrophobic enough. Thus, the chains spend more time aggregating than those in Micelle-DD. This is illustrated in Figure 3c, where Rg and Rh increase more slowly than in Micelle-DD. Step 2 is very fast for both Micelle-WA and Micelle-DD. The micelles collide and stack tightly together. The sharp increase in Rg and Rh for Micelle-DD indicates that the solvated PDMAEMA chains in the corona are short. Furthermore, for Micelle-WA or Micelle-DD, the micelles continued to aggregate and the size increased when the temperature was kept above the transition temperature. The micellar clusters grew bigger and faster as the temperature continuously rose. Thus, the system tries to lower the free energy and reach the thermodynamic stable state during the heating process. MicelleWA and Micelle-DD continued to aggregate until they were big enough to precipitate from the solution. However, the cooling process should begin before precipitation happens. pH/Temperature-Responsive Behavior during the Cooling Process. Figures 3 and 4 show the change in Rg and Rh during the cooling process. At pH = 6.2 and 7.4, the initial situations at 24.2 C and subsequently 24.3 C after a heatingand-cooling cycle were compared. For Micelle-WA, Rh is from 93.0 to 93.7 nm at pH = 6.2 and from 97.8 to 100.3 nm at pH = 7.4. For Micelle-DD, Rh is from 128.3 to 134.5 nm at pH = 6.2 and from 132.1 to 129.2 nm at pH = 7.4. The situation of Rg exhibits almost the same trend as that of Rh. The data indicate that Micelle-WA and Micelle-DD almost return to their initial states as the environment cools down. A dramatic process occurs at pH = 8.3 and 8.6. For example, at pH = 8.3 and with temperature back to 24.3 C, the Rg and Rh of Micelle-WA are 7388
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Langmuir 294.7 and 590.9 nm, respectively. These are even larger than the aggregated state at 36.3 C, which are 272.8 and 513.0 nm, respectively. This means the micellar clusters do not disaggregate at all. At higher temperature, micelles stack together to minimize the free energy. The long hydrophobic PDMAEMA chains (much longer than the PLLA chains) from different micelles entangle and interpenetrate with each other. The hydrophobic interaction is strong and the micelles tie each other very tightly. At lower temperature, the hydrogen bonding with water molecules recovers and the interfacial energy between the micelles increases. The Ecorona also increases. This time, the hydrogen bonding will drive micelles to leave each other to pursue the ideal thermodynamic stable state with the lowest free energy. However, separating the long and entangled PDMAEMA chains from each other by themselves will take a long time. Thus, micellar clusters from Micelle-WA experience a slow kinetic process. Even when the solution was kept at ambient temperature for 48 h or longer, the large micellar clusters did not return to the initial single micelles. The micellar clusters could not disaggregate to reach the thermodynamic stable state on a reasonable time scale. However, the PDMAEMA chains were hydrophilic again, becoming more stretched than at higher temperature. Thus, Rg is larger. The micellar clusters move slower because of increased water content. This leads to a smaller average transitional diffusive coefficient (D) and larger Rh (according to Stokes Einstein equation of Rh = kBT/6πηD, where kB, η, and T are the Boltzmann constant, the solvent viscosity, and absolute solution temperature, respectively). For Micelle-DD back at temperature 24.3 C, Rg and Rh are 197.9 and 191.8 nm, respectively. These values are much smaller than the aggregated state at 40.0 C, which are 319.3 and 587.5 nm, respectively. However, these were larger than the initial state of 99.5 and 103.3 nm, respectively. Thus, the micellar clusters can disaggregate, but the micelles have been rearranged. Micelles may have become much smaller micellar clusters, with 2 or 3 micelles together. The size of the final state is nearly twice as large as that of the initial state (the situation at pH = 8.6 is almost the same). The mechanism is not clear yet; possibly it will take longer to reach the thermodynamic equilibrium. When temperature decreases below the transition temperature, the entangled PDMAEMA chains could easily untangle. This means the “wet” PDMAEMA chains were short and could be easily pulled apart by hydrogen bonding formed below the transition temperature. Thus, micellar clusters from Micelle-DD mainly experienced a quick kinetic process, where the micellar clusters quickly disaggregated and reached a lower free energy state. Figures 5 and 6 thus illustrate the important morphological changes of Micelle-WA and Micelle-DD at pH = 8.3 and 8.6 during a complete heating-and-cooling cycle. Micelle and Micellar Cluster Structure. The ratio of Rg/Rh is sensitive to the density profile of a polymeric molecule37,38 and provides information about the shape of the micelle and the micellar structures. Ratios of Rg/Rh measured for uncharged block copolymer micelles are usually in the range 0.71.4, which is typical for starlike polymeric structures, and ∼0.77 for a uniform hard sphere.39,40 Figure 7 shows the ratios at different temperatures for pH = 6.2 and pH = 8.3. First, at 24.2 C, the Rg/ Rh are 1.00 for Micelle-WA and 0.96 for Micelle-DD at pH = 8.3 (close to the value of micellar aggregates). At pH = 6.2, Rg/Rh are 0.85 for Micelle-WA and 0.80 for Micelle-DD (close to the value of uniform hard sphere). Micelle-WA and Micelle-DD lead to the same case where Rg/Rh at pH = 8.3 is higher than at pH = 6.2.
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Figure 5. Schematic of morphological change of Micelle-WA at basic pH values (8.3 and 8.6) during a heating-and-cooling cycle.
Figure 6. Schematic of morphological change of Micelle-DD at basic pH values (8.3 and 8.6) during a heating-and-cooling cycle.
Figure 7. Temperature dependence of ratio of average radius of gyration to average hydrodynamic radius (ÆRgæ/ÆRhæ) of micelles at pH = 6.2 and 8.3 in one heating-and-cooling cycle: (a, b) Micelle-WA; (c, d) Micelle-DD.
This indicates a more swollen corona at lower pH. The corona swells as a few charge increases, and Rh increases more rapidly than Rg with increased coronal swelling.38 Second, at pH = 6.2 < pKa (7.4), the ratio changed little during the heatingcooling cycle. The Rg/Rh of Micelle-WA is around 0.85, and the Rg/Rh of Micelle-DD is around 0.80. This means Micelle-WA and MicelleDD are spherical aggregates, but the latter has a denser core. This is where the difference from the preparation methods becomes evident. Third, at pH = 8.3, for Micelle-WA below the transition temperature, the ratio is around 1.0. At the slowly growing stage, the ratio increased to 1.14. The micelles began to aggregate, and then the ratio decreased sharply to around 0.43. This indicates that the Rg of the micellar clusters were more heavily weighted by the core. The “core” in the present study means the center part of the micellar cluster, which is very compact. The density of the 7389
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Langmuir core was much higher than the corona. Several groups37,38,41 reported a similar value for individual micelles. For Micelle-DD, the ratio Rg/Rh of the heating process is similar to that of MicelleWA. When temperature decreases, the ratio increases from approximately 0.4 to 1.1. The micellar clusters change from compact structures to loose micelles. Therefore, the ratio Rg/Rh showed a relatively clear picture of the shape change of the micelles during a heating-and-cooling cycle.
’ CONCLUSIONS Two different methods, namely, WA and DD, are explored to prepare PLLA-b-PDMAEMA micelles with hydrophobic PLLA core and hydrophilic PDMAEMA corona. The DLS and zeta potential results show that the size of Micelle-WA is smaller but more stable than that of Micelle-DD. Thus, the two micelle preparations are shown to be different. The pH/temperature responsive behavior of Micelle-WA and Micelle-DD is investigated at different pH (6.2, 7.4, 8.3, and 8.6) during a heating-and-cooling cycle. The electrostatic force, hydrophobic interaction, and hydrogen bonding coexist in the system. During a heating-and-cooling cycle, the electrostatic repulsion and hydrogen bonding at pH = 6.2 are two key interactions that could stabilize the micelles. The size of Micelle-WA and Micelle-DD has no change. At pH = 7.4, the micelles without electrostatic repulsion slightly decreased as temperature increased. The repulsion among PDMAEMA chains (Ecorona) and the interfacial energy between PDMAEMA chains and water (Einterface2) become dominant factors to total free energy Emicelle under basic conditions. At pH = 8.3 and 8.6 (>pKa = 7.4 of PDMAEMA) during the heating process, Micelle-WA and Micelle-DD aggregate into large micellar clusters above a transition temperature. The Einterface2 increases; thus, the strong hydrophobic interaction drives the micelles to aggregate to lower the free energy. During the cooling process, the Ecorona increases, and the hydrogen bonding recovers, driving the micellar clusters to disaggregate. However, micellar clusters from Micelle-WA experience a slow kinetic process. The tightly entangled and long PDMAEMA chains cannot untie themselves, and the clusters could not disaggregate. In contrast, the micellar clusters from Micelle-DD mainly experience a quick kinetic process. The chains disaggregate easily and reach a lower free energy. The transition temperature of Micelle-WA is much lower than that of Micelle-DD at pH = 8.3 and 8.6. MicelleWA spends more time than Micelle-DD to aggregate into large micellar clusters. Thus, the intrinsic difference between Micelle-WA and Micelle-DD are shown. The PDMAEMA chains of Micelle-WA are fully solvated in water. In contrast, only the outer part of the PDMAEMA chains of Micelle-DD is solvated in water. ’ ASSOCIATED CONTENT
bS
Supporting Information. Hydrodynamic radii (Rh) and size distributions (μ2/Γ2) of Micelle-WA and Micelle-DD at different pH/temperature. This material is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*Tel: þ86 431 85262876. Fax: þ86 431 85685653. E-mail:
[email protected] (S.B.),
[email protected] (X.J.).
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’ ACKNOWLEDGMENT This work was subsidized by the National Natural Science Foundation of China (Key Project: 50633030, Innovation Group: 50621302, 50921062), the Science and Technology Bureau of Changchun City (2008228), and the Jilin Province (20090132), China. ’ REFERENCES (1) Kataoka, K.; Harada, A.; Nagasaki, Y. Adv. Drug Delivery Rev. 2001, 47, 113. (2) Kakizawa, Y.; Kataoka, K. Adv. Drug Delivery Rev. 2002, 54, 203. (3) Karanikolopoulos, N.; Zamurovic, M.; Pitsikalis, M.; Hadjichristidis, N. Biomacromolecules 2010, 11, 430. (4) Alarcon, C. d. l. H.; Pennadam, S.; Alexander, C. Chem. Soc. Rev. 2005, 34, 276. (5) Schmaljohann, D. Adv. Drug Delivery Rev. 2006, 58, 1655. (6) Moffitt, M.; Khougaz, K.; Eisenberg, A. Acc. Chem. Res. 1996, 29, 95. (7) Jeong, B.; Gutowska, A. Trends Biotechnol. 2002, 20, 305. (8) Zhang, L.; Eisenberg, A. Polym. Adv. Technol. 1998, 9, 677. (9) Lim Soo, P.; Eisenberg, A. J. Polym. Sci., Part B: Polym. Phys. 2004, 42, 923. (10) Gohy, J. F. Adv. Polym. Sci. 2005, 190, 65. (11) Zhang, L.; Eisenberg, A. J. Am. Chem. Soc. 1996, 118, 3168. (12) Cui, H.; Chen, Z.; Zhong, S.; Wooley, K. L.; Pochan, D. J. Science 2007, 317, 647. (13) Fairley, N.; Hoang, B.; Allen, C. Biomacromolecules 2008, 9, 2283. (14) Selb, J.; Gallot, Y. In Developments in Block Copolymers 2; Goodman, I., Ed.; Elsevier: Amsterdam, 1985; p 27. (15) Selb, J.; Gallot, Y. Makromol. Chem. 1980, 181, 809. (16) Tuzar, Z. In Solvents and Self-Organization of Polymer; NATO ASI Series, Series E: Applied Sciences; Webber, S. E., Munk, P., Tuzar, Z., Eds.; Kluwer Academic Publisher: Dordrecht, 1996. (17) Baines, F. L.; Armes, S. P.; Billingham, N. C.; Tuzar, Z. Macromolecules 1996, 29, 8151. (18) Gao, Z.; Varshney, S. K.; Wong, S.; Eisenberg, A. Macromolecules 1994, 27, 7923. (19) Valint, P. L.; Bock, J. Macromolecules 1988, 21, 175. (20) Zhang, L.; Eisenberg, A. Science 1995, 268, 1728. (21) Won, Y.-Y.; Davis, H. T.; Bates, F. S. Science 1999, 283, 960. (22) Svensson, B.; Olsson, U.; Alexandridis, P. Langmuir 2000, 16, 6839. (23) Xu, R.; Winnik, M. A.; Hallett, F. R.; Riess, G.; Croucher, M. D. Macromolecules 1991, 24, 87. (24) Lombardo, D.; Micali, N.; Villari, V.; Kiselev, M. A. Phys. Rev. E 2004, 70, 021402. (25) Liu, S.; Weaver, J. V. M.; Tang, Y.; Billingham, N. C.; Armes, S. P.; Tribe, K. Macromolecules 2002, 35, 6121. (26) Plamper, F. A.; Ruppel, M.; Schmalz, A.; Borisov, O.; Ballauff, M.; M€uller, A. H. E. Macromolecules 2007, 40, 8361. (27) Spasova, M.; Mespouille, L.; Coulembier, O.; Paneva, D.; Manolova, N.; Rashkov, I.; Dubois, P. Biomacromolecules 2009, 10, 1217. (28) Mao, J.; Ji, X. L.; Bo, S. Q. Macromol. Chem. Phys. 2011, 212, 744. (29) Chu, B. Laser Light Scattering, 2nd ed; Academic Press: New York, 1991. (30) Guinier, A.; Fournet, G. Small-Angle Scattering of X-rays; John Wiley: New York, 1955. (31) Teraoka, I. Polymer Solutions; John Wiley & Sons: New York, 2002. (32) Rakhmatullina, E.; Braun, T.; Chami, M.; Malinova, V.; Meier, W. Langmuir 2007, 23, 12371. (33) Stejskal, J.; Hlavata, D.; Sikora, A.; Konnak, C.; Plestil, J.; Kratochvíl, P. Polymer 1992, 33, 3675. 7390
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