Article pubs.acs.org/Langmuir
Thermal Aggregation Properties of Nanoparticles Modified with Temperature Sensitive Copolymers Kristen L. Hamner and Mathew M. Maye* Department of Chemistry, Syracuse University, Syracuse, New York 13244, United States S Supporting Information *
ABSTRACT: In this paper, we describe the use of a temperature responsive polymer to reversibly assemble gold nanoparticles of various sizes. Temperature responsive, low critical solution temperature (LCST) pNIPAAm-co-pAAm polymers, with transition temperatures (TC) of 51 and 65 °C, were synthesized with a thiol modification, and grafted to the surface of 11 and 51 nm gold nanoparticles (AuNPs). The thermal-responsive behavior of the polymer allowed for the reversible aggregation of the nanoparticles, where at T < TC the polymers were hydrophilic and extended between particles. In contrast, at T > TC, the polymer shell undergoes a hydrophilic to hydrophobic phase transition and collapses, decreasing interparticle distances between particles, allowing aggregation to occur. The AuNP morphology and polymer conjugation were probed by TEM, FTIR, and 1H NMR. The thermal response was probed by UV−vis and DLS. The structure of the assembled aggregates at T > TC was studied via in situ small-angle X-ray scattering, which revealed interparticle distances defined by polymer conformation.
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INTRODUCTION The ability to prepare nanostructures with dynamic and stimuli responsive structure and function is a contemporary goal in nanoparticle self-assembly. Today, many different approaches exist to self-assemble nanomaterials from the bottom-up.1−4 Using surface chemistry approaches, scientists can choose from a range of self-assembled monolayer exchange routes,4−8 introduce organic, inorganic, or biological cross-linkers,9,10 or utilize the properties of polymers, like dendrimers.11−14 One class of polymers that may be particularly useful in creating dynamic nanostructures are stimuli-responsive “smart” polymers, which can undergo physical or chemical changes in response to changes in light, pH, and/or temperature.15−18 Properties like these have been shown recently for the tunable and reversible self-assembly of gold (Au) nanoparticles (NPs).19−24 One avenue not studied in great detail to date is the use of temperature responsive polymers. These polymers and copolymers place emphasis on the monomer N-isopropylacrylamide (NIPAAm), which has a low critical solution temperature (LCST) of 32 °C. Below this critical temperature (TC), the chains are solvated and form an extended structure, and above which the chains undergo collapse due to a combination of dehydration and depletion forces.25−28 The TC can be tuned through copolymerization with acrylamide (AAm) or other hydrophilic monomers.18,29−31 Of particular interest is that these conformational changes are highly reversible, and © 2013 American Chemical Society
important parameters such as the number of grafting points, grafting density, solvent conditions, and chain height27,32−35 can affect the kinetics of temperature response when comparing grafted polymers and bulk polymer solutions.22,36 Researchers recently probed the temperature responsive behavior of bulk and surface grafted PNIPAAm, and found that surface bound polymers exhibited more gradual responses over a wider range of temperatures.22,32,36−38 When grafted to a surface, the outermost segments of the brush remain highly solvated until the TC has been reached, whereas the inner less solvated brush segments undergo dehydration and collapse over a broad range of temperatures.32 In addition, researchers have shown many versatile applications such as targeted cellular uptake39,40 and drug delivery,29,30,41,42 which rely on the ability to easily manipulate the response of the system. For example, researchers recently used the thermal response of LCST copolymers to release drug cargo from the interior of gold nanocages.30 Inspired by that work, we recently showed that a LCST copolymer could be used to regulate sequence-specific hybridization in DNA-mediated NP self-assembly, as well as the drug release in DNA-encoded nanocarriers.42 In addition to applications like these, NPs with LCST surfaces may also exhibit fine-tunable aggregation properties, possibly leading to Received: October 2, 2013 Revised: November 15, 2013 Published: November 18, 2013 15217
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Information) revealed molecular weight (MW) and polydispersity index (PDI) values of ≈290 000 g/mol (PDI = 1.12) and ≈71 000 g/ mol (PDI = 1.45) for p 1 and 2, respectively. The thermal properties were analyzed by UV−vis and DLS. Polymer Functionalization. The AuNPs were functionalized with the temperature responsive p 1 and 2. To initiate binding of the p to the Au surface, the disulfide linkage was reduced with 100 mM tris(2carboxyethyl) hydrochloride (TCEP) for 30 min at room temperature. Then the p (1 or 2) was added to 1 mL of AuNPs in a 40 molar excess for Au11 ([p]:[AuNP] = 40) and a 1400 molar excess for Au51 ([p]: [AuNP] = 1400) and left to anneal overnight. The excess p was removed by centrifugation at least three times. Calculations. Gold Nanoparticle (AuNP) Concentrations. The AuNP concentrations were calculated based on UV−vis optical measurement of the surface plasmon resonance (SPR) wavelength (λSPR) using AuNP size dependent optical extinction coefficients (εAuNP). The final AuNP concentrations were then obtained using the Beer−Lambert relationship Abs = εbc; where ε is the estimated extinction coefficient (M−1 cm−1), b is the path length (cm), and c is concentration (M). The AuNP concentrations for particles with diameter (D) of 11.5 ± 1.1 nm were calculated using εAuNP = 1.0 × 108 L mol−1 cm−1,43 and the AuNPs with D of 51.6 ± 8.3 nm using a εAuNP = 2.10 × 1010 L mol−1 cm−1.45 Instrumentation. UV−Visible (UV−vis) Spectrophotometry. The UV−vis measurements were collected on a Varian Cary100 Bio UV− vis spectrophotometer between 200 and 900 nm using a cuvette with a 2 mm path length. Temperature control was achieved using an integrated high precision Peltier heating controller, and heating was carried out at 1 °C/min. Transmission Electron Microscopy (TEM). TEM measurements were performed on a JEOL 2000EX instrument operated at 120 kV with a tungsten filament at the SUNY-ESF, N.C. Brown Center for Ultrastructure Studies. Particle size was analyzed by modeling each particle as a sphere, with statistical analysis performed using ImageJ software on populations of at least 100 counts. Dynamic Light Scattering (DLS). DLS measurements were performed on a Malvern Zetasizer Nano ZS instrument utilizing a 173° backscattering detector. The hydrodynamic diameter (Dh) and Zaverage (Zave) were calculated using CONTIN analysis. Samples were filtered by a 0.2 μm filter prior to analysis and were averaged over three data sets. For experiments performed at elevated temperatures, the samples were briefly gently dispersed with a pipet before each new temperature and allowed to equilibrate for 3 min. The CONTIN analysis was performed using the temperature dependent viscosity values for water. Fourier Transform Infrared (FTIR) Spectroscopy. FTIR measurements were collected on a Thermo Nicolet 6700 FTIR instrument equipped with a diamond smart iTR attenuated internal reflectance accessory and a liquid N2 cooled MCT-A detector. Samples were drop cast as neat solutions, or dried powders, and dried under N2. Gel Permeation Chromatography (GPC). The GPC characterization of polymer MW was determined using a Waters GPC apparatus equipped with a Wyatt miniDAWN multi angle laser light scatter, Waters 2313 refractive index detector, and a Plaquagel-OHmixed-H column. For analysis, a known mass of sample was dried thoroughly and then dissolved in ultrapure water to create a solution of known weight per volume. Just prior to analysis, the sample was filtered through a 0.2 μm filter. Small Angle X-ray Scattering (SAXS). SAXS experiments were performed at the Cornell High Energy Synchrotron Source (CHESS) D1 beamline. The scattering data was collected with a charge-coupled device (CCD) area detector at wavelength λ = 1.1614 Å. The data are presented as the structure factor S(q) versus scattering vector, q = 4π sin(θ)/λ, where θ is the scattering angle. The values of q were calibrated with silver behenate (q = 0.1076 Å−1). S(q) was calculated as I(q)/Ip(q), where I(q) and Ip(q) are the background-corrected onedimensional scattering intensities of a system under consideration and the unaggregated control, respectively.
dynamic thin-films or organized metamaterials forming via thermal signals. There have been few reports of LCST based NP aggregation since the proof-of-principle was described,23 and little is known about the ultimate performance, the NP size or polymer LCST effects on the properties, or the microstructures formed. Herein, we focus on the thermal aggregation properties of Au NPs with LCST polymer surfaces. Both 11 and 51 nm Au NPs were modified with two different thiolated pNIPAAm-co-pAAm copolymers, with LCST of 51 and 65 °C. We show that the polymer−AuNP (p-Au) conjugates have thermal properties very similar to those of the bulk polymer. The reversible temperature effects and self-assembly behavior are characterized through UV−visible spectrophotometry (UV−vis) and dynamic light scattering (DLS). The organization of the aggregates was characterized in situ by synchrotron small-angle X-ray scattering (SAXS).
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EXPERIMENTAL SECTION
Materials. Hydrogen tetrachloroaurate hydrate (HAuCl4·H2O, 99.99%), sodium citrate tribasic dihydrate (Na3C6H5O7·2H2O, 99.9%), silver nitrate (AgNO 3 , 99%), N-isopropylacrylamide (NC6H11O, 99%), acrylamide (NC3H5O, 40%), copper(I) bromide (CuBr, 98%), N,N,N′,N′,N″-pentamethyldiethylenetriamine (N 3C 9 H20 , 99%), tris(2-carboxyethyl)phosphine hydrochloride (C9H15O6P·HCl, 98%), methanol (CH3OH, ≥99.8%), and bis[2-(2′bromoisobutyryloxy)ethyl] disulfide (C12H20Br2O4S2) were purchased from Sigma Aldrich. Sodium chloride (NaCl, 99%) was purchased from Fisher Scientific. Ultrapure water (18.2 MΩ) was prepared via a Sartorius Stedim Arium 61316 reverse osmosis unit combined with an Arium 611DI polishing unit. Gold Nanoparticle Synthesis. Gold nanoparticles (AuNPs) of D = 11.5 ± 1.1 nm (Au11) were synthesized by a citrate (Cit) reduction procedure.43 Briefly, an aged 1 mM HAuCl4 solution was heated to ∼95 °C for 30 min. To this solution, a warm 38 mM trisodium citrate solution (10 mL) was added in one aliquot. Upon initial color change to red, the solution was then immediately removed from heat and allowed to cool naturally to room temperature and allowed to stir overnight. AuNPs of D = 51.6 ± 8.3 nm (Au51) were synthesized by seed-mediated growth approach.44 Briefly, 20 mM HAuCl4 solution (4 mL) was added to ultrapure water (170 mL) and allowed to anneal. To this solution, a 10 mM silver nitrate solution (400 μL) was added in one aliquot, along with 3 mL of a Au core solution, prepared using a standard sodium citrate reduction procedure.44 To this solution, 30 mL of a 5.3 mM ascorbic acid solution was added drop wise with stirring over the course of 1.5 h, and then the solution was left to anneal overnight with stirring at room temperature. Both Au11 and Au51 were stored protected from light. Polymer Synthesis. Polymers consisting of N-isopropylacrylamide (NIPAAm) and acrylamide (AAm) units of tailored ratios were used to modify the low critical solution temperature (LCST, TC) of the pNIPAAm-co-pAAm polymer (p), via an atom transfer radical polymerization.30 Successful syntheses of p with a TC of 51 °C (1) and TC of 65 °C (2) were achieved. The tailored monomer ratio of 90:10 NIPAAm:AAm was used to achieve a desired TC of 51 °C, while a tailored monomer ratio of 75:25 NIPAAm:AAm was used to achieve the desired TC of 65 °C. In the typical synthesis, the monomers were dissolved in ultrapure water and methanol and allowed to mix at room temperature for 20 min. After which the disulfide containing initiator bis[2-(2′-bromoisobutyryloxy)ethyl] disulfide [(BiBOE)2S2] was added along with N,N,N′,N′,N″-pentamethyldiethylenetriamine (PMDETA). The sample was stirred at room temperature for 20 min and then frozen and degassed under vacuum. To the frozen sample CuBr was added, and then the sample was thawed at room temperature and purged under argon and allowed to stir overnight. After reacting overnight, the resulting blue gel was dispersed in ultrapure water (10 mL) and purified via dialysis. After purification, gel permeation chromatography (GPC) analysis (Table S1, Supporting 15218
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RESULTS AND DISCUSSION In this section, we first describe the thermal properties of the two LCST copolymers prepared in this study. We then describe the grafting of these polymers to AuNP interfaces of various sizes, characterize the resulting conjugate’s interface, and then probe the thermal aggregation behavior of the conjugates. It is important to note that the first example of thermal aggregation of nanoparticles using LCST copolymers was carried out by Li and co-workers,23 but since then little focus has been paid to the topic by the field, and thus the optimum properties and performance of the response is still unknown. A pair of smart LCST pNIPAAm-co-pAAm copolymers (p) equipped with an internal disulfide linker were synthesized following recent work by others.29,30 The monomer (NIPAAm, AAm) ratios were tailored to modify the so-called critical temperature (TC). In our systems, a molar ratio of [NIPAAm]: [AAm] = 90:10 (denoted as 1) and [NIPAAm]:[AAm] = 75:25 (denoted as 2) were prepared, and analysis by gel permeation chromatography (GPC) resulted in average MW of ≈290 000 and ≈71 000 g/mol, respectively (Table S1, Supporting Information). UV−vis spectroscopy was used to determine the TC of 1 and 2. UV−vis monitors the change in the turbidity of the solution that occurs at TC, which is characteristic of the copolymers aggregation/gelling as it undergoes a hydrophilic-to-hydrophobic phase change.30,41 Figure 1a shows a typical UV−vis
illustrated in Scheme 1. In this work, we synthesized AuNPs of two sizes, namely, with D of 11.5 ± 1.1 nm (denoted as Au11) and 51.6 ± 8.3 nm (denoted as Au51), as shown in Figure 2. To initiate p grafting, the internal disulfide linkage, originating from the polymerization initiator (see Experimental Section),30 was first reduced to thiols using TCEP in 150-fold molar excess for 30 min at room temperature, resulting in two p-chains. The molar concentration of p was estimated based on the dried weight of a sample, and the MW determined by GPC. Then the p (1 or 2) was added to 1 mL of AuNPs in a 40 molar excess for Au11 ([p]:[AuNP] = 40) and a 1400 molar excess for Au51 ([p]:[AuNP] = 1400) and left to anneal overnight. This ratio was determined sufficient to saturate the surfaces after testing many ratios (data not shown). The excess p was removed by centrifugation at least three times. The p-modification was confirmed by FTIR (Figure 3) and DLS (Figure 4). Figure 3 shows the FTIR spectra characterizing the NIPAAm (i) and AAm (ii) monomers, the NIPAAmco-AAm 1-polymer (iii), and the 1-functionalized Au 11 (denoted as 1-Au11) (iv). The monomers show FTIR signatures consistent with their alkyl chains and methyl termination, namely, −CH2 and −CH3 stretching at v1 and v2, respectively, as well as vibrations associated with the primary and secondary amide stretches (v3 and v4). Also observed are carbonyl stretching (v5 and v6) and a −CH3CHCH3 signature umbrella region associated with NIPAAm (v7). The stretching consistent with the composition of the individual monomers is observed for the 1 polymer as well as the 1-Au11 conjugate. Figure 4 characterizes the observed Dh change during functionalization with p. For instance, the AuNP show Dh values consistent with their TEM determined sizes, due to the small contribution of their citrate capping, Au11 ≈ 11 nm (a,i), Au51 ≈ 52 nm (b,i). However, both show a Dh increase after pmodification, 1-Au11 (a,ii) ≈ 44 nm, 2-Au11 (a,iii) ≈ 51 nm, and 1-Au51 ≈ 164 nm (b,ii), 2-Au51 ≈ 295 nm (b,iii), respectively. Once functionalized, the thermal properties of the p-Au were characterized by UV−vis. UV−vis measures the SPR band of the nanoparticles, which arises from the collective oscillation of conduction electrons in the presence of light. The SPR wavelength and extinction is influenced by particle size and shape, the local dielectric at the interface, and particle-toparticle coupling due to aggregation or self-assembly.46,47 Figure 5 shows a typical set of UV−vis spectra for, 1-Au11 (a), 2-Au11(b), 1-Au51(c), and 2-Au51(d), both at 25 °C (i) and at T > TC (ii). For example, Figure 5a-i shows the thermal response of 1-Au11 at 25 (i) and 60 °C (ii). A red shift in SPR was observed from 520 to 540 nm at T > TC. We attribute this to a change in local dielectric at the Au interface due to the p-chains collapsing to the interface,37,38 as well as NP-to-NP aggregation (see below), which effectively screens much of the NP absorption. This SPR response was found to be reversible by temperature cycling (Figure 5a-i, inset). Similar red shifts and thermal reversibility were observed in each of the samples. The thermal profile of the NP aggregation was directly compared to that of 1 and 2. The right column of Figure 5 shows the thermal profile of the two systems. For instance, the right column in Figure 5a compares the profile of 1-Au11 (iii) vs 1 (1). We observe that the onset of aggregation (decrease in SPR at 520 nm) closely matches that of the 1 polymer (increase in absorbance at 520 nm), but is slightly higher in temperature than that of the 2 polymer. Taken together, these results suggest that thermal properties of the p-Au largely resemble the p used.
Figure 1. Thermal profile (1 °C/min) of 1 (i) and 2 (ii) in solution as probed by UV−vis (a) and DLS (b) ([1] ≈ 2.0 mg/mL, [2] ≈ 2.3 mg/mL, 18.2 MΩ H2O).
result and reveals a sharp gel transition of TC = 51 °C for 1 (i), and a broader gel transition for 2 centered at TC = 65 °C (ii). This aggregation was also observed by DLS, as shown in Figure 1b, where a reversible increase in the hydrodynamic diameter (Dh) for 1 from Dh = 16 nm in monomer form to ∼330 nm in the aggregated/gel form was observed (i). A similar trend for 2 was observed, which shows a reversible transition between Dh = 15 and 300 nm (ii). Taken together, these results show that 1 has a TC = 51 °C and 2 has a TC = 65 °C. The chemical structure of 1 and 2 were also confirmed by 1H NMR (Figure S1, Supporting Information). The general strategy employed for AuNP surface functionalization and reversible thermal aggregation using 1 and 2 is 15219
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Scheme 1. Idealized Schematic Illustrating the AuNP Functionalization Steps and Thermal Aggregationa
a The disulfide containing 1 or 2 pNIPAAm-co-pAAm copolymers are reduced via TCEP and incubated with Au11 or Au51. After purification of excess 1 or 2, the polymer-capped AuNP (b) is heated to its respective critical temperature (TC), upon which the copolymer undergoes a hydrophilic to hydrophobic phase transition (c), which causes aggregation (d). Upon cooling, the system returns to its original state.
Figure 3. FTIR results characterizing the monomers NIPAAm (i) and AAm (ii), the 1-polymer (iii), and the 1-Au11 conjugate (iv).
Figure 2. Representative TEM micrographs for the synthesized Au11 (a) and Au51 (b) NPs with corresponding statistical analysis revealing D of 11.5 ± 1.1 and 51.6 ± 8.3 nm, respectively.
Figure 4. Representative DLS of Au11 (a) and Au51 (b) before pmodification (i) and after modification with 1 (ii) and 2 (iii) ([Au11] = 17 nM, [Au51] = 0.7 nM, 18.2 MΩ H2O).
DLS provided a number of additional insights into the system. For example, Figure 6 shows a plot of observed Dh for the unmodified NP, the NP after conjugation at room temperature (+p), and after one heating cycle (T > TC), and back to room temperature (T < TC). The 1-Au11 showed a Dh increase from ∼44 nm at 25 °C to ∼1700 nm at 55 °C, which indicates significant aggregation. Interestingly, the Dh upon cooling to 25 °C shows the system is not as reversible as the SPR suggested, and that a relatively large Dh of ∼220 nm was measured, indicating slight irreversibility due to either clustering of the AuNPs or a highly extended final polymer conjugation. These trends were general across each p-AuNP
system. The relatively large Dh at T < TC across each p-Au system, regardless of the p, TC, and composition, suggests that the hydration process upon cooling is slow. For example, it has been shown that, due to intra- and interchain interactions when in the collapsed state, the hydration of the p-chains may be hindered.22,32,36 To better understand the aggregation behavior, these systems were further probed in situ by investigating the interparticle spatial properties during thermal aggregation via synchrotron SAXS. Figure 7 shows the representative SAXS scattering 15220
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Figure 5. Representative UV−vis characterizing the thermal behavior of the 1-Au11 (a), 2-Au11 (b), 1-Au51 (c), and 2-Au51 (d). Left panel: UV−vis monitoring of SPR at 25 °C (i) and 70 °C (ii) after 1 h heating, with insets showing the thermal cycling ([Au11] = 50 nM, [Au51] = 0.73 nM, 18.2 MΩ H2O). Right panel: Thermal profile monitored at Abs of 520 nm during heating at 1 °C/min for the corresponding p-Au (iii), with the profile for the isolated 1 or 2 shown as reference ([Au11] = 77 nM, [Au51] = 0.73 nM, 18.2 MΩ H2O).
Figure 6. Thermal response measured by DLS for 1-Au11, 2-Au11, 1Au51, and 2-Au51 before p-modification (NP), after p-modification at 25 °C before heating (+p), at TC (T > TC), and after cooling to 25 °C (T < TC). TC’s used were 51 and 65 °C for 1 and 2, respectively.
Figure 7. Synchrotron SAXS results of the 2-Au11 aggregates measured during a heating cycle at T = 55 (i), 65 (ii), 68 °C (iii), and a subsequent cooling cycle at T = 40 (iv) and 30 °C (v). Note that no significant scattering was observed at T < 55 °C during initial heating cycle. Inset: Corresponding surface-to-surface d′ spacing trend for heating (red circles) and cooling (blue triangles) (λ = 1.1614 Å, 0.2 M PBS).
structure factors (S(q)) for the 2-Au11. The SAXS were collected by using a highly concentrated solution of 2-Au11 ([2Au11] = 610 nM) dispersed in buffer (∼50 μL) within a quartz capillary. To ensure maximum scattering, the X-ray was positioned ∼0.5 mm from the bottom of the capillary. The sample was then heated and annealed at each temperature for ∼5 min. At room temperature, the solution shows no appreciable scattering, only the form factor of the AuNP (not shown); however, upon heating we first observed a scattering
S(q) at 55 °C (i), and upon heating to 65 (ii) and 68 °C (iii), both of which are > TC for 2-Au11, the diffraction was significantly stronger and shifted to higher q, indicating both the better ordering of the aggregate internals, as well as shorter interparticle distances. We next cooled the sample without disturbing it, to 40 (iv) and 30 °C (v), and observed a decrease 15221
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Notes
in S(q), and a shift back to lower q, indicating less long-range ordering and longer interparticle distances. Interestingly, we still observed scattering after cooling for >1 h, which we attribute to the interparticle 2-chains possibly becoming intertwined, forming a permanent cluster, and also due to the system becoming highly concentrated and not having time to diffuse to the normal concentrations (due to aggregation and sedimentation during the heating). Such results complement the UV−vis and DLS studies. To better quantify these results, we calculated the approximate surface-to-surface distance between AuNPs in the aggregate. Since the first diffraction is q1 = 2π/d, where d is the center-to-center distance of the average scattering planes in the aggregate, the surface-to-surface distance (d′) could be calculated via d′ = d −D, where D is the Au11 diameter (11.5 nm). These results are shown in the inset of Figure 7. The d′ first appears at ≈9.8 nm at 55 °C, decreases to 5.7 nm at 68 °C (see heating cycle), and then increases again to d′ ≈ 10.2 nm at 30 °C (see cooling cycle). Taken together, these results suggest that AuNPs can be modified to have thermally responsive interfaces, aggregation behavior, and interparticle distances by using LCST copolymers. The p-modified AuNPs have reversible aggregation at T > TC, which very closely resembles the thermal response of bulk p in solution. This aggregation is largely reversible, as demonstrated by UV−vis and DLS. The size of the AuNPs and the MW of the polymer did not significantly alter the behavior. While the general aggregation is reversible, the structure of the p changes after a heating/cooling cycle, in which the data suggests that the p stays in an extended form. SAXS confirmed this hypothesis in which aggregation was shown to bring about a well-ordered aggregate that had interparticle distances that were defined by the p-chains in extended and compressed configurations. Smart polymer functionalized nanoparticles like these may be used in the future to regulate interfacial processes like catalysis, selfassembly, or drug release. The thermally sensitive nanoparticles may also allow nanoparticles to be more easily integrated into modern 3D printing devices or shape memory processes. Moreover, the SPR based thermal shifts may allow for the development of single particle thermometers, which would be useful when investigating biological processes.
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CONCLUSIONS
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ASSOCIATED CONTENT
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by a grant from the Air Force Office of Scientific Research (AFOSR, #FA9550-10-1-0033). M.M.M. acknowledges a DoD PECASE award sponsored by the AFOSR. Additional support was provided the Syracuse Biomaterials Institute (SBI) and the Syracuse University Forensics and National Security Science Institute (FNSSI). We thank Deb Kerwood at the SU NMR facility for assistance, Prof. Rebekka Bader and Prof. Patrick Mather from the SBI for GPC, and Robert Smith at SUNY-ESF for assistance with TEM. The Cornell High Energy Synchrotron Source (CHESS) is supported by the NSF (DMR-0936384) and the NIH/ NIGMS (GM-103485). We thank Dr. Detlef Smilgies at CHESS for assistance with SAXS data collection processing, and for building the temperature controlled capillary holder.
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(1) Katz, E.; Willner, I. Integrated Nanoparticle-Biomolecule Hybrid Systems: Synthesis, Properties, and Applications. Angew. Chem. 2004, 43, 6042−6108. (2) Yeh, Y.-C.; Creran, B.; Rotello, V. M. Gold Nanoparticles: Preparation, Properties, and Applications in Bionanotechnology. Nanoscale 2012, 4, 1871−1880. (3) Zhang, Z.; Horsch, M. A.; Lamm, M. H.; Glotzer, S. C. Tethered Nano Building Blocks: Towards a Conceptual Framework for Nanoparticle Self-Assembly. Nano Lett. 2003, 3, 1341−1346. (4) Daniel, M. C.; Astruc, D. Gold Nanoparticles: Assembly, Supramolecular Chemistry, Quantum-Size-Related Properties, and Applications Toward Biology, Catalysis, and Nanotechnology. Chem. Rev. 2004, 104, 293−346. (5) Zamborini, F. P.; Hicks, J. F.; Murray, R. W. Quantized Double Layer Charging of Nanoparticle Films Assembled Using Carboxylate/ (Cu2+ or Zn2+)/Carboxylate Bridges. J. Am. Chem. Soc. 2000, 122, 4514−4515. (6) Zheng, W.; Maye, M. M.; Leibowitz, F. L.; Zhong, C. J. Imparting Biomimetic Ion-Grating Recognition to Electrodes with a HydrogenBonding Structured Core−Shell Nanoparticle Network. Anal. Chem. 2000, 72, 2190−2199. (7) Templeton, A. C.; Wuelfing, W. P.; Murray, R. W. MonolayerProtected Cluster Molecules. Acc. Chem. Res. 2000, 33, 27−36. (8) Fresco, Z. M.; Fréchet, J. M. Selective Surface Activation of a Functional Monolayer for the Fabrication of Nanometer Scale Thiol Patterns and Directed Self-Assembly of Gold Nanoparticles. J. Am. Chem. Soc. 2005, 127, 8302−8303. (9) Maye, M. M.; Chun, S. C.; Han, L.; Rabinovich, D.; Zhong, C. J. Novel Spherical Assembly of Gold Nanoparticles Mediated by a Tetradentate Thioether. J. Am. Chem. Soc. 2002, 124, 4958−4959. (10) Maye, M. M.; Lim, I. I. S.; Luo, J.; Rab, Z.; Rabinovich, D.; Liu, T.; Zhong, C. J. Mediator-Template Assembly of Nanoparticles. J. Am. Chem. Soc. 2005, 127, 1519−1529. (11) Frankamp, B. L.; Boal, A. K.; Rotello, V. M. Controlled Interparticle Spacing through Self-Assembly of Au Nanoparticles and Poly(amidoamine) Dendrimers. J. Am. Chem. Soc. 2002, 124, 15146− 15147. (12) Boal, A. K.; Rotello, V. M. Fabrication and Self-Optimization of Multivalent Receptors on Nanoparticle Scaffolds. J. Am. Chem. Soc. 2000, 122, 734−735. (13) Boal, A. K.; Ilhan, F.; DeRouchey, J. E.; Thurn-Albrecht, T.; Russell, T. P.; Rotello, V. M. Self-Assembly of Nanoparticles into Structured Spherical and Network Aggregates. Nature 2000, 404, 746−748. (14) Ofir, Y.; Samanta, B.; Rotello, V. M. Polymer and Biopolymer Mediated Self-Assembly of Gold Nanoparticles. Chem. Soc. Rev. 2008, 37, 1814−1825.
In summary, LCST smart polymers consisting of pNIPAAm-copAAm copolymers equipped with a thiol modification were synthesized and grafted onto gold nanoparticle interfaces. At temperatures below the TC, the p shell was extended at the surface and thus establishing a buffer region between particles. However, at T > TC, aggregation was observed, due in large part to the hydrophobic collapse of the p, eliminating the buffer region, decreasing the interparticle distances to values defined by the polymer sterics.
* Supporting Information S
Supporting Table S1 and Figure S1. This material is available free of charge via the Internet at http://pubs.acs.org.
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REFERENCES
AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected]. 15222
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Prepared by Surface-Initiated Polymerizations. Adv. Mater. 2002, 14, 1130−1134. (36) Chirra, H. D.; Hilt, Z. J. Nanoscale Characterization of the Equilibrium and Kinetic Response of Hydrogel Structures. Langmuir 2010, 26, 11249−1125. (37) Wischerhoff, E.; Zacher, T.; Laschewsky, A.; Rekaï, E. D. Direct Observation of the Low Critical Solution Temperature of SurfaceAttached Thermo-Responsive Hydrogels by Surface Plasmon Resonance. Angew. Chem., Int. Ed. 2000, 39, 4602−4604. (38) Mangeney, C.; Ferrage, F.; Aujard, I.; Marchi-Artzner, V.; Jullien, L.; Ouari, O.; Rékaï, E. D.; Laschewsky, A.; Vikholm, I.; Sadowski, J. W. Synthesis and Properties of Water-Soluble Gold Colloids Covalently Derivatized with Neutral Polymer Monolayers. J. Am. Chem. Soc. 2002, 124, 5811−5821. (39) Liang, M.; Lin, I.-C.; Whittaker, M. R.; Minchin, R. F.; Monteiro, M. J.; Toth, I. Cellular Uptake of Densely Packed Polymer Coatings on Gold Nanoparticles. ACS Nano 2010, 4, 403−413. (40) Kim, C.; Lee, Y.; Kim, J. S.; Jeong, J. H.; Park, T. G. Thermally Triggered Cellular Uptake of Quantum Dots Immobilized with Poly(N-isopropylacrylamide) and Cell Penetrating Peptide. Langmuir 2010, 26, 14965−14969. (41) Wei, H.; Zhang, X.; Cheng, C.; Cheng, S. X.; Zhuo, R. X. SelfAssembled Thermosensitive Micelles of a Star Block Copolymer Based on PMMA and PNIPAAm for Controlled Drug Delivery. Biomaterials 2007, 28, 99−107. (42) Hamner, K. L.; Alexander, C. M.; Coopersmith, K.; Reishofer, D.; Provenza, C.; Maye, M. M. Using Temperature-Sensitive Smart Polymers to Regulate DNA-Mediated Nanoassembly and Encoded Nanocarrier Drug Release. ACS Nano 2013, 7, 7011−7020. (43) Maye, M. M.; Nykypanchuk, D.; van der Lelie, D.; Gang, O. A. Simple Method for Kinetic Control of DNA-Induced Nanoparticle Assembly. J. Am. Chem. Soc. 2006, 128, 14020−14021. (44) Park, Y. K.; Park, S. Directing Close-Packing of Midnanosized Gold Nanoparticles at a Water/Hexane Interface. Chem. Mater. 2008, 20, 2388−2393. (45) Concurrent Analytical Inc. Nanopartz, http://nanopartz.com (accessed Sep. 26, 2011). (46) Burda, C.; Chen, X.; Narayanan, R.; El-Sayed, M. A. Chemistry and Properties of Nanocrystals of Different Shapes. Chem. Rev. 2005, 105, 1025−1102. (47) Saha, K.; Agasti, S. S.; Kim, C.; Li, X.; Rotello, V. M. Gold Nanoparticles in Chemical and Biological Sensing. Chem. Rev. 2012, 112, 2739−2779.
(15) Jochum, F. D.; Theato, P. Thermo- and Light Responsive Micellation of Azobenzene Containing Block Copolymers. Chem. Commun. 2010, 46, 6717−6719. (16) Grunlan, J. C.; Liu, L.; Kim, Y. S. Tunable Single-Walled Carbon Nanotube Microstructure in the Liquid and Solid States Using Poly(acrylic acid). Nano Lett. 2006, 6, 911−915. (17) Lee, R. S.; Huang, Y. T.; Chen, W. H. Synthesis and Characterization of Temperature-Sensitive Block Copolymers from Poly(N-Isopropylacrylamide) and 4-Methyl-ε-caprolactone or 4Phenyl-ε-caprolactone. J. Appl. Polym. Sci. 2010, 118, 1634−1642. (18) Gil, E. S.; Hudson, S. M. Stimuli Responsive Polymers and Their Bioconjugates. Prog. Polym. Sci. 2004, 29, 1173−1222. (19) Hribar, K. C.; Lee, M. H.; Lee, D.; Burdick, J. A. Enhanced Release of Small Molecules from Near-Infrared Light Responsive Polymer-Nanorod Composites. ACS Nano 2011, 5, 2948−2956. (20) Sardar, R.; Bjorge, N. S.; Shumaker-Perry, J. S. PH-Controlled Assemblies of Polymeric Amine-Stabilized Gold Nanoparticles. Macromolecules 2008, 41, 4347−4352. (21) Li, D.; He, L.; Cui, Y.; Li, J. Fabrication of pH-Responsive Nanocomposites of Gold Nanoparticles/Poly(4-vinylpyridine). Chem. Mater. 2007, 19, 412−417. (22) Chakraborty, S.; Bishnoi, S. W.; Pérez-Luna, V. H. Gold Nanoparticles with Poly(N-isopropylacrylamide) Formed via Surface Initiated Atom Transfer Free Radical Polymerization Exhibit Unusually Slow Aggregation Kinetics. J. Phys. Chem. C 2010, 114, 5947−5955. (23) Zhu, M.-Q.; Wang, L.-Q.; Exarhos, G. J.; Li, A. D. Q. Thermosensitive Gold Nanoparticles. J. Am. Chem. Soc. 2004, 126, 2656−2657. (24) Durand-Gasselin, C.; Capelot, M.; Sanson, N.; Lequeux, N. Tunable and Reversible Aggregation of Poly(ethylene oxide-stpropylene oxide) Grafted Gold Nanoparticles. Langmuir 2010, 26, 12321−12329. (25) Zhang, J.; Pelton, R.; Deng, Y. Temperature-Dependent Contact Angles of Water on Poly(N-isopropylacrylamide) Gels. Langmuir 1995, 11, 2301−2302. (26) Schild, H. G. Poly(N-Isopropylacrylamide): Experiment, Theory, and Application. Prog. Polym. Sci. 1992, 17, 163−249. (27) Takei, Y. G.; Aoki, T.; Sanui, K.; Ogata, N.; Sakurai, Y.; Okano, T. Dynamic Contact Angle Measurement of Temperature-Responsive Surface Properties for Poly(N-isopropylacrylamide) Grafted Surfaces. Macromolecules 1994, 27, 6163−6166. (28) Gong, X.; Wu, C.; Ngai, T. Surface Interaction Forces mediated by Poly(N-Isopropylacrylamide) (PNIPAM) Polymers: Effects on Concentration and Temperature. Colloid Polym. Sci. 2010, 288, 1167− 1172. (29) Hoffman, A. S. Hydrogels for Biomedical Applications. Adv. Drug Delivery Rev. 2002, 65, 18−23. (30) Yavuz, M. S.; Cheng, J.; Cobley, C. M.; Zhang, Q.; Rycenga, M.; Xie, J.; Kim, C.; Song, K. H.; Schwartz, A. G.; Wang, L. V.; Xia, Y. Gold Nanocages Covered by Smart polymers for Controlled Release with Near-Infrared Light. Nat. Mater. 2009, 8, 935−939. (31) Topp, M. D. C.; Dijkstra, P. J.; Talsma, H.; Feijen, J. Thermosensitive Micelle-Forming Block Copolymers of Poly(ethylene glycol) and Poly(N-isopropylacrylamide). Macromolecules 1997, 30, 8518−8520. (32) Balamurugan, S.; Mendez, S.; Balamurugan, S. S.; O’Brian, M. J.; López, G. P. Thermal Response of Poly(N-isopropylacrylamide) Brushes Probed by Surface Plasmon Resonance. Langmuir 2003, 19, 2545−2549. (33) Yim, H.; Kent, M. S. Temperature-Dependent Conformational Change of PNIPAM Grafted Chains at High Surface Density in Water. Macromolecules 2004, 37, 1994−1997. (34) Yim, H.; Kent, M. S.; Huber, D. L. Conformation of EndTethered PNIPAM Chains in Water and in Acetone by Neutron Reflectivity. Macromolecules 2003, 36, 5244−5251. (35) Jones, D. M.; Smith, J. R.; Huck, W. T. S.; Alexander, C. Variable Adhesion of Micropatterned Thermoresponsive Polymer Brushes: AFM Investigations of Poly(N-isopropylacrylamide) Brushes 15223
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Thermal Aggregation Properties of Nanoparticles Modified with Temperature Sensitive Copolymers Kristen L. Hamner and Mathew M. Maye* Department of Chemistry, Syracuse University, Syracuse, New York 13244, United States S Supporting Information *
ABSTRACT: In this paper, we describe the use of a temperature responsive polymer to reversibly assemble gold nanoparticles of various sizes. Temperature responsive, low critical solution temperature (LCST) pNIPAAm-co-pAAm polymers, with transition temperatures (TC) of 51 and 65 °C, were synthesized with a thiol modification, and grafted to the surface of 11 and 51 nm gold nanoparticles (AuNPs). The thermal-responsive behavior of the polymer allowed for the reversible aggregation of the nanoparticles, where at T < TC the polymers were hydrophilic and extended between particles. In contrast, at T > TC, the polymer shell undergoes a hydrophilic to hydrophobic phase transition and collapses, decreasing interparticle distances between particles, allowing aggregation to occur. The AuNP morphology and polymer conjugation were probed by TEM, FTIR, and 1H NMR. The thermal response was probed by UV−vis and DLS. The structure of the assembled aggregates at T > TC was studied via in situ small-angle X-ray scattering, which revealed interparticle distances defined by polymer conformation.
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INTRODUCTION The ability to prepare nanostructures with dynamic and stimuli responsive structure and function is a contemporary goal in nanoparticle self-assembly. Today, many different approaches exist to self-assemble nanomaterials from the bottom-up.1−4 Using surface chemistry approaches, scientists can choose from a range of self-assembled monolayer exchange routes,4−8 introduce organic, inorganic, or biological cross-linkers,9,10 or utilize the properties of polymers, like dendrimers.11−14 One class of polymers that may be particularly useful in creating dynamic nanostructures are stimuli-responsive “smart” polymers, which can undergo physical or chemical changes in response to changes in light, pH, and/or temperature.15−18 Properties like these have been shown recently for the tunable and reversible self-assembly of gold (Au) nanoparticles (NPs).19−24 One avenue not studied in great detail to date is the use of temperature responsive polymers. These polymers and copolymers place emphasis on the monomer N-isopropylacrylamide (NIPAAm), which has a low critical solution temperature (LCST) of 32 °C. Below this critical temperature (TC), the chains are solvated and form an extended structure, and above which the chains undergo collapse due to a combination of dehydration and depletion forces.25−28 The TC can be tuned through copolymerization with acrylamide (AAm) or other hydrophilic monomers.18,29−31 Of particular interest is that these conformational changes are highly reversible, and © 2013 American Chemical Society
important parameters such as the number of grafting points, grafting density, solvent conditions, and chain height27,32−35 can affect the kinetics of temperature response when comparing grafted polymers and bulk polymer solutions.22,36 Researchers recently probed the temperature responsive behavior of bulk and surface grafted PNIPAAm, and found that surface bound polymers exhibited more gradual responses over a wider range of temperatures.22,32,36−38 When grafted to a surface, the outermost segments of the brush remain highly solvated until the TC has been reached, whereas the inner less solvated brush segments undergo dehydration and collapse over a broad range of temperatures.32 In addition, researchers have shown many versatile applications such as targeted cellular uptake39,40 and drug delivery,29,30,41,42 which rely on the ability to easily manipulate the response of the system. For example, researchers recently used the thermal response of LCST copolymers to release drug cargo from the interior of gold nanocages.30 Inspired by that work, we recently showed that a LCST copolymer could be used to regulate sequence-specific hybridization in DNA-mediated NP self-assembly, as well as the drug release in DNA-encoded nanocarriers.42 In addition to applications like these, NPs with LCST surfaces may also exhibit fine-tunable aggregation properties, possibly leading to Received: October 2, 2013 Revised: November 15, 2013 Published: November 18, 2013 15217
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Information) revealed molecular weight (MW) and polydispersity index (PDI) values of ≈290 000 g/mol (PDI = 1.12) and ≈71 000 g/ mol (PDI = 1.45) for p 1 and 2, respectively. The thermal properties were analyzed by UV−vis and DLS. Polymer Functionalization. The AuNPs were functionalized with the temperature responsive p 1 and 2. To initiate binding of the p to the Au surface, the disulfide linkage was reduced with 100 mM tris(2carboxyethyl) hydrochloride (TCEP) for 30 min at room temperature. Then the p (1 or 2) was added to 1 mL of AuNPs in a 40 molar excess for Au11 ([p]:[AuNP] = 40) and a 1400 molar excess for Au51 ([p]: [AuNP] = 1400) and left to anneal overnight. The excess p was removed by centrifugation at least three times. Calculations. Gold Nanoparticle (AuNP) Concentrations. The AuNP concentrations were calculated based on UV−vis optical measurement of the surface plasmon resonance (SPR) wavelength (λSPR) using AuNP size dependent optical extinction coefficients (εAuNP). The final AuNP concentrations were then obtained using the Beer−Lambert relationship Abs = εbc; where ε is the estimated extinction coefficient (M−1 cm−1), b is the path length (cm), and c is concentration (M). The AuNP concentrations for particles with diameter (D) of 11.5 ± 1.1 nm were calculated using εAuNP = 1.0 × 108 L mol−1 cm−1,43 and the AuNPs with D of 51.6 ± 8.3 nm using a εAuNP = 2.10 × 1010 L mol−1 cm−1.45 Instrumentation. UV−Visible (UV−vis) Spectrophotometry. The UV−vis measurements were collected on a Varian Cary100 Bio UV− vis spectrophotometer between 200 and 900 nm using a cuvette with a 2 mm path length. Temperature control was achieved using an integrated high precision Peltier heating controller, and heating was carried out at 1 °C/min. Transmission Electron Microscopy (TEM). TEM measurements were performed on a JEOL 2000EX instrument operated at 120 kV with a tungsten filament at the SUNY-ESF, N.C. Brown Center for Ultrastructure Studies. Particle size was analyzed by modeling each particle as a sphere, with statistical analysis performed using ImageJ software on populations of at least 100 counts. Dynamic Light Scattering (DLS). DLS measurements were performed on a Malvern Zetasizer Nano ZS instrument utilizing a 173° backscattering detector. The hydrodynamic diameter (Dh) and Zaverage (Zave) were calculated using CONTIN analysis. Samples were filtered by a 0.2 μm filter prior to analysis and were averaged over three data sets. For experiments performed at elevated temperatures, the samples were briefly gently dispersed with a pipet before each new temperature and allowed to equilibrate for 3 min. The CONTIN analysis was performed using the temperature dependent viscosity values for water. Fourier Transform Infrared (FTIR) Spectroscopy. FTIR measurements were collected on a Thermo Nicolet 6700 FTIR instrument equipped with a diamond smart iTR attenuated internal reflectance accessory and a liquid N2 cooled MCT-A detector. Samples were drop cast as neat solutions, or dried powders, and dried under N2. Gel Permeation Chromatography (GPC). The GPC characterization of polymer MW was determined using a Waters GPC apparatus equipped with a Wyatt miniDAWN multi angle laser light scatter, Waters 2313 refractive index detector, and a Plaquagel-OHmixed-H column. For analysis, a known mass of sample was dried thoroughly and then dissolved in ultrapure water to create a solution of known weight per volume. Just prior to analysis, the sample was filtered through a 0.2 μm filter. Small Angle X-ray Scattering (SAXS). SAXS experiments were performed at the Cornell High Energy Synchrotron Source (CHESS) D1 beamline. The scattering data was collected with a charge-coupled device (CCD) area detector at wavelength λ = 1.1614 Å. The data are presented as the structure factor S(q) versus scattering vector, q = 4π sin(θ)/λ, where θ is the scattering angle. The values of q were calibrated with silver behenate (q = 0.1076 Å−1). S(q) was calculated as I(q)/Ip(q), where I(q) and Ip(q) are the background-corrected onedimensional scattering intensities of a system under consideration and the unaggregated control, respectively.
dynamic thin-films or organized metamaterials forming via thermal signals. There have been few reports of LCST based NP aggregation since the proof-of-principle was described,23 and little is known about the ultimate performance, the NP size or polymer LCST effects on the properties, or the microstructures formed. Herein, we focus on the thermal aggregation properties of Au NPs with LCST polymer surfaces. Both 11 and 51 nm Au NPs were modified with two different thiolated pNIPAAm-co-pAAm copolymers, with LCST of 51 and 65 °C. We show that the polymer−AuNP (p-Au) conjugates have thermal properties very similar to those of the bulk polymer. The reversible temperature effects and self-assembly behavior are characterized through UV−visible spectrophotometry (UV−vis) and dynamic light scattering (DLS). The organization of the aggregates was characterized in situ by synchrotron small-angle X-ray scattering (SAXS).
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EXPERIMENTAL SECTION
Materials. Hydrogen tetrachloroaurate hydrate (HAuCl4·H2O, 99.99%), sodium citrate tribasic dihydrate (Na3C6H5O7·2H2O, 99.9%), silver nitrate (AgNO 3 , 99%), N-isopropylacrylamide (NC6H11O, 99%), acrylamide (NC3H5O, 40%), copper(I) bromide (CuBr, 98%), N,N,N′,N′,N″-pentamethyldiethylenetriamine (N 3C 9 H20 , 99%), tris(2-carboxyethyl)phosphine hydrochloride (C9H15O6P·HCl, 98%), methanol (CH3OH, ≥99.8%), and bis[2-(2′bromoisobutyryloxy)ethyl] disulfide (C12H20Br2O4S2) were purchased from Sigma Aldrich. Sodium chloride (NaCl, 99%) was purchased from Fisher Scientific. Ultrapure water (18.2 MΩ) was prepared via a Sartorius Stedim Arium 61316 reverse osmosis unit combined with an Arium 611DI polishing unit. Gold Nanoparticle Synthesis. Gold nanoparticles (AuNPs) of D = 11.5 ± 1.1 nm (Au11) were synthesized by a citrate (Cit) reduction procedure.43 Briefly, an aged 1 mM HAuCl4 solution was heated to ∼95 °C for 30 min. To this solution, a warm 38 mM trisodium citrate solution (10 mL) was added in one aliquot. Upon initial color change to red, the solution was then immediately removed from heat and allowed to cool naturally to room temperature and allowed to stir overnight. AuNPs of D = 51.6 ± 8.3 nm (Au51) were synthesized by seed-mediated growth approach.44 Briefly, 20 mM HAuCl4 solution (4 mL) was added to ultrapure water (170 mL) and allowed to anneal. To this solution, a 10 mM silver nitrate solution (400 μL) was added in one aliquot, along with 3 mL of a Au core solution, prepared using a standard sodium citrate reduction procedure.44 To this solution, 30 mL of a 5.3 mM ascorbic acid solution was added drop wise with stirring over the course of 1.5 h, and then the solution was left to anneal overnight with stirring at room temperature. Both Au11 and Au51 were stored protected from light. Polymer Synthesis. Polymers consisting of N-isopropylacrylamide (NIPAAm) and acrylamide (AAm) units of tailored ratios were used to modify the low critical solution temperature (LCST, TC) of the pNIPAAm-co-pAAm polymer (p), via an atom transfer radical polymerization.30 Successful syntheses of p with a TC of 51 °C (1) and TC of 65 °C (2) were achieved. The tailored monomer ratio of 90:10 NIPAAm:AAm was used to achieve a desired TC of 51 °C, while a tailored monomer ratio of 75:25 NIPAAm:AAm was used to achieve the desired TC of 65 °C. In the typical synthesis, the monomers were dissolved in ultrapure water and methanol and allowed to mix at room temperature for 20 min. After which the disulfide containing initiator bis[2-(2′-bromoisobutyryloxy)ethyl] disulfide [(BiBOE)2S2] was added along with N,N,N′,N′,N″-pentamethyldiethylenetriamine (PMDETA). The sample was stirred at room temperature for 20 min and then frozen and degassed under vacuum. To the frozen sample CuBr was added, and then the sample was thawed at room temperature and purged under argon and allowed to stir overnight. After reacting overnight, the resulting blue gel was dispersed in ultrapure water (10 mL) and purified via dialysis. After purification, gel permeation chromatography (GPC) analysis (Table S1, Supporting 15218
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RESULTS AND DISCUSSION In this section, we first describe the thermal properties of the two LCST copolymers prepared in this study. We then describe the grafting of these polymers to AuNP interfaces of various sizes, characterize the resulting conjugate’s interface, and then probe the thermal aggregation behavior of the conjugates. It is important to note that the first example of thermal aggregation of nanoparticles using LCST copolymers was carried out by Li and co-workers,23 but since then little focus has been paid to the topic by the field, and thus the optimum properties and performance of the response is still unknown. A pair of smart LCST pNIPAAm-co-pAAm copolymers (p) equipped with an internal disulfide linker were synthesized following recent work by others.29,30 The monomer (NIPAAm, AAm) ratios were tailored to modify the so-called critical temperature (TC). In our systems, a molar ratio of [NIPAAm]: [AAm] = 90:10 (denoted as 1) and [NIPAAm]:[AAm] = 75:25 (denoted as 2) were prepared, and analysis by gel permeation chromatography (GPC) resulted in average MW of ≈290 000 and ≈71 000 g/mol, respectively (Table S1, Supporting Information). UV−vis spectroscopy was used to determine the TC of 1 and 2. UV−vis monitors the change in the turbidity of the solution that occurs at TC, which is characteristic of the copolymers aggregation/gelling as it undergoes a hydrophilic-to-hydrophobic phase change.30,41 Figure 1a shows a typical UV−vis
illustrated in Scheme 1. In this work, we synthesized AuNPs of two sizes, namely, with D of 11.5 ± 1.1 nm (denoted as Au11) and 51.6 ± 8.3 nm (denoted as Au51), as shown in Figure 2. To initiate p grafting, the internal disulfide linkage, originating from the polymerization initiator (see Experimental Section),30 was first reduced to thiols using TCEP in 150-fold molar excess for 30 min at room temperature, resulting in two p-chains. The molar concentration of p was estimated based on the dried weight of a sample, and the MW determined by GPC. Then the p (1 or 2) was added to 1 mL of AuNPs in a 40 molar excess for Au11 ([p]:[AuNP] = 40) and a 1400 molar excess for Au51 ([p]:[AuNP] = 1400) and left to anneal overnight. This ratio was determined sufficient to saturate the surfaces after testing many ratios (data not shown). The excess p was removed by centrifugation at least three times. The p-modification was confirmed by FTIR (Figure 3) and DLS (Figure 4). Figure 3 shows the FTIR spectra characterizing the NIPAAm (i) and AAm (ii) monomers, the NIPAAmco-AAm 1-polymer (iii), and the 1-functionalized Au 11 (denoted as 1-Au11) (iv). The monomers show FTIR signatures consistent with their alkyl chains and methyl termination, namely, −CH2 and −CH3 stretching at v1 and v2, respectively, as well as vibrations associated with the primary and secondary amide stretches (v3 and v4). Also observed are carbonyl stretching (v5 and v6) and a −CH3CHCH3 signature umbrella region associated with NIPAAm (v7). The stretching consistent with the composition of the individual monomers is observed for the 1 polymer as well as the 1-Au11 conjugate. Figure 4 characterizes the observed Dh change during functionalization with p. For instance, the AuNP show Dh values consistent with their TEM determined sizes, due to the small contribution of their citrate capping, Au11 ≈ 11 nm (a,i), Au51 ≈ 52 nm (b,i). However, both show a Dh increase after pmodification, 1-Au11 (a,ii) ≈ 44 nm, 2-Au11 (a,iii) ≈ 51 nm, and 1-Au51 ≈ 164 nm (b,ii), 2-Au51 ≈ 295 nm (b,iii), respectively. Once functionalized, the thermal properties of the p-Au were characterized by UV−vis. UV−vis measures the SPR band of the nanoparticles, which arises from the collective oscillation of conduction electrons in the presence of light. The SPR wavelength and extinction is influenced by particle size and shape, the local dielectric at the interface, and particle-toparticle coupling due to aggregation or self-assembly.46,47 Figure 5 shows a typical set of UV−vis spectra for, 1-Au11 (a), 2-Au11(b), 1-Au51(c), and 2-Au51(d), both at 25 °C (i) and at T > TC (ii). For example, Figure 5a-i shows the thermal response of 1-Au11 at 25 (i) and 60 °C (ii). A red shift in SPR was observed from 520 to 540 nm at T > TC. We attribute this to a change in local dielectric at the Au interface due to the p-chains collapsing to the interface,37,38 as well as NP-to-NP aggregation (see below), which effectively screens much of the NP absorption. This SPR response was found to be reversible by temperature cycling (Figure 5a-i, inset). Similar red shifts and thermal reversibility were observed in each of the samples. The thermal profile of the NP aggregation was directly compared to that of 1 and 2. The right column of Figure 5 shows the thermal profile of the two systems. For instance, the right column in Figure 5a compares the profile of 1-Au11 (iii) vs 1 (1). We observe that the onset of aggregation (decrease in SPR at 520 nm) closely matches that of the 1 polymer (increase in absorbance at 520 nm), but is slightly higher in temperature than that of the 2 polymer. Taken together, these results suggest that thermal properties of the p-Au largely resemble the p used.
Figure 1. Thermal profile (1 °C/min) of 1 (i) and 2 (ii) in solution as probed by UV−vis (a) and DLS (b) ([1] ≈ 2.0 mg/mL, [2] ≈ 2.3 mg/mL, 18.2 MΩ H2O).
result and reveals a sharp gel transition of TC = 51 °C for 1 (i), and a broader gel transition for 2 centered at TC = 65 °C (ii). This aggregation was also observed by DLS, as shown in Figure 1b, where a reversible increase in the hydrodynamic diameter (Dh) for 1 from Dh = 16 nm in monomer form to ∼330 nm in the aggregated/gel form was observed (i). A similar trend for 2 was observed, which shows a reversible transition between Dh = 15 and 300 nm (ii). Taken together, these results show that 1 has a TC = 51 °C and 2 has a TC = 65 °C. The chemical structure of 1 and 2 were also confirmed by 1H NMR (Figure S1, Supporting Information). The general strategy employed for AuNP surface functionalization and reversible thermal aggregation using 1 and 2 is 15219
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Scheme 1. Idealized Schematic Illustrating the AuNP Functionalization Steps and Thermal Aggregationa
a The disulfide containing 1 or 2 pNIPAAm-co-pAAm copolymers are reduced via TCEP and incubated with Au11 or Au51. After purification of excess 1 or 2, the polymer-capped AuNP (b) is heated to its respective critical temperature (TC), upon which the copolymer undergoes a hydrophilic to hydrophobic phase transition (c), which causes aggregation (d). Upon cooling, the system returns to its original state.
Figure 3. FTIR results characterizing the monomers NIPAAm (i) and AAm (ii), the 1-polymer (iii), and the 1-Au11 conjugate (iv).
Figure 2. Representative TEM micrographs for the synthesized Au11 (a) and Au51 (b) NPs with corresponding statistical analysis revealing D of 11.5 ± 1.1 and 51.6 ± 8.3 nm, respectively.
Figure 4. Representative DLS of Au11 (a) and Au51 (b) before pmodification (i) and after modification with 1 (ii) and 2 (iii) ([Au11] = 17 nM, [Au51] = 0.7 nM, 18.2 MΩ H2O).
DLS provided a number of additional insights into the system. For example, Figure 6 shows a plot of observed Dh for the unmodified NP, the NP after conjugation at room temperature (+p), and after one heating cycle (T > TC), and back to room temperature (T < TC). The 1-Au11 showed a Dh increase from ∼44 nm at 25 °C to ∼1700 nm at 55 °C, which indicates significant aggregation. Interestingly, the Dh upon cooling to 25 °C shows the system is not as reversible as the SPR suggested, and that a relatively large Dh of ∼220 nm was measured, indicating slight irreversibility due to either clustering of the AuNPs or a highly extended final polymer conjugation. These trends were general across each p-AuNP
system. The relatively large Dh at T < TC across each p-Au system, regardless of the p, TC, and composition, suggests that the hydration process upon cooling is slow. For example, it has been shown that, due to intra- and interchain interactions when in the collapsed state, the hydration of the p-chains may be hindered.22,32,36 To better understand the aggregation behavior, these systems were further probed in situ by investigating the interparticle spatial properties during thermal aggregation via synchrotron SAXS. Figure 7 shows the representative SAXS scattering 15220
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Figure 5. Representative UV−vis characterizing the thermal behavior of the 1-Au11 (a), 2-Au11 (b), 1-Au51 (c), and 2-Au51 (d). Left panel: UV−vis monitoring of SPR at 25 °C (i) and 70 °C (ii) after 1 h heating, with insets showing the thermal cycling ([Au11] = 50 nM, [Au51] = 0.73 nM, 18.2 MΩ H2O). Right panel: Thermal profile monitored at Abs of 520 nm during heating at 1 °C/min for the corresponding p-Au (iii), with the profile for the isolated 1 or 2 shown as reference ([Au11] = 77 nM, [Au51] = 0.73 nM, 18.2 MΩ H2O).
Figure 6. Thermal response measured by DLS for 1-Au11, 2-Au11, 1Au51, and 2-Au51 before p-modification (NP), after p-modification at 25 °C before heating (+p), at TC (T > TC), and after cooling to 25 °C (T < TC). TC’s used were 51 and 65 °C for 1 and 2, respectively.
Figure 7. Synchrotron SAXS results of the 2-Au11 aggregates measured during a heating cycle at T = 55 (i), 65 (ii), 68 °C (iii), and a subsequent cooling cycle at T = 40 (iv) and 30 °C (v). Note that no significant scattering was observed at T < 55 °C during initial heating cycle. Inset: Corresponding surface-to-surface d′ spacing trend for heating (red circles) and cooling (blue triangles) (λ = 1.1614 Å, 0.2 M PBS).
structure factors (S(q)) for the 2-Au11. The SAXS were collected by using a highly concentrated solution of 2-Au11 ([2Au11] = 610 nM) dispersed in buffer (∼50 μL) within a quartz capillary. To ensure maximum scattering, the X-ray was positioned ∼0.5 mm from the bottom of the capillary. The sample was then heated and annealed at each temperature for ∼5 min. At room temperature, the solution shows no appreciable scattering, only the form factor of the AuNP (not shown); however, upon heating we first observed a scattering
S(q) at 55 °C (i), and upon heating to 65 (ii) and 68 °C (iii), both of which are > TC for 2-Au11, the diffraction was significantly stronger and shifted to higher q, indicating both the better ordering of the aggregate internals, as well as shorter interparticle distances. We next cooled the sample without disturbing it, to 40 (iv) and 30 °C (v), and observed a decrease 15221
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Notes
in S(q), and a shift back to lower q, indicating less long-range ordering and longer interparticle distances. Interestingly, we still observed scattering after cooling for >1 h, which we attribute to the interparticle 2-chains possibly becoming intertwined, forming a permanent cluster, and also due to the system becoming highly concentrated and not having time to diffuse to the normal concentrations (due to aggregation and sedimentation during the heating). Such results complement the UV−vis and DLS studies. To better quantify these results, we calculated the approximate surface-to-surface distance between AuNPs in the aggregate. Since the first diffraction is q1 = 2π/d, where d is the center-to-center distance of the average scattering planes in the aggregate, the surface-to-surface distance (d′) could be calculated via d′ = d −D, where D is the Au11 diameter (11.5 nm). These results are shown in the inset of Figure 7. The d′ first appears at ≈9.8 nm at 55 °C, decreases to 5.7 nm at 68 °C (see heating cycle), and then increases again to d′ ≈ 10.2 nm at 30 °C (see cooling cycle). Taken together, these results suggest that AuNPs can be modified to have thermally responsive interfaces, aggregation behavior, and interparticle distances by using LCST copolymers. The p-modified AuNPs have reversible aggregation at T > TC, which very closely resembles the thermal response of bulk p in solution. This aggregation is largely reversible, as demonstrated by UV−vis and DLS. The size of the AuNPs and the MW of the polymer did not significantly alter the behavior. While the general aggregation is reversible, the structure of the p changes after a heating/cooling cycle, in which the data suggests that the p stays in an extended form. SAXS confirmed this hypothesis in which aggregation was shown to bring about a well-ordered aggregate that had interparticle distances that were defined by the p-chains in extended and compressed configurations. Smart polymer functionalized nanoparticles like these may be used in the future to regulate interfacial processes like catalysis, selfassembly, or drug release. The thermally sensitive nanoparticles may also allow nanoparticles to be more easily integrated into modern 3D printing devices or shape memory processes. Moreover, the SPR based thermal shifts may allow for the development of single particle thermometers, which would be useful when investigating biological processes.
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CONCLUSIONS
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ASSOCIATED CONTENT
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by a grant from the Air Force Office of Scientific Research (AFOSR, #FA9550-10-1-0033). M.M.M. acknowledges a DoD PECASE award sponsored by the AFOSR. Additional support was provided the Syracuse Biomaterials Institute (SBI) and the Syracuse University Forensics and National Security Science Institute (FNSSI). We thank Deb Kerwood at the SU NMR facility for assistance, Prof. Rebekka Bader and Prof. Patrick Mather from the SBI for GPC, and Robert Smith at SUNY-ESF for assistance with TEM. The Cornell High Energy Synchrotron Source (CHESS) is supported by the NSF (DMR-0936384) and the NIH/ NIGMS (GM-103485). We thank Dr. Detlef Smilgies at CHESS for assistance with SAXS data collection processing, and for building the temperature controlled capillary holder.
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In summary, LCST smart polymers consisting of pNIPAAm-copAAm copolymers equipped with a thiol modification were synthesized and grafted onto gold nanoparticle interfaces. At temperatures below the TC, the p shell was extended at the surface and thus establishing a buffer region between particles. However, at T > TC, aggregation was observed, due in large part to the hydrophobic collapse of the p, eliminating the buffer region, decreasing the interparticle distances to values defined by the polymer sterics.
* Supporting Information S
Supporting Table S1 and Figure S1. This material is available free of charge via the Internet at http://pubs.acs.org.
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REFERENCES
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*E-mail: [email protected]. 15222
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