Functionalization of Magnetic Nanoparticles with Amphiphilic Block

Article pubs.acs.org/Langmuir

Functionalization of Magnetic Nanoparticles with Amphiphilic Block Copolymers: Self-Assembled Thermoresponsive Submicrometer Particles Angela M. Budgin,† Yuri A. Kabachii,‡ Zinaida B. Shifrina,‡ Pyotr M. Valetsky,‡ Sergey S. Kochev,‡ Barry D. Stein,§ Andrey Malyutin,† and Lyudmila M. Bronstein*,† †

Department of Chemistry, Indiana University, 800 E. Kirkwood Avenue, Bloomington, Indiana 47405, United States A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov Street, Moscow, 119991 Russia § Department of Biology, Indiana University, 1001 East Third Street, Bloomington, Indiana 47405, United States ‡

S Supporting Information *

ABSTRACT: For the first time the four block copolymers derived from 1alkyl[2-(acryloyloxy)ethyl]dimethylammonium bromides with hexyl (ADA) or cetyl (ADHA) groups and 2-hydroxyethylacrylate (HEA) or Nisopropylacrylamide (NIPAM) were synthesized and employed for functionalization of monodisperse iron oxide nanoparticles (NPs). The polyADA (pADA) or polyADHA (pADHA) block consists of long hydrophobic tails (C6 or C16) connected to a positively charged quaternary ammonium group, making this block amphiphilic. The second block was either fully hydrophilic (pHEA) or thermoresponsive (pNIPAM). The dependence of the NP coating on the length of the hydrophobic tail in the amphiphilic block, the composition of the hydrophilic block, and the NP sizes have been studied. Unusual self-assembling of iron oxide NPs into well-defined composite submicrometer particles was observed for pADHA-b-pNIPAM in the wide range of concentrations (at the pADHA repeating unit concentrations of 0.065 × 10−2−2.91 × 10−2 mmol/mL per 1 mg/mL NPs) but only two concentrations, 1.62 × 10−2 and 1.94 × 10−2 mmol/mL, led to regular spherical particles. The thermoresponsive behavior of these composite particles was tested using ζ-potential and dynamic light scattering measurements, while the morphology of particles was characterized by transmission electron microscopy. Coating of NPs with pADHA-b-pHEA results in the formation of individually coated NPs. The different composite particle morphologies are explained by different properties of pHEA and pNIPAM. It is demonstrated that the composite particles based on pADHA-b-pNIPAM are responsive to a magnetic field and can be recommended as magnetic stoppers in biorelated membrane separations. The incorporation of Pd species in submicrometer particles makes them promising candidates for catalytic applications as magnetically recoverable catalysts with a high magnetic response. saturated hydrocarbons with oleic acid as a surfactant.22,23 Assynthesized NPs are coated with oleic acid and thus hydrophobic. In order to be useful in biomedical applications or in catalytic reactions in aqueous media, the NPs must be hydrophilic and soluble in water and/or buffers. The NPs can be made hydrophilic through their coating with amphiphilic molecules due to formation of a hydrophobic bilayer on the NP surface.24−26 In addition, to withstand buffers, steric stabilization is needed because ions screen charges, thus often canceling electrostatic stabilization. In our earlier papers, we reported hydrophilization of iron oxide NPs by coating them with phospholipids containing poly(ethylene glycol) (PEG) tails27,28 and alternating copoly-

1. INTRODUCTION Magnetic nanoparticles (NPs) received considerable attention over the past decade due to many promising applications such as contrast enhancement agents for magnetic resonance imaging,1−4 magnetic sensors,5 drug delivery,6 in molecular biology,7 catalysis,8 metal recovery, water purification,9 and so forth. Iron oxide NPs are often recommended for bioapplications because they are easily metabolized or degraded in vivo under physiological conditions.10,11 Since magnetic properties are size dependent, a narrow NP size distribution is crucial for a number of the above applications.8,12−14 Monodisperse iron oxide NPs can be prepared by thermal decomposition of iron acetylacetonates15−17 or carboxylates17−21 in high-boiling solvents in the presence of surfactants such as oleic acid and/ or oleylamine. In our preceding work we synthesized monodisperse iron oxide NPs of various sizes and shapes using thermal decomposition of Fe(III) oleate in long chain © 2012 American Chemical Society

Received: December 21, 2011 Revised: February 3, 2012 Published: February 3, 2012 4142

dx.doi.org/10.1021/la205056k | Langmuir 2012, 28, 4142−4151

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ponsive behavior.38 Thermosensitive magnetite NPs coated with the pNIPAM-based copolymer were synthesized in aqueous solutions using a silanized block for direct interaction with forming magnetic NPs.42 Alternatively, the nanocomposite made by incorporation of 6 nm magnetic NPs on pNIPAM microgels resulted in both thermally and magnetically responsive particles with LCST increasing to 40 °C.43 These nanocomposite particles displayed thermosensitivity and superparamagnetic behavior, which depended on the thickness of the copolymer shell. Trifunctional hybrid NPs with thermoresponsive, magnetic, and fluorescent properties, Fe3O4@SiO2pNIPAM, were prepared via surface-initiated reversible addition−fragmentation chain transfer (RAFT) polymerization, using fluorescent RAFT agent-functionalized magnetic silica NPs.44 Their promising properties as MRI contrast agents have been demonstrated. Another example of multifunctional particles was reported in ref 45 where the authors fabricated a SERS substrate consisting of magnetic and silver NPs encapsulated within a pNIPAM microgel. This colloidal substrate demonstrated the ability to absorb analytes from solution at low temperature (when it is swollen) and reversibly generate hot spots upon collapse at high temperature or drying. Some nanocomposites based on pNIPAM and magnetic NPs showed promise in biomedical applications, such as multimodal cancer therapy, hyperthermia, controlled drug delivery, and so forth.46−48 The literature data presented above show an increased interest to nanocomposites of magnetic NPs and pNIPAM. In this paper, we studied the dependence of the NP coating on the length of the hydrophobic tails in the amphiphilic block, the composition of hydrophilic blocks, and the NP sizes. Unusual self-assembling of iron oxide NPs into submicrometer particles was observed for pADHA-b-pNIPAM. In addition, the thermoresponsive behavior of these composite particles was tested using ζ-potential and dynamic light scattering (DLS) measurements, while the morphology of particles was characterized by transmission electron microscopy (TEM). The incorporation of Pd species in submicrometer particles makes them promising candidates for catalytic applications as magnetically recoverable catalysts with high magnetic response.

mers based on poly(maleic anhydride-alt-octadecene) (PMAOD) with29,30 or without31 additional PEG tails. The hydrophilic shells of the resultant NPs were either neutral27 or negatively charged.28,31 In the case of copolymer coatings, they were exceptionally stable in hydrophilic media even in the presence of hydrophobic molecules.31 Considering that coating of hydrophobic magnetic NPs with copolymers containing hydrophobic tails is very robust and the NPs are stable, this procedure can be also recommended for developing cationic magnetic NPs. To the best of our knowledge, however, only a few papers reported coating of magnetic NPs with cationic copolymers32−34 and in neither case, good quality monodisperse magnetic nanoparticles were used for functionalization. At the same time, cationic magnetic nanoparticles are preferable for the transfection of plasmid DNA35 and oligonucleotides36 in mammalian cells and in many other applications. However, no alternating copolymers with long hydrophobic tails and cationic groups are commercially available. Besides developing merely cationic NPs, we were also interested in exploring NPs with thermoresponsive shells because in this case, the NPs can be additionally manipulated by a simple change in temperature, an application which may be used in drug release.37,38 In this paper, for the first time, the four block copolymers derived from 1-alkyl[2-(acryloyloxy)ethyl]dimethylammonium bromides with hexyl (ADA) or cetyl (ADHA) groups and 2-hydroxyethylacrylate (HEA) or Nisopropylacrylamide (NIPAM) (Scheme 1) were synthesized Scheme 1a

a

(Left) Structures of pADA-b-pHEA and pADHA-b-pHEA at n = 4 and 14, respectively. (Right) pADA-b-pNIPAM and pADHA-bpNIPAM at n = 4 and 14, respectively.

2. EXPERIMENTAL SECTION

and employed for functionalization of iron oxide NPs. The polyADA (pADA) or polyADHA (pADHA) block consists of long hydrophobic tails (C6 or C16) connected to a positively charged quaternary ammonium group, making this block amphiphilic. The second polymer block is either fully hydrophilic (pHEA) or thermosensitive (pNIPAM). The latter is hydrophilic below the lower critical solution temperature (LCST, ∼32 °C) but loses associated water and becomes hydrophobic above this temperature, leading to aggregation in aqueous solution.39 This critical temperature can be controlled by the addition of charged units which broaden the critical temperature range and often increase LCST, allowing the polymer to remain hydrophilic at higher temperatures.37,40 Nanocomposites composed of magnetic NPs and pNIPAM have already been synthesized and their thermoresponsive behavior has been explored. For example, cobalt NPs coated with carbon and modified with covalently attached pNIPAM chains exhibited promising behavior as self-separating phaseswitching palladium catalysts for Suzuki cross-coupling reaction.41 Magnetite NPs coated with pNIPAM chains crosslinked with poly(ethylene glycol) demonstrated a thermores-

2.1. Materials. FeCl3·6H2O (98%) and docosane (99%) were purchased from Sigma-Aldrich and used as received. Hexanes (85%), ethanol (95%), tetrahydrofuran (THF, 99%), and acetone (99.78%) were purchased from EMD and used as received. Chloroform (Mallinckrodt, 100%), oleic acid (TCI, 95%), TBE buffer (1.3 M Tris, 450 mM boric acid, 25 mM EDTA.Na2 in H2O, Fluka), and oleic acid sodium salt (ScienceLab.com, 95%) were used without further purification. N,N-Dimethylformamide (DMF, Aldrich, 99.8%) was stored under KOH and distilled over BaO. Dimethyl sulfoxide (DMSO, Aldrich, 99%) was stored under NaOH and distilled over BaO under reduced pressure. 1,4-Dioxane (Aldrich, 99%) was distilled over Na. 2,2′-Azobis(2-methylpropionitrile) (AIBN, Aldrich, 98%) was recrystallized from methanol. 2-(Dimethylamino)ethyl acrylate (DMAEA, Aldrich, 98%), 1-bromohexane (HexBr, Aldrich, 98%), 1bromohexadecane (HDBr, Aldrich, 97%), and N-isopropylacrylamide (NIPAM, Aldrich, 97%) were used as received. 2-Hydroxyethyl acrylate (HEA, Aldrich, 96%) was distilled in vacuum and stored in the freezer prior to use. 1-Phenylethyl dithiobenzoate (PEDTB) was synthesized according to the patent49 and was additionally distilled in vacuum at 190 °C/1 Torr. A pNIPAM homopolymer with a molecular weight of 26 000 Da was obtained as a gift from Prof. Francois Winnik’s group. 4143


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placed into an oil bath at 60 °C. After 1 h stirring, the temperature was raised to 70 °C and the tube was allowed to stay at that temperature for 24 h. After that the tube content was dissolved in 3 mL of methanol (or chloroform), precipitated in 35 mL of ether (or hexane/ ether =1:1), filtered, washed with the precipitant, and dried in vacuum at 45 °C for 4 h. The yield of pADHA-b-pHEA was 0.62 g (78%). The yield of pADHA-b-pNIPAM was 0.74 g (93%). DP = 220 and Mn = 26 kDa for the pHEA block or DP = 240 and Mn = 27 kDa for the pNIPAM block were calculated using the 1H NMR data in MeOH-d4 or CDCl3, respectively, by measuring the ratio of the sum of NMR signals of 2H (δ = 4.23 ppm) of the oxymethylene group of pHEA plus 2H (δ = 4.23 ppm) of the oxymethylene group of pADHA to NMR signals of 3H (δ = 0.97 ppm) of the methyl group of pADHA or the ratio of signals 6H (δ = 1.18 ppm) of the two methyl groups of pNIPAM to those of 3H (δ = 0.92 ppm) of the methyl group of pADHA. The syntheses of pADA-b-pHEA and pADA-b-pNIPAM are described in the Supporting Information. 2.3. Synthesis of Iron Oxide Nanoparticles. The synthesis of iron oleate was carried out using a published procedure.19 Iron oxide nanoparticles (NPs) were synthesized in eicosane and docosane as solvents using published procedures.22,23 The NP samples with diameters 16.5 nm (NP1) and 14 nm (NP2) were prepared in eicosane as a solvent,23 while 28 nm NPs (NP3) were synthesized in docosane.22 The solid reaction solutions were stored in a refrigerator and NPs were precipitated, collected, and washed when needed. The magnetic properties of these NPs were described earlier in refs 27, 28, and 31. 2.4. Encapsulation of Iron Oxide Nanoparticles with Block Copolymers. To encapsulate the iron oxide NPs in a block copolymer, a stock solution of a block copolymer in chloroform or in the mixture of chloroform with 5 vol % of methanol was prepared with a desired concentration and left to stir for 24 h. The desired ratio of NPs to a block copolymer was varied with each block copolymer. In a typical example, 1 mL of the 1 mg/mL chloroform solution of NP1 was added to 1 mL of the pADHA-b-PNIPAM solution containing 25 mg of a block copolymer (matching 1.62 × 10−2 mmol of the pADHA repeating units) and allowed to stir for 1 h. Chloroform was then removed under vacuum, and 2 mL of distilled water was added. The solution was sonicated for 15 min, then allowed to stir for 24 h. A turbid solution was centrifuged at 3000 rpm (three times for 15 min), each time followed by addition of water and sonication. Each time the composite particles were collected as a precipitate while supernatant was discarded. After the final sonication, the solution was allowed to sit at room temperature overnight in order to settle. The upper and middle layers as well as the precipitate were then collected in separate vials. If not indicated otherwise, in this paper, we discuss only middle (major) layers obtained by idle sedimentation at room temperature for 24 h. Upper layers were normally similar to middle layers but with a lower concentration of the species. The precipitates did not show any regular structures. Similar experiments were carried with the same amount of NPs and different amounts of pADHA-b-PNIPAM: 1, 10, 20, 30, 35, 40, and 45 mg containing 0.065 × 10−2, 0.65 × 10−2, 1.29 × 10−2, 1.94 × 10−2, 2.26 × 10−2, 2.59 × 10−2, and 2.91 × 10−2 mmol of the pADHA repeating units, respectively, in 1 mL of solvent. The pADHA repeating unit concentrations of 0.033−0.13 × 10−2 mmol/ mL were also tested. The nanocomposites based on a pNIPAM homopolymer were prepared in a similar way with the 25 mg/mL polymer concentration. After addition of water and sonication NPs do not disperse, however, after 24 h stirring the dispersion takes place. In the case of pADHA-b-pHEA, chloroform with 5% of methanol was used as a solvent. Because no large composite particles were formed in this case, the purification procedure was different. The aggregates present in the reaction solution were removed by 15 min centrifugation while supernatant was collected. If necessary, ultracentrifugation was used (1 h, 90 000 rpm, 4 °C). The pADHA-bPHEA amounts used in these experiments were varied in the range 0.5−2.0 mg, matching the pADHA repeating unit concentration in the range 0.033−0.13 × 10−2 mmol. In the case of the experiments with

2.2. Block Copolymer Synthesis. In a typical synthesis, of 1alkyl[2-(acryloyloxy)ethyl]dimethylammonium bromides, HexBr (2.76 g, 16.4 mmol) or HDBr (5.0 g, 16.4 mmol), DMAEA (2.46 g, 17.2 mmol), and 10 mL of DMF were loaded into a Schlenk tube equipped with a magnetic stir bar. The tube was subjected to three freeze− pump−thaw cycles, filled with argon, and placed into the oil bath at 70 °C. After 20 h of stirring, the tube was cooled to ambient temperature, filled with 5 mL of degassed acetone, and placed into refrigerator overnight. The precipitate was filtered, washed with acetone 3 times, and dried under vacuum for 4 h at ambient temperature. The yield of ADA was 3.0 g (59%). 1H NMR (400 MHz, CDCl3): δ 0.89 (t, 3H), 1.34 (m, 6H), 1.78 (m, 2H), 3.52 (s, 6H), 3.62 (m, 2H), 4.17 (m, 2H), 4.70 (m, 2H), 5.95 (d, 1H), 6.14 (q, 1H), 6.46 (d, 1H). 13 C NMR (100.1 MHz, CDCl3): δ 13.88, 22.37, 22.65, 25.85, 31.52, 51.88, 57.98, 62.04, 65.47, 127.0, 133.0, 165.1. The yield of ADHA was 4.6 g (62%). 1H NMR (400 MHz, CDCl3): δ 0.81 (t, 3H), 1.18−1.28 (m, 28H), 1.70 (m, 2H), 3.45 (s, 6H), 3.57 (m, 2H), 4.10 (m, 2H), 4.62 (m, 2H), 5.87 (d, 1H), 6.06 (q, 1H), 6.43 (d, 1H). 13C NMR (100.1 MHz, CDCl3): δ 13.80, 22.37, 22.65, 29.38, 31.61, 51.63, 57.71, 61.80, 65.19, 126.8, 132.6, 164.8. In a typical polymerization of ADA, ADA (1.0 g, 3.25 mmol) and AIBN (8.8 mg, 54.0 μmol) were loaded into a Schlenk tube equipped with a magnetic stir bar. The tube was purged twice with argon and filled with the solution of PEDTB (28.0 mg, 108 μmol) in 1.45 mL of 1,4-dioxane. The tube was subjected to three freeze−pump−thaw cycles, filled with argon, and placed into an oil bath at 60 °C. After 24 h stirring, the temperature was raised to 70 °C and the tube was allowed to stay at this temperature for another 24 h. After that the tube content was dissolved in 5 mL of chloroform, precipitated in 25 mL of warm acetone, filtered, washed with acetone, and dried in vacuum at 45 °C for 4 h. The yield of pADA (viscous pink oil) was 0.79 g (79%). The number average molecular weight Mn = 9.8 kDa, Mw/Mn = 1.22 and degree of polymerization DP = 32 of pADA was detected using GPC method (see below). For comparison, the pADA degree of polymerization DP = 34 and the number average molecular weight Mn = 10.5 kDa, respectively, were calculated using the 1H NMR data in CDCl3 by measuring the ratio of NMR signals of 3H (δ = 0.92 ppm) of the methyl group of pADA to those of 2H (δ = 8.04 ppm) of the oPh dithiobenzoate end group. The both methods show similar results. In the same manner as pADA, pADHA was synthesized from ADHA (0.400 g, 0.892 mmol), AIBN (1.3 mg, 7.92 μmol), PEDTB (8.2 mg, 31.7 μmol), and 0.68 mL of 1,4-dioxane. The pADHA (pink powder) yield was 0.34 g (80%). The pADHA degree of polymerization DP = 24 and the number average molecular weight Mn = 11 kDa, respectively, were calculated using the 1H NMR data in CDCl3 by measuring the ratio of NMR signals of 3H (δ = 0.90 ppm) of the methyl group of pADHA to those of 2H (δ = 8.03 ppm) of the o-Ph dithiobenzoate end group (Table 1).49

Table 1. Molecular Characteristics of Block Copolymer Samples block copolymer notation

l/Mn (kDa)a

m/Mn (kDa)a

Σ Mn (kDa)

pADA-b-pHEA pADA-b-pNIPAM pADHA-b-pHEA pADHA-b-pNIPAM

32/9.8 26/8.0 24/11.0 24/11.0

370/43.0 150/17.0 220/26.0 240/27.0

52.8 25.0 37.0 38.0

a

l and m are the polymerization degrees shown in Scheme 1.

In a typical syntheses of pADHA-b-pHEA and pADHA-b-pNIPAM, pADHA (0.2 g, 18.1 μmol), HEA (0.6 g, 5.17 mmol) or NIPAM (0.6 g, 5.28), and 1.9 mL of degassed 1,4-dioxane were loaded into a Schlenk tube preliminarily purged with argon and equipped with a magnetic stir bar. The content of the tube was warmed to 60 °C and stirred for 5−10 min for pADHA dissolution. After cooling to ambient temperature AIBN (1.1 mg, 6.7 μmol) was added and the tube was subjected to three freeze−pump−thaw cycles, filled with argon, and 4144


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pADA based block copolymers, amounts of block copolymers were equivalent to 0.065 × 10−2 and 1.62 × 10−2 mmol of pADA repeating units. 2.5. Characterization. 1H NMR (400 MHz) and 13C NMR (100.1 MHz) were performed at room temperature on Bruker AC 400 spectrometers in CDCl3, MeOH-d4 or DMSO-d6 as a solvent (tetramethylsilane was used as a reference). The molecular weight data were obtained by gel permeation chromatography (GPC) at 25 °C with the PL Aquagel−OH 8 μm MIXED-H Polymer Laboratories column, connected to an Agilent 1100 refractive index detector. The eluent was a pH 3.3 buffer solution comprising 0.30 M NaH2PO4 and 1.0 M acetic acid at a flow rate of 1.0 mL min−1. Eight near-monodisperse polyethylene glycol standards (Mp) 100−965 000 g mol−1 were used for calibration. The data were analyzed using Agilent Chemstation software. DLS and ζ -potential measurements were performed using Malvern Zetasizer Nano ZS instrument equipped with an MPT-2 autotitrator containing HCl (0.1 and 0.01 M) and NaOH (0.1 M). Before the measurements, samples were sonicated for 10−15 min and then diluted with water 1:10 or 1:100. Measurement duration was set to be determined automatically, and data were averaged from at least three runs. Intensity and volume distributions of the particle sizes were recorded. The block copolymer samples were examined in chloroform at the concentration of 1 mg/mL without dilution. A ζ-potential was measured at pH 7.4. The data was processed using the absorption of bulk iron oxide, the indices of refraction of iron oxide and solvent, and the viscosity of the pure water. The Smoluchowski approximation was used to convert the electrophoretic mobility to the ζ-potential. Electron-transparent specimens for TEM were prepared by placing a drop of solution onto a carbon-coated Cu grid. Images were acquired at an accelerating voltage of 80 kV on a JEOL JEM1010 transmission electron microscope. Images were analyzed with ImageJ software package to estimate NP diameters. Normally 150−300 NPs were used for analysis.

between the tails in two neighboring pADHA repeating units presented in Scheme 1, we expected that the NP coating with pADHA-b-pNIPAM can be efficient at a lower amphiphilic block loading. To probe this hypothesis, we varied the pADHA block concentration which determines the amount of hydrophobic tails interacting with oleic acid hydrophobic tails in the range 0.65 × 10−2−2.91 × 10−2 mmol/mL. We also tested much lower concentrations in the range 0.033−0.13 × 10−2 mmol/mL. Surprisingly, instead of coating of individual NPs as in the case of PMAOD or PEG-modified PMAOD,29−31 the interaction of pADHA-b-pNIPAM with NP1 yielded nearly spherical, submicrometer particles containing evenly distributed iron oxide NPs in the pADHA repeating unit concentration range of 1.29 × 10−2−1.94 × 10−2 mmol/mL (Figure 1). For

Figure 1. TEM images of the composite particles based on NP1 and pADHA-b-pNIPAM at the pADHA repeating unit concentration of 1.29 × 10−2 mmol/mL (a), 1.62 × 10−2 mmol/mL (b), and 1.94 × 10−2 mmol/mL (c).

the most regular sample, prepared at the 1.62 × 10−2 mmol/mL pADHA repeating unit concentration (Figure 1b), the average composite particle size was 514 nm with the 22% standard deviation (calculated out of 75 particles). At the 1.29 × 10−2 mmol/mL concentration (Figure 1a), the spherical particles tend to attach to each other which might be caused by the insufficient amount of block copolymer molecules. At the 1.94 × 10−2 mmol/mL concentration, the mean particle size increases to 847 nm with a standard deviation of 18% (Figure 1c). At the concentrations below 1.29 × 10−2 mmol/mL, the aggregation is rather irregular (not shown), while at higher concentrations rodlike particles begin to form (Figure S1, Supporting Information). It is noteworthy that, for NP2 (14 nm in diameter), similar structures were formed (not shown). On the other hand, for larger NPs, such as those with a diameter of 28 nm (NP3), although submicrometer particles were formed, their morphology was very different. Taking into consideration that 1 mg of 28 nm NPs (NP3) contains 1.6 × 1013 particles with the total surface area of 3.9 × 1016 nm2, while 1 mg of 16.5 nm NPs (NP1) contains 7.9 × 1013 particles with the total surface area of 6.8 × 1016 nm2, the NP3 sample should require less pADHA-b-pNIPAM by a factor of 1.74 to provide the same surface coverage. Based on this data, we prepared a composite sample based on NP3 (Figure S2, Supporting Information) with the pADHA repeating unit concentration of 1.29 × 10−2 mmol/mL, which is equivalent to the concentration of 2.24 mmol/mL when multiplied by a 1.74 factor. Thus, this sample can be compared to the pADHA-bpNIPAM-NP1 sample shown in Figure S1a. As is clearly seen from the comparison, the composite particles based on NP1 demonstrate even distribution of NPs, while for the pADHA-bpNIPAM-NP3 sample, the NPs are not evenly distributed through the block copolymer areas, showing significant

3. RESULTS AND DISCUSSION Controlled “living” radical RAFT polymerization49−51 was used to obtain four new amphiphilic block copolymers consisting of the amphiphilic pADA or pADHA blocks (hydrophobic and polycationic) and the hydrophilic pHEA or pNIPAM (below 32 °C) blocks (Table 1). In order to clarify the influence of the hydrophobic tail length (hexyl in pADA vs cetyl in pADHA) and the nature of the hydrophilic block (pNIPAM vs pHEA), we synthesized these block copolymers with comparable amphiphilic and hydrophilic blocks, yet hydrophilic blocks are much longer than amphiphilic. The details of the block copolymer syntheses are presented in the Experimental Section and Supporting Information. Hydrophilization of hydrophobic NPs with amphiphilic copolymers bearing a brush of hydrophobic tails takes place due to hydrophobic interactions and formation of hydrophobic bilayers as discussed in our preceding papers.29−31 Similar to PMAOD or PMAOD modified with PEG tails,29−31 we expected that pADHA-b-pHEA and pADHA-b-pNIPAM will individually coat iron oxide NPs with limited aggregation. However, it was unknown how the nature of pHEA (multiple hydroxyl groups) and pNIPAM (certain hydrophobicity) will affect the NP coating. 3.1. Functionalization of Iron Oxide NPs with pADHAb-pNIPAM. The influence of a block copolymer loading on the efficiency of NP incorporation by pADHA-b-pNIPAM was studied using 16.5 nm NPs (NP1). In the case of NP coating with PMAOD,31 we used 2.94 × 10−2 mmol of PMAOD per 1 mg of NPs. Considering that in PMAOD the distance between hydrophobic tails (∼0.4 nm) is larger than that (∼0.2 nm) 4145


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aggregation within less uniform composite particles. We believe this is due to increased magnetic interactions for larger NPs. It is noteworthy that parent pADHA-b-pNIPAM prepared in the same way as the sample with NPs but without the latter does not show any regular structures (Figure S3, Supporting Information). When the block copolymer with a shorter (hexyl) hydrophobic tail, pADA-b-pNIPAM (Table 1), has been used for interaction with NP1 at the pADA repeating unit concentration of 1.62 × 10−2 mmol/mL, no regular composite particles were formed (Figure S4, Supporting Information). As was recently demonstrated for C10-C16 surfactants, hydrophilization of hydrophobic particles by surfactants is directly dependent on the hydrophobic tail length, with long-chain surfactants dispersing particles much more efficiently than their lower homologues.52 Apparently, the hexyl tails in pADA are too short to provide such hydrophilization, preventing selfassembling into regular structures. To our surprise, a pNIPAM homopolymer with a comparable molecular weight as that of the pNIPAM block in pADHA-bpNIPAM also allowed NP1 redispersion in water at room temperature indicating significant hydrophobicity of pNIPAM in chloroform and ability of the pNIPAM chains to envelope hydrophobic NPs. However, the composites formed were completely irregular (Figure S5, Supporting Information) and easily precipitated from the solution after a few days, while the composite particles based on pADHA-b-pNIPAM were stable for several months. To probe thermoresponsive behavior of the composite particles, the sample based on pADHA-b-pNIPAM and NP1 and prepared at the pADHA repeating unit concentration of 1.62 × 10−2 mmol/mL was characterized with DLS and ζpotential measurements in the temperature range 25−45 °C (Figure 2). The hydrodynamic diameter of the composite particles at 25 °C is 574 nm (Table S1, Supporting Information), revealing a good agreement with the TEM data (D = 514 nm). The larger value of the hydrodynamic diameter (by ∼11%) compared to the value obtained from the TEM images is due to diminishing the particle size upon drying on the TEM grid. When the temperature in solution increased to 30 °C, the Dh value remained nearly the same (Figure 2a and Table S1, Supporting Information), indicating no hydrophobicity change at that temperature. The further temperature increase to 35 °C led to slightly smaller particles of 540 nm in diameter, revealing no interparticle aggregation. Contrary, the increase of the pNIPAM hydrophobicity accompanying the temperature increase resulted in shrinkage of each individual particle. This process was completed at 40 °C, yielding the smallest composite particles of 471 nm. Only when the temperature reached 45 °C, the particle size increased suggesting some aggregation. Apparently the composite particle shrinking occurs in a broad temperature range between 30 and 40 °C, which is consistent with the literature data on broadening the phase transition of pNIPAM-based materials when hydrophobic tails or additional charges or hydrophilic particles are present.37,42 In our case, iron oxide NPs are hydrophobic which might lower the LCST, but the cationic groups of pADHA might increase it, thus broadening the phase transition. It is noteworthy that the particle size changes are fully reversible when the temperature is decreased. The above behavior is markedly different from that of the homopolymer pNIPAM where uncontrolled aggregation is observed above the LCST53 and can be attributed to the

Figure 2. Dependencies of the hydrodynamic diameters obtained from DLS volume distributions (a) and ζ-potentials (b) on the temperature for composite particles based on pADHA-b-pNIPAM and NP1 and prepared at the pADHA repeating unit concentration of 1.62 × 10−2 mmol/mL.

presence of positive charges in the composite pHEA-bpNIPAM-NP1 particles. This is confirmed by ζ-potential data upon the temperature increase. The ζ-potential value steadily increased from 30 to 40 mV when the temperature increased from 25 to 40 °C. This is easily explained by increasing hydrophobicity of the pNIPAM units which become buried in the composite particle interior, while the cationic groups become more exposed to the particle surface. Apparently, this process was completed when the temperature reached 40 °C as no changes were observed upon heating to 45 °C. When the concentrations of pADHA-b-pNIPAM were much smaller and varied in the range 0.5−2.0 mg/mL matching to the pADHA repeating unit concentrations of 0.033−0.13 × 10−2 mmol/mL, the NP1 particles were transferred into aqueous phase, but the sample was extremely heterogeneous containing both individually coated particles (Figure 3a) and

Figure 3. TEM images of the NP1 samples coated with pADHA-bpNIPAM at the pADHA repeating unit concentration of 0.065 × 10−2 mmol/mL. Individually coated NPs are shown in (a), while aggregates are shown in (b). 4146


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these samples. Remember that hydrophobic NPs and pADHAb-pNIPAM are mixed in a chloroform solution where the pNIPAM block is fully soluble while the pADHA block should form micelles. For pADHA-b-pHEA, 5 vol % of methanol was added to chloroform to ensure a transparent solution because pHEA is too hydrophilic and poorly soluble in pure chloroform. To elucidate the block copolymers structures formed in these solutions, we carried out DLS measurements of the neat block copolymers after solubilization in an organic solvent. We used volume distributions of hydrodynamic diameters (the volume is proportional to R3),54 to minimize the influence of possible aggregation on nanocomposite sizes (the scattering intensity is proportional to the squared volume, i.e., to R6). DLS data presented in Figure 5a show that the chloroform solution of pADHA-b-pNIPAM contained two types of

various aggregates (Figure 3b). Apparently the block copolymer concentration was insufficient to allow any regular selfassembling. 3.2. Functionalization of Iron Oxide NPs with pADHAb-pHEA. Coating of NP1 with pADHA-b-pHEA (Table 1) was tested at the pADHA repeating unit concentrations in the range 0.033−0.13 × 10−2 mmol/mL. TEM images of the NP samples coated with pADHA-b-pHEA are shown in Figure 4 and Figure

Figure 4. TEM image of NP1 coated with pADHA-b-pHEA at the pADHA repeating unit concentration of 0.065 × 10−2 mmol/mL. Red arrows show block copolymer excess.

S6 (Supporting Information). The pADHA repeating unit concentration of 0.065 × 10−2 mmol/mL (Figure 4) resulted in the NPs being individually and fully coated similar to coating with PMAOD and modified PMAOD alternating copolymers described in our preceding papers.29−31 These figures demonstrate, however, that NPs are individually coated only at the pADHA repeating unit concentration of 0.065 × 10−2 mmol/mL. At the lower concentration of 0.033 × 10−2 mmol/mL, it appears that not enough block copolymer is available to fully coat NPs, leading to small aggregation, whereas at the higher concentration (0.13 × 10−2 mmol/mL), large irregular aggregates are formed. Only irregular aggregation was observed at the pADHA repeating unit concentration of 1.62 × 10−2 mmol/mL (compare with pADHA-b-pNIPAM in Figure 1b). The sample shown in Figure 4 contains some polymer excess (see red arrows). Normally, in order to remove it, ultracentrifugation is used as was demonstrated in our earlier work for nonmodified and modified PMAOD.29−31 However, attempts to remove the pADHA-b-pHEA excess from this sample resulted in aggregation. It was baffling that a combination of positive charges (electrostatic stabilization) and long hydrophilic tails (steric stabilization) did not prevent aggregation of NPs, unless the polymer was partially stripped off the NPs under a centrifugal force due to long pHEA chains (26 kDa). Such long side chains were not studied for PEG modified PMAOD. Replacement of pADHA-b-pHEA with pADA-b-pHEA, resulted in large aggregation at all block copolymer concentrations, revealing once more that a sufficient length of the hydrophobic tail is needed for hydrophilization of NPs. 3.3. Mechanism of Composite Particle Formation. In order to understand the differences in the interaction of NPs with pADHA-b-pNIPAM leading to regular submicrometer particles and with pADHA-b-pHEA leading to individually coated NPs, one needs to consider the preparation methods of

Figure 5. DLS volume distributions vs hydrodynamic diameter for pADHA-b-pNIPAM (a) in chloroform solution (red) and in the solution of 5% of methanol in chloroform (black) and pADHA-bpHEA (b) in the solution of 5% (black) and 10% (blue) of methanol in chloroform.

structures with Dh of 8 and 21 nm. The former was ascribed to reverse micelles formed along the pADHA block, while the latter can be assigned to small micellar clusters. Please note that the size of 8 nm is much larger than the size of the surfactant micelles with the surfactant length of ∼2 nm (similar to the pADHA tail), but considering that in the pADHA micelles polymer chain should also be involved, size could increase significantly. When 5 vol % of methanol (for comparison of pADHA-b-pNIPAM and pADHA-b-pHEA) was added to the chloroform solution of pADHA-b-pNIPAM, only micellar clusters of 21 nm in size and large 220 nm aggregates are present. In the case of pADHA-b-pHEA (Figure 5b), despite the chloroform solution containing 5 vol % of methanol looked 4147


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transparent, DLS showed the presence of single structures with a mean size of 205 nm, indicating that complete block copolymer solubilization does not occur. Addition of 10 vol % of methanol led to smaller (103 nm) and more narrow distributed aggregates; however, this reaction solution interferes with NP solubility and was not used in our studies. Thus, the solvent composition strongly influences the condition of the block copolymer in solution. When in the case of the pADHA-b-pNIPAM sample, chloroform was being evaporated and the concentration increased, the hydrophobic tails of the pADHA micelles are getting imbedded into the hydrophobic shell of iron oxide NPs formed by oleic acid. At the same time, because in the absence of water pNIPAM is hydrophobic and has a considerable chain length (240 units), multiple pNIPAM chains may bridge and encapsulate multiple hydrophobic NPs forming NP clusters (Scheme 2). The experiments with NP1 and homopolymer pNIPAM (see above) confirmed such encapsulation.

Scheme 3. Interaction of Hydrophobic NPs with pADHA-bpHEA

can only speculate that at the higher concentration of pADHAb-pHEA, block copolymer aggregation in a mixed organic solvent is so pronounced that it prevents regular incorporation of the pADHA hydrophobic tails in the oleic acid shell on the NP surface, thus preventing individual NP coating. 3.4. Behavior of Composite Particles. Because the iron oxide NPs employed in this work are superparamagnetic,27 that is, responsive to a magnetic field, but become nonresponsive when the magnetic field is absent, it was reasonable to explore possible applications of submicrometer composite particles related to their magnetic response. Here we propose two promising avenues for exploration of these particles: (i) as magnetic stoppers for membranes with submicrometer pores and (ii) as magnetically recoverable catalysts.55,56 To demonstrate the promise for the former application, we placed a carbon coated TEM grid with a drop of the aqueous solution of the composite particles based on NP1 and pADHAb-pNIPAM (at the pADHA repeating unit concentration of 1.62 × 10−2 mmol/mL) between two rare earth magnets. The TEM image in Figure 6 shows that the composite particles

Scheme 2. Encapsulation of Hydrophobic Iron Oxide NPs with pADHA-b-pNIPAM

When water was added and the reaction solution was sonicated, water penetrated only through mostly accessible pathways of the composite particles formed, making their surface hydrophilic, while the interior might still remain densely packed with hydrophobic particles and thus hydrophobic. As is discussed above, this process was mainly determined by the ratio between the NPs and the block copolymer. Increase of the block copolymer fraction (see Figures 1 and S1, Supporting Information) leads to emergence of elongated particles, whose shape is probably caused by preferable packing of block copolymers at such high concentrations. It is noteworthy that when composite particles were formed from the 5 vol % of methanol/chloroform pADHA-b-pNIPAM solution in the otherwise identical conditions, the particles were extremely irregular (Figure S7, Supporting Information), revealing that the presence of reverse micelles (and not micellar clusters) is crucial for formation of regular composite particles. Clearly, pADHA-b-pHEA which formed large aggregates in the methanol/chloroform solution did not lead to submicrometer composite particles upon mixing with iron oxide NPs; however, other factors could be of even greater significance. For example, the pHEA block is too hydrophilic, forms multiple hydrogen bonds due to hydroxyl groups, and cannot penetrate hydrophobic NP areas as shown in Scheme 2. On the other hand, pADHA-b-pHEA coated individual particles (as is shown in Scheme 3) at the pADHA repeating unit concentration of 0.065 × 10−2 mmol/mL, but not at the higher concentration. Here we

Figure 6. TEM image of the pADHA-b-pNIPAM/NP1 sample under magnetic field. Red arrow shows the direction of the magnetic field.

orient themselves along the direction of the magnetic field (red arrow). Although the particles look deformed, this can be a promising avenue for magnetic membrane separations after particle cross-linking to avoid deformation. To explore the possibility of developing catalysts based on submicrometer magnetic NPs, we reacted pADHA-b-pNIPAM/ NP1 with Na2PdCl4. As might be expected, the electrostatic interaction between the pADHA cationic groups and the PdCl42‑ anions occurred immediately,57 yielding the incorporation of PdCl42‑ anions into the submicrometer particles. The TEM image presented in Figure S8 (Supporting Information) 4148


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containing pADHA-b-pNIPAM/NP1 composite particles can be of interest for magnetically recoverable catalysts in aqueous hydrogenation reactions.

shows much higher electron contrast of this sample after incorporation of Pd species (see Figure 2b for comparison) and changes in the composite particle surface and morphology. Fast magnetic separation of the composite particles in aqueous solution (Figure 7) suggests that the pADHA-b-

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ASSOCIATED CONTENT

S Supporting Information *

Discussion of block copolymer formation, TEM images of composite nanoparticles; hydrodynamic diameters obtained from DLS volume distributions and ζ-potentials. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes Figure 7. Photographs of the pADHA-b-pNIPAM/NP1-PdCl42‑ particles after sonication (a) and after 2 min at the Neodymium magnet (b).

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work has been supported, in part, by the IU FRSP Grant. Z.B.S. and L.M.B. thank the Federal Program “Scientists and Educators of Innovative Russia” 2009-20013, Contract #14.740.11.0380 and the RFBR Grants 11-03-00064 and 1003-01114-a. We also thank Prof. Francoise Winnik for the gift of the pNIPAM homopolymer and fruitful discussions.

pNIPAM/NP1-PdCl42‑ particles can be promising candidates for hydrogenation of water-soluble substrates with subsequent magnetic recovery. Magnetically recoverable catalysts are of great interest nowadays due to easy separation of the catalysts from reactions solutions making many catalytic processes more robust. The catalytic and membrane separation applications of the composite particles discussed in this paper are the subject of our future studies but here we demonstrated a proof-ofconcept.

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REFERENCES

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