Dual Thermoresponsive Aggregation of Schizophrenic PDMAEMA-b

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Article

Dual-thermoresponsive aggregation of schizophrenic PDMAEMA-b-PSBMA copolymer with an unrepeatable pH response and a recycled CO/N response 2

2

Hui Sun, Xiaolu Chen, Xia Han, and Honglai Liu Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.7b00065 • Publication Date (Web): 23 Feb 2017 Downloaded from http://pubs.acs.org on February 24, 2017

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Dual-thermoresponsive aggregation of schizophrenic PDMAEMA-b-PSBMA copolymer with an unrepeatable pH response and a recycled CO2/N2 response Hui Sun, Xiaolu Chen, Xia Han*, Honglai Liu Key Laboratory for Advanced Materials and School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, PR China

KEYWORDS: Dual-thermoresponsive, schizophrenic micellization, pH-responsive, salt-responsive, CO2-switchable ABSTRACT:

A

dual-thermoresponsive

block

copolymer

of

poly[2-(dimethylamino)ethyl

methacrylate]-block-poly(sulfobetaine methacrylate) (PDMAEMA-b-PSBMA) exhibited reversible schizophrenic aggregation behavior in water because of the upper critical solution temperature (UCST) of the PSBMA block and the lower critical solution temperature (LCST) of the PDMAEMA block. Both the UCST and LCST shifted to lower values with increasing DMAEMA/SBMA block ratios, which was ascribed to the hydrophobic/hydrophilic balance of both blocks. Due to the salt-sensitive PSBMA and pH-responsive PDMAEMA, the UCST and LCST values of PDMAEMA-b-PSBMA were codetermined by varying the salt concentrations and pH. Specifically, increasing the salt concentration resulted in a notable decrease in the UCST and slight increase in the LCST due to the salt-induced screening of the electrostatic attractions of the PSBMA and salt-enhanced solubility of the PSBMA blocks, respectively.

The LCST decreased with increasing pH because of the deprotonation

of PDMAEMA, and the UCST first increased and then decreased with increasing pH. Besides, the ACS Paragon Plus Environment

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copolymer with larger PDMAEMA content was more sensitive to pH. For the repetitive adjustment to thermoresponsive aggregation, repeated addition of acids and bases induced salt accumulation and diminish the switchability of pH, while repeated switching cycles were achieved by CO2/N2 bubbling without introducing salt enrichment. The difference of HCl/NaOH titration and CO2/N2 bubbling also existed in the switching cycles when PDMAEMA-b-PSBMA served as a stimulus-responsive emulsifier. INTRODUCTION Stimuli-responsive block copolymers that respond to different stimuli have attracted much attention for the design of intelligent materials that have versatile applications in drug/gene delivery,1-3 phase-transfer reagents4 and protein-resistant surfaces.5-6 Armes and co-workers7-10 demonstrated that certain amphiphilic AB diblock copolymers could self-assemble into A-core and B-core micelles at different pH values and salt concentrations, and they first described these copolymers as “schizophrenic” in 2001.8 Laschewsky11 reported the first temperature-controlled schizophrenic block copolymer

based

on

N-isopropylacrylamide

(NIPAM)

and

3-[N-(3-methacrylamidopropyl)-N,N-dimethyl]ammoniopropane sulfonate] (SPP) in 2002. The incorporation of the electrostatic interactions between zwitterionic SPP blocks and the hydrophobic interactions between the PNIPAM blocks resulted in the coexistence of an upper critical solution temperature (UCST) and a lower critical solution temperature (LCST).11-12 The block copolymer exhibited a “micelle-unimer-inverse micelle” transformation between the UCST and LCST. Since then, many dual-thermoresponsive copolymers based on UCST-type monomers bearing sulfobetaine groups and LCST-type monomers bearing hydrophobic interactions have been developed. The UCST-type monomers

include

[2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) ACS Paragon Plus Environment

ammonium

hydroxide

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(sulfobetaine

SBMA)13

methacrylate,

3-[N-(3-methacrylamidopropyl)-N,N-dimethyl]ammoniopropane LCST-type

monomers

include

2-(N-morpholino)ethyl

sulfonate]

and (SPP),14

methacrylate

and

the

(MEMA),13

N,N-diethylacrylamide (DEA),15 oligo(ethylene glycol) methyl ether methacrylate (OEGMA),16 N-vinylcaprolactam

(VCL),17

N-isopropylacrylamide

(NIPAM),15

2-(2-methoxyethoxy)ethyl

methacrylate (MEO2MA),18 and 2-(dimethylamino)ethyl methacrylate (DMAEMA).19-20 Block copolymers composed of both types of these monomers usually show UCST and LCST double phase behaviors, which are influenced by the composition, molecular weight, salt concentration and pH. For example, PSPP-PMEO2MA-b-PSPP showed an increasing UCST with an increasing block length of PSPP.18 PNIPAM-b-PSBMA with different block lengths at the same block ratio displayed decreased UCSTs and increased LCSTs with increasing molecular weights.21 PNIPAM-b-PSPP exhibited a decreased LCST and the absence of a UCST with the addition of NaCl.14 Similarly, the salt-responsive P(VCL-co-SBMA) copolymer showed lower shifts in the LCST and UCST with increasing salt concentrations.17 Star-shaped β-CD@PDMAEMA-b-PSBMA showed only UCST behavior in the outer PSBMA blocks, and the aggregates in alkaline pH conditions were larger than those at neutral pH.19 However, the adjustment of pH to control the LCST and UCST of schizophrenic polymers has not been studied in detail. PDMAEMA is a weak polyelectrolyte with a molecular weight-dependent and pH-dependent LCST varying from 14 °C to 50 °C,22 while PSBMA is a polyzwitterion and exhibits a salt-induced “anti-polyelectrolyte” effect. Due to its stimuli-responsive colloidal behavior and excellent biocompatibility23-26, PDMAEMA-b-PSBMA can be designed to be a schizophrenic copolymer and applied in pH/thermo-responsive drug/gene delivery.27-29 Since the LCST and UCST of ACS Paragon Plus Environment

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PDMAEMA-b-PSBMA are both pH- and salt- tunable, the precise control of the thermoresponsiveness of this schizophrenic copolymer under different conditions is of great importance. The pH is commonly adjusted using HCl/NaOH, which inevitably introduces salt enrichment and triggers the salt stimuli simultaneously. However, CO2/N2 bubbling will also result in a changing pH that can be repeated between pH 4.7 and pH 7.5, avoiding the salt effect on the responsive behavior of the copolymer solution. This paper elaborates on the distinction between the pH-tunable and CO2-switchable thermoresponsive behaviors of PDMAEMA-b-PSBMA, a block copolymer composed of a pH/CO2-sensitive polycation and a salt-sensitive polyzwitterion. EXPERIMENTAL SECTION 2-(Dimethylamino)ethyl

Materials.

methacrylate

(DMAEMA,

98

%),

[2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) ammonium hydroxide (sulfobetaine methacrylate, SBMA,

97

%),

N,N,N′,N′′,N′′-pentamethyldiethylenetriamine

(PMDETA,

99

%),

and

α-bromoisobutyryl bromide (BIBB, 98 %) were from Sigma-Aldrich. The monomers were destabilized after passing through a basic aluminum oxide column before use. Copper(I) bromide (CuBr, 98 %, Sinopharm Chemical Reagent Co., Ltd.) was treated with glacial acetic acid, washed with ethanol, and then dried in a vacuum oven. Regenerated cellulose membranes (MWCO 3500) were used for dialysis. Ultrapure water with a minimum resistivity of 18.2 MΩ·cm was purified using a Millipore water purification system. The syringe filter (nylon, 13 mm, 0.22 µm) was purchased from RephiLe Bioscience, Ltd. Synthesis and characterization of the polymers. An atom transfer radical polymerization (ATRP) technique was used in this paper.30 PDMAEMA-b-PSBMA block copolymers were synthesized in an ethanol/water mixture and purified by dialysis.31 A sequential synthetic route (Scheme 1) was ACS Paragon Plus Environment

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developed

to

synthesize

the

PDMAEMA-b-PSBMA

diblock

copolymers.27

Different

PDMAEMA-b-PSBMA diblock copolymers were synthesized using molar feed ratios of [DMAEMA]/[SBMA]/[BIBB]/[CuBr]/[PMDETA] = x:y:1:1:1.1 in deoxygenated ethanol/water solutions at 40 °C. After DMAEMA was polymerized and the conversion was calculated, a degassed SBMA solution was injected into the flask under nitrogen gas, and the reaction was carried out. The final products were obtained after dialysis and freeze-drying, and they were denoted as PDMAEMAm-b-PSBMAn according to the compositional analyses by 1H NMR spectroscopy (Bruker 500 MHz spectrometer). The number-average molecular weight (Mn) and polydispersity (Mw/Mn) of the polymers were determined by gel permeation chromatography (GPC, Agilent, PL-GPC 50 PLUS) with an aqueous NaNO3 (0.1 M) solution as the eluent at a flow rate of 0.8 mL/min at 30 °C, and polyethylene glycol was used as the calibration standard. Dynamic light scattering (DLS). The hydrodynamic diameters of the polymers at different temperatures were detected by DLS on a Zetasizer Nano ZS Instrument (ZEM4228, Malvern Instruments, UK) at a scattering angle of 173°. The measurements were performed over a temperature range of 5-75 °C at temperature intervals of 2 °C, after a 10 min thermal equilibration period. The LCST and UCST of the polymer solutions were defined as the temperature thresholds that induce hydrodynamic diameter (Dh) changes. The isoelectric points (IEPs) of the polymers in aqueous solution were determined according to the pH-dependent zeta potentials (ζ-potentials). The polymer solutions were prepared in ultrapure water and filtered through a 0.22-µm filter before measurement. Turbidity measurements. The transmittances of the aqueous solutions of polymers at various temperatures was measured at 450 nm with a UV-vis spectrophotometer (UV-2450, Shimadzu, Japan). Heating and cooling scans were performed between 5 and 75 °C at temperature intervals of 2 °C, after ACS Paragon Plus Environment

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thermal equilibration for 10 min. pH adjustment and CO2/N2 bubbling. Diluted HCl and NaOH solutions were used to adjust the pH of the copolymer solution. CO2/N2 gas was bubbled for 30 min during the CO2/N2 cycles. The pH of the polymer solution was 4.7 after CO2 bubbling. During the HCl/NaOH cycles, the pH was set to be the same as in the CO2/N2 cycles, i.e., pH 4.7 and pH 7.5. RESULTS AND DISCUSSION Synthesis and characterization of the polymers. Six block copolymers with different compositions were prepared by changing the monomer/monomer ratio during polymerization, and their characteristics are listed in Table 1. The number-averaged degree of polymerization of DMAEMA (m) and SBMA (n) were determined by 1H NMR spectroscopy (Figure S1), and the block copolymers were denoted as m-n. The molar content of PDMAEMA in the prepared copolymer increased gradually from 26.3 mol% in polymer 30-84 to 84.2 mol% in polymer 160-30, although the lengths of both segments of all copolymers were not kept the same, which suggested the tunable amphiphilic nature of these copolymers.

Scheme 1. Synthetic route of PDMAEMA-b-PSBMA from ATRP. Dual-thermoresponsive phase behavior of PDMAEMA-b-PSBMA copolymers. The

ACS Paragon Plus Environment

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dual-thermoresponsive phase behaviors of the polymers in aqueous solutions were observed by the temperature-dependent transmittance and Dh measurements. As shown in Figure 1, the PDMAEMA-b-PSBMA copolymers displayed both UCST and LCST phase behaviors at pH 9.0, and the transition temperatures varied with the copolymer compositions. At temperatures below the UCST, the copolymer was considered to exist as a collapsed coil and precipitated in water due to strong inter-/intra-chain electrostatic interactions between the zwitterionic SBMA segments.32 At moderate temperatures, the copolymer solution became transparent with a Dh of approximately 10 nm because the soluble PSBMA segment contributed to the dominant temperature-induced entropy of mixing,33 and the soluble PDMAEMA segment resulted from the hydrogen bonding between the tertiary amine groups and water molecules. As the temperature increased, the LCST phase separation occurred, driven by the unfavorable entropy of mixing.34 The temperature-dependent 1H NMR spectra of the 30-60 samples indicated the dehydration of PDMAEMA chains and the hydration of PSBMA chains with increasing temperatures (Figure S2). The schizophrenic phase transition process of the diblock copolymer is illustrated in Figure S3, and the aggregates that formed below the UCST and above the LCST were visualized by TEM (Figure S4). In addition, the transitions were reversible with similar critical temperature values and exhibited slight hysteresis. (Figure S5).


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B

A

100

Transmittance (%)

30-84 30-60 18-27 33-36 45-15 160-30

1000

Dh (nm)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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100

10

30-84 30-60 18-27 33-36 45-15 160-30

80

60

40

20

0

0

20

40

o

0

60

20

Temperature ( C)

40

o

60

80

Temperature ( C)

Figure 1. Temperature dependence of the apparent hydrodynamic diameter (Dh) (A) and transmittance (B) of the polymer in aqueous solutions (1 g/L) at pH 9.0. The insets (B) are optical photographs of PDMAEMA33-b-PSBMA36 in aqueous solution (1 g/L) at different temperatures. pH-responsive

phase

behavior

of

the

PDMAEMA-b-PSBMA

copolymers.

The

thermoresponsive aggregation of the copolymers was determined by their hydrophilic/hydrophobic properties and intermolecular interactions, such as hydrogen bonds and electrostatic interactions. Therefore, the LCST and UCST values of the polyelectrolyte not only depended on the composition but were also influenced by the pH of the solution media. The ζ-potentials of the PDMAEMA-b-PSBMA copolymers versus pH varied from positive to negative and indicated zero charge at the isoelectric point (IEP) (Figure 2). At low pH, the amino residues on the PDMAEMA chain were protonated, resulting in positive ζ-potentials related to the PDMAEMA length. At high pH, the zwitterionic SBMA segments behaved like polyanions. After adding NaOH, the interaction between the ‘hard’ base OH- and the ‘hard’ acid quaternary ammonium groups was stronger than that between the ‘hard’ acid Na+ and the ‘soft’ base sulfonate groups,34-35 which resulted in the polyanion phenomenon of PDMAEMA-b-PSBMA in alkaline media.36 The IEPs of the PDMAEMA-b-PSBMA copolymers were detected to be approximately 8.4 with PDMAEMA contents of 26.3 mol%, 33.3 mol% ACS Paragon Plus Environment

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and 40.0 mol% and ~9.9 with PDMAEMA contents of 47.8 mol%, 75.0 mol% and 84.2 mol%, which were influenced by their compositions and block lengths.22 Interestingly, the IEP values did not vary with the PDMAEMA content smoothly, and a significant jump in the IEP value was observed as the PDMAEMA content increased from 40.0 mol% to 47.8 mol%. We assigned the copolymers with PDMAEMA contents of 47.8 mol% and above as PDMAEMA-dominated copolymers and those with PDMAEMA contents below 47.8 mol% as PSBMA-dominated copolymers. 60

30-84 30-60 18-27 33-36 45-15 160-30

40

Zeta Potential (mV)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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20

0 4

5

6

7

8

9

10

11

pH -20

Figure 2. ζ-potentials of PDMAEMA-b-PSBMA at different pH values; the solution concentration was 1.0 g/L. Composition-tunable UCST and LCST. The PDMAEMA-b-PSBMA copolymers exhibited composition-dependent UCST and LCST phase transitions. At pH 9.0, the UCST and LCST exhibited a decreasing tendency with increasing PDMAEMA molar ratios in the copolymers. First, with approximately the same PDMAEMA length, the copolymers 30-84, 30-60, and 33-36 displayed decreasing LCST values with decreasing PSBMA chain lengths. This was because the hydrophilicity ACS Paragon Plus Environment

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of copolymers decreased with the decreasing length of PSBMA because the PSBMA segments were hydrophilic at temperatures above the UCST. Second, with similar PSBMA lengths, the copolymers 18-27, 33-36, and 160-30 displayed decreasing UCST values with increasing PDMAEMA chain lengths. This may be ascribed to the increasing length of the hydrophilic PDMAEMA chains at temperatures below the LCST. Third, with similar molecular weights, the UCST and LCST of copolymers 18-27, 33-36 and 45-15 decreased gradually with an increasing PDMAEMA content. In addition, the copolymer 50-70 with a similar DMAEMA content (41.6 mol%) to 18-27 (40.0 mol%) was synthesized to investigate the influence of the molecular weight on the thermoresponsive behavior. With 2.6 times the molecular weight of 18-27, the phase transition temperatures of 50-70 were almost identical to those of 18-27 (Figure 4A). It was supposed that the influence of the composition dominated. To sum up (Figure 3), the UCST and LCST values of the PDMAEMA-b-PSBMA series decreased monotonously with an increasing PDMAEMA content from 31 °C to < 5 °C and from 73 °C to 48 °C, respectively. The clear point and cloud point values decreased with the increasing PDMAEMA content as well. As Figure 3 shows, PDMAEMA-b-SBMA with comparable lengths of both blocks (i.e., 18-27 and 33-36) showed a narrow temperature range of dissolution. A broad phase transition temperature range of the copolymers could widen its potential applications. The composition-tunable UCST and LCST values will benefit the design of custom, tailored copolymers with specific transition temperatures.


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18

UCST LCST IEP

70

15

60

50

40

9

30

IEP

12

o

UCST/LCST ( C)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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6

20 3

PDMAEMA-dominated

PSBMA-dominated

10 20

30

40

50

60

70

80

PDMAEMA content (mol%)

Figure 3. Composition dependence of the IEPs and the phase transition temperatures. Table 1. Characteristic data for the PDMAEMA-b-PSBMA copolymers and the critical temperatures of PDMAEMA-b-PSBMA in aqueous solution at pH 9.0. Samplea m-n

a

PDMAEMA content (mol%)

Mna

Mnb

(kDa)

(kDa)

PDI

b

IEP

UCSTc

LCSTc

(°C)

(°C)

Clear

Cloud

d

pointd

point (°C)

(°C)

Dh minc (nm)

30-84

26.3

28.4

11.7

1.28

8.20

31

73

33

83

13.0

30-60

33.3

21.7

13.3

1.24

8.46

29

59

27

63

10.3

18-27

40.0

10.6

6.89

1.30

8.42

27

53

27

55

9.35

50-70

41.6

27.6

10.2

1.22

8.40

27

57

41

55

18.4

33-36

47.8

15.4

7.31

1.23

9.85

24

52

20

54

10.3

45-15

75.0

11.5

8.31

1.23

9.80

17

49

17

51

9.18

160-30

84.2

33.7

25.9

1.21

9.98

< 5e

48

< 5e

48

21.0

As determined by 1H NMR spectroscopy.

b

As determined by GPC. c The LCST and UCST were


Langmuir

defined as the temperature thresholds that induce hydrodynamic diameter (Dh) changes of the polymer. The Dh

min

values were determined by the minimum values of the DLS measurements in the

temperature range. d The clear points and cloud points were determined as the change temperatures of the turbidity-versus-temperature curves of the copolymers. e The values were not detected. B

A

18-27 50-70

100

18-27 50-70

80

Transmittance (%)

1000

Dh (nm)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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100

60

40

20

10 0

10

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70

80

0 0

10

20

o

Temperature ( C)

30

40

50

60

70

80

o

Temperature ( C)

Figure 4. Temperature dependence of the apparent hydrodynamic diameter (Dh) (A) and transmittance (B) at pH 9.0 for 18-27 and 50-70 in aqueous solutions (1 g/L). pH-tunable

UCST

and

LCST.

The

influence

of

pH

on

the

thermoresponsive

aggregation/dissolution of PDMAEMA-b-PSBMA was investigated using DLS in solution at pH 5.0, pH 7.0 and pH 9.0. Taking 18-27 and 33-36 for example, the thermoresponsive behaviors differed greatly between the acidic, neutral, and alkaline conditions, as shown in Figure 5. Both copolymers exhibited pH-dependent UCST and LCST phase transitions except for the LCST of PDMAEMA33-b-PSBMA36 at pH 5.0, which was beyond the limitation of our measurements. As Figure 5C shows, the LCST values of both copolymers decreased with increasing pH, which is attibuted to the pH-responsive PDMAEMA block. The hydrophilicity of the PDMAEMA block decreased with increasing pH due to the decreasing protonation degree of the tertiary amine groups, whereas the hydrophilicity of PSBMA was pH-independent. The enhanced hydrophobic interactions between the PDMAEMA chains at high pH resulted in LCST phase transitions at low temperatures. ACS Paragon Plus Environment

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The UCST values of 18-27 and 33-36 first increased and then decreased with increasing pH. As for the copolymer 18-27 in the neutral solution, the UCST transition was observed at 37 °C. In an acidic solution with pH 5.0, the positive charges of the protonated PDMAEMA segments resulted in an enhanced hydration state and solubility of the copolymer, in which a decreased UCST at 33 °C and smaller aggregates were observed. In an alkaline solution with pH 9.0, the neutral and hydrophobic PDMAEMA chains interfered with the electrostatic interactions between the ammonium cation and sulfo anion of the zwitterionic PSBMA segment, which lowered the UCST to 27 °C. For copolymer 33-36, the UCST values in the acidic, neutral and alkaline solutions were 35 °C, 62 °C and 24 °C, respectively. Although both the UCST and LCST of the two copolymers showed similar variations with pH, the critical temperatures of 33-36 showed more significant fluctuations with the pH. As aforementioned, 18-27 was designated as a PSBMA-dominated polymer, while 33-36 was assigned as a PDMAEMA-dominated polymer, and they showed very different IEPs. Herein, the pH-dependence of the critical temperatures was wholly dependent on the pH-responsive PDMAEMA chain. The larger PDMAEMA content in 33-36 resulted in the notable difference between the critical temperatures at different pH values (Figure 5C).

B

A pH=5.0 pH=7.0 pH=9.0

pH=5.0 pH=7.0 pH=9.0

1000

Dh (nm)

1000

Dh (nm)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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o

Temperature ( C)

Temperature ( C)


60

70

80

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80

80 UCST of 18-27 LCST of 18-27 UCST of 33-36 LCST of 33-36

70

o

70 60

50

50

40

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o

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UCST ( C)

C

LCST ( C)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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5

6

7

8

9

pH

Figure 5. Thermoresponsive behavior of (A) PDMAEMA18-b-PSBMA27 and (B) PDMAEMA33-b-PSBMA36 at 1 g/L and different pH values. (C) pH dependence of the critical transition temperatures of PDMAEMA18-b-PSBMA27 and PDMAEMA33-b-PSBMA36. Salt-tunable UCST and LCST. Figure 6 shows the Dh versus temperature curves for PDMAEMA18-b-PSBMA27 aqueous solution at different salt concentration in heating processes. Different temperature ranges of dissolution were observed at different salt concentration. With increasing NaCl concentration from 0 mM to 80 mM, an obvious shift in the UCST from 27 °C to 9 °C and a slight shift in the LCST from 63 °C to 65 °C were observed. When salt was added, the polyelectrolyte PDMAEMA block and the zwitterionic PSBMA block were supposed to show the “salting out” effect and the “anti-polyelectrolyte” effect, respectively. The electrostatic attractions between the ammonium cation and the sulfo anion were screened by Na+ and Cl-, which required less thermal energy to break and resulted in a significant reduction in the UCST. The salt-enhanced solubility of the PSBMA-dominated copolymer PDMAEMA18-b-PSBMA27 contributed to the small increase in the LCST in spite of the “salting out” effect of the PDMAEMA block.


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0 mM 20 mM 40 mM 80 mM

1000

Dh (nm)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Figure 6. Dual-thermoresponsive phase behaviors of PDMAEMA18-b-PSBMA27 in neutral aqueous solutions (1 g/L) with different NaCl concentrations (0 mM, 20 mM, 40 mM, 80 mM). Unrepeatable pH adjustment for dual-thermoresponsive aggregation. As demonstrated above, the dual-thermoresponsive aggregation behaviors of PDMAEMA-b-PSBMA are pH- and salt-responsive. However, they correlatively occurred during the pH-adjusted cycles. During the recycled pH adjustment by HCl/NaOH titration, the salt (NaCl) accumulation resulted in the competition between the pH-tunable and salt-tunable aggregation. As shown in Figure 7, the Dh distributions of the PDMAEMA18-b-PSBMA27 aggregates at 25 °C (below the UCST) and 65 °C (above the LCST) were tracked during the cycles of acidic and neutral conditions. In the original state with pH 7.5, aggregates of approximately 825 nm and 390 nm formed at 25 °C and 65 °C, respectively. After HCl was added to adjust the solution pH to 4.7, smaller aggregates (190 nm at 25 °C, 110 nm at 65 °C) and unimers (11 nm) indicated the disaggregation of the large aggregates at both temperatures, which is consistent with the aforementioned enlarged dissolution temperature range in acidic media (Figure 5A). After NaOH was added and the pH had recovered to 7.5, large aggregates formed again. ACS Paragon Plus Environment

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However, when the pH was changed from 4.7 to 7.5 during the second cycle, large aggregates were not recovered at 25 °C, indicating that the pH was incapable of tuning the thermoresponsive aggregation. It was the salt-enhanced solubility that dominated the aggregation mechanism. Nevertheless, the large aggregates at 65 °C indicated that the pH sensitivity of the LCST-type aggregation was not significantly affected by salt. Above all, the UCST-type aggregation could not be tuned repeatedly by pH stimuli adjusted by HCl/NaOH because of salt accumulation, but the pH stimulus maintained the capability to adjust the UCST-type aggregation after two cycles. This phenomenon can be well explained by the salt-induced UCST decrease and the slightly salt-influenced LCST (Figure 6). A

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Figure 7. Dh distributions of PDMAEMA18-b-PSBMA27 in aqueous solution (1 g/L) at (A) 25 °C and (B) 65 °C during the pH stimulus cycles adjusted using HCl/NaOH. CO2-switchable UCST and LCST. Another method for changing the pH is to purge the solution


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with an acidic gas such as CO2. The pH of the PDMAEMA18-b-PSBMA27 solution after 30 min of CO2 bubbling was 4.7. CO2 could react with the tertiary amine groups of PDMAEMA in water to form ammonium bicarbonate, rendering the PDMAEMA chain stretched and soluble. The enhancement of hydrophilicity of the PDMAEMA block after CO2 bubbling broadened the temperature range of the dissolution of PDMAEMA-b-PSBMA. The LCST value shifted to 71 °C from 59 °C, and the UCST-type aggregation was observed at a slightly lower temperature with smaller aggregates. The influence of CO2 gas bubbling on the UCST and LCST was consistent with that of HCl in Figure 5A.

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Figure 8. The thermoresponsive behaviors of PDMAEMA18-b-PSBMA27 in aqueous solution (1g/L) before (initial, pH 7.5) and after CO2 bubbling (CO2, pH 4.7) for 30 min. Recycled CO2/N2 adjustment to thermoresponsive aggregation. Although the solution pH can be easily tuned by HCl/NaOH between acidic and neutral condition, the repeated adding of acid and base could result in salt accumulation. However, pH could be changed between 4.5 and 7.5 by repeat CO2/N2 bubbling without salt accumulation. The size distributions of aggregates formed at 25 °C and 65 °C during the CO2/N2 cycles were illustrated in Figure 9. At the original state, aggregates ACS Paragon Plus Environment

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approximately 700 nm and 250 nm were observed at 25 °C (below the UCST) and 65 °C (above the LCST), respectively. After CO2 bubbling, smaller aggregates (200 nm) and unimers (11 nm) were observed at 25 °C, indicating the dissolution of the large aggregates due to the CO2-enhanced hydrophilicity of PDMAEMA-b-PSBMA. Correspondingly, aggregates were absolutely dissolved to be unimers of 10 nm at 65 °C, which is in good agreement with the increased LCST after CO2 bubbling in Figure 8. Interestingly, the aggregation state below UCST and above LCST can be recovered after N2 bubbling in two CO2/N2 cycles, which is different from that in HCl/NaOH cycles. Thus, CO2/N2 could be used as a repeatable stimulus to tune the double thermoresponsive phase behaviors in this system. 25oC

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Figure 9. Size distributions of PDMAEMA18-b-PSBMA27 in aqueous solution (1 g/L) at 25 °C (A) and 65 °C (B) during the CO2/N2 cycles.


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Different recyclability of the polymer as an emulsifier during CO2/N2 bubbling and HCl/NaOH titration cycles. The amphiphilic polymer could stabilize toluene-in-water emulsions, in which the size of the toluene droplets was 2~4 µm (Figure 10). The emulsion was supposed to be sensitive to pH, CO2 and salt at specific temperatures. A difference in recyclability between the CO2/N2 bubbling and HCl/NaOH titration also existed. As Figure 10 shows, CO2 bubbling and HCl titration both triggered demulsification because the PDMAEMA segments became hydrophilic in acidic conditions and the polymer was driven into the water from the interface. N2 bubbling could recover the solution properties, and the emulsion formed again after application of sonication, even after three cycles. In contrast, the repeated addition of HCl and NaOH induced an increase in ionic strength, and the polymer could not emulsify the two phases after three cycles. The electrostatic repulsions that stabilized and dispersed the colloidal particles in solution were shielded by ions, inducing ineffective emulsification.

Figure 10. CO2-triggered demulsification and N2-recovered emulsification cycles after CO2/N2 bubbling for 20 min (A) and HCl-triggered demulsification and NaOH- unrecoverable emulsification cycles (B). The toluene-in-water emulsion (2 mL of toluene and 2 mL of the aqueous PDMAEMA33-b-PSBMA36 solution (1 g/L) ) was formed at room temperature. The scale bar of the ACS Paragon Plus Environment

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optical microscopy images of toluene droplets in water corresponds to 20 µm. CONCLUSIONS A series of poly[2-(dimethylamino)ethyl methacrylate]-block-poly(sulfobetaine methacrylate) (PDMAEMA-b-PSBMA) polymers with various block ratios were synthesized via an ATRP technique. The block copolymers in aqueous solutions exhibited schizophrenic aggregation behavior with double thermoresponsiveness due to the combination of the PSBMA block with an upper critical solution temperature (UCST) and the PDMAEMA block with a lower critical solution temperature (LCST). At temperatures below the UCST and above the LCST, micelles with a PSBMA-core surrounded by a PDMAEMA corona and micelles with a PDMAEMA-core surrounded by a PSBMA-corona were obtained. Additionally, because PDMAEMA is pH- and CO2-responsive and PSBMA is salt-responsive, the PDMAEMA-b-PSBMA copolymer in aqueous solution exhibited composition-dependent, pH-tunable, CO2-switchable and salt-tunable dual-thermoresponsive phase transitions. Specifically, with the increasing molar content of PDMAEMA, both the UCST and LCST shifted to lower values. The LCST decreased with increasing pH due to the deprotonated PDMAEMA. The UCST shifted to a lower value after adding HCl or NaOH, which is ascribed to the enhanced electrostatic interactions or hydrophobicity of the PDMAEMA block. Thus, the copolymers with larger PDMAEMA content showed a more significant fluctuation with pH than those with smaller PDMAEMA content. Additionally, the PSBMA-dominated copolymer showed a sharp decrease in the UCST and a small increase in the LCST with the increasing salt concentrations, where the former was attributed to the screening of electrostatic interactions, and the latter was attributed to the salt-enhanced solubility of the PDMAEMA-b-PSBMA. By adjusting the solution pH by adding HCl/NaOH and by CO2/N2 bubbling, we found that the temperature range of dissolution was widened after adding HCl ACS Paragon Plus Environment

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droplets as well as CO2 bubbling. Surprisingly, alternative purging with CO2/N2 enhanced/reduced the solubility of PDMAEMA-b-PSBMA and widened/narrowed the temperature range of dissolution repeatedly but repeated addition of acid and base resulted in salt accumulation that prevented the pH from adjusting the thermoresponsive aggregation of the polymer. Additionally, the different recycling behavior of the polymer as an emulsifier during CO2/N2 bubbling and HCl/NaOH titration cycles was also observed. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (Nos. 21376073, 91534103), the 111 Project of the Ministry of Education of China (No. B08021) and the Fundamental Research Funds for the Central Universities of China.

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Scheme 1. Synthetic route of PDMAEMA-b-PSBMA from ATRP. 378x96mm (120 x 120 DPI)


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Figure 1. Temperature dependence of the apparent hydrodynamic diameter (Dh) (A) and transmittance (B) of the polymer in aqueous solutions (1 g/L) at pH 9.0. The insets (B) are optical photographs of PDMAEMA33b-PSBMA36 in aqueous solution (1 g/L) at different temperatures. 303x105mm (120 x 120 DPI)


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Figure 2. ζ-potentials of PDMAEMA-b-PSBMA at different pH values; the solution concentration was 1.0 g/L. 150x105mm (120 x 120 DPI)


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Figure 3. Composition dependence of the IEPs and the phase transition temperatures. 150x105mm (120 x 120 DPI)


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Figure 4. Temperature dependence of the apparent hydrodynamic diameter (Dh) (A) and transmittance (B) at pH 9.0 for 18-27 and 50-70 in aqueous solutions (1 g/L). 311x109mm (120 x 120 DPI)


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Figure 5. Thermoresponsive behavior of (A) PDMAEMA18-b-PSBMA27 and (B) PDMAEMA33-b-PSBMA36 at 1 g/L and different pH values. (C) pH dependence of the critical transition temperatures of PDMAEMA18-b-PSBMA27 and PDMAEMA33-b-PSBMA36. 408x97mm (120 x 120 DPI)


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Figure 6. Dual-thermoresponsive phase behaviors of PDMAEMA18-b-PSBMA27 in neutral aqueous solutions (1 g/L) with different NaCl concentrations (0 mM, 20 mM, 40 mM, 80 mM). 150x105mm (120 x 120 DPI)


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Figure 7. Dh distributions of PDMAEMA18-b-PSBMA27 in aqueous solution (1 g/L) at (A) 25 °C and (B) 65 °C during the pH stimulus cycles adjusted using HCl/NaOH. 202x151mm (120 x 120 DPI)


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Figure 8. The thermoresponsive behaviors of PDMAEMA18-b-PSBMA27 in aqueous solution (1g/L) before (initial, pH 7.5) and after CO2 bubbling (CO2, pH 4.7) for 30 min. 150x105mm (120 x 120 DPI)


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Figure 9. Size distributions of PDMAEMA18-b-PSBMA27 in aqueous solution (1 g/L) at 25 °C (A) and 65 °C (B) during the CO2/N2 cycles. 200x152mm (120 x 120 DPI)


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Figure 10. CO2-triggered demulsification and N2-recovered emulsification cycles after CO2/N2 bubbling for 20 min (A) and HCl-triggered demulsification and NaOH- unrecoverable emulsification cycles (B). The toluenein-water emulsion (2 mL of toluene and 2 mL of the aqueous PDMAEMA33-b-PSBMA36 solution (1 g/L) ) was formed at room temperature. The scale bar of the optical microscopy images of toluene droplets in water corresponds to 20 µm. 309x100mm (150 x 150 DPI)


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Dual Thermoresponsive Aggregation of Schizophrenic PDMAEMA-b

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