Self-Sorting of Amphiphilic Copolymers for Self-Assembly Materials in

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Self-Sorting of Amphiphilic Copolymers for SelfAssembly Materials in Water: Polymer Can Recognize Itself Shota Imai, Mikihito Takenaka, Mitsuo Sawamoto, and Takaya Terashima J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b11364 • Publication Date (Web): 03 Dec 2018 Downloaded from http://pubs.acs.org on December 3, 2018

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Journal of the American Chemical Society

Self-Sorting of Amphiphilic Copolymers for Self-Assembly Materials in Water: Polymer Can Recognize Itself Shota Imai,1 Mikihito Takenaka,2,3 Mitsuo Sawamoto,1,4 Takaya Terashima1* 1

Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan 3 RIKEN SPring-8 Center, Sayo-cho, Sayo-gun, Hyogo 679-5148, Japan 4 Institute of Science and Technology Research, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan 2

ABSTRACT: Amphiphilic random copolymers bearing hydrophilic poly(ethylene glycol) (PEG) and hydrophobic alkyl pendants showed dynamic self-sorting behavior, i.e., self-recognition, under competitive conditions in aqueous media. The self-sorting universally takes place not only in water but also in hydrogels and on the material surfaces, according to encoded information originating from the primary structure of composition and pendants. Binary blends of the copolymers with different composition and/or alkyl pendants readily induced composition and/or alkyl pendant-dependent self-sorting to simultaneously provide discrete and size-controlled micelles with hydrophobic cores. Surprisingly, the micelles reversibly keep exchanging polymer chains exclusively between identical polymer micelles even in the presence of different counterparts. Owing to the dynamic self-sorting behavior, ABA-triblock copolymers comprising the amphiphilic random copolymer A segments and a hydrophilic PEG chain B segment further provided hydrogels with self-healing yet selectively adhesive properties.

Introduction Self-sorting, self-recognition or -discrimination, is a key process to orthogonally construct self-assembly objects in living systems.1-9 Biomacromolecules have precise and inherent structures as encoded information to successfully find specific targets via dynamic recognition processes in complex aqueous media. They can thus afford exact self-assembly (e.g., DNA, quaternary structure of proteins, virus capside) performing biological functions including signal transduction, enzymatic catalysis, and RNA transcription. To artificially create self-sorting systems, elaborate supramolecular compounds10-20 and proteins21,22 have been often designed; those molecules allow wellorganized self-assembly under complex media via site-specific physical interactions (e.g., hydrophobic, hydrogen-bonding, metal-ligand coordination) and/or selective recognition based on size, shape, steric factors, and chirality. However, synthetic polymers have been hardly applied to self-sorting systems for compartmentalized and/or functional materials.23,24 We have recently developed self-assembly systems of amphiphilic random copolymers carrying PEG and alkyl pendants (e.g., dodecyl, butyl) via intra- or inter-polymer association into small unimer or multi-chain micelles (~10 nm) in water.25-31 Uniquely, the copolymers below chain length critically suitable for self-folding always induce intermolecular self-assembly to form uniform and globular micelles. The size of the micelles in water is determined exclusively by composition (the ratio of PEG and alkyl pendants) and the alkyl pendant length, independent of chain length; the size increases with increasing the hydrophobicity of copolymers.25-29 Given the unique yet precise size controllability, we suggested that binary blends of their copolymers should induce self-sorting in water, dependent on

the composition and alkyl pendants, to result in discrete micelles with different components and size under competitive conditions. Herein, we report innovative dynamic self-sorting systems based on amphiphilic random copolymers bearing hydrophilic poly(ethylene glycol) (PEG) and hydrophobic alkyl pendants in aqueous media (Figure 1). The self-sorting universally occurs not only in water but also in hydrogels and on the material surfaces, according to the primary structure of composition and pendants as encoded information. Binary blends of the copolymers with different composition and/or alkyl pendants, after dissolution in water, readily induced composition and/or alkyl pendant-dependent self-sorting to simultaneously provide discrete yet size-controlled micelles with hydrophobic cores. Surprisingly, the micelles reversibly keep exchanging polymer chains exclusively between identical polymer micelles in the presence of different counterparts, as if the micelles selectively communicated through chain exchange with each other. Furthermore, the dynamic self-sorting behavior afforded the creation of selfhealing hydrogels with controlled viscoelasticity and macroscopic self-recognition properties. The reversible exchange of polymer chains on the gel surface resulted in adhesiveness selective to identical hydrogels without any affinity to different ones. Namely, the amphiphilic random copolymers can universally and dynamically recognize themselves in aqueous media. To our best knowledge, this is the first example of self-sorting systems based on common amphiphilic copolymers into versatile self-assembly materials.

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Journal of the American Chemical Society 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

a

Inter-Polymer Association

Cl

O O

O m O 8.5

O n

O p

O R

O Np or Py

-R: -C4H9 (B) -C12H25 (D)

Amphiphilic Random Copolymers

Np

Py

Self-Sorting

Selective

Dynamic

+

Nagg

H 2O Binary Polymer Blends

b

Mw,H2O Rh,H2O

Discrete Micelles

Contact

Contact A

Cl O

O m O 8.5

O

O n O R

on Surface l

No Exchange

No Adhesion

H 2O ABA-Triblock Copolymers

Self-Healing

Figure 1. Dynamic self-sorting of amphiphilic random copolymers in water. (a) The random copolymers dynamically self-recognize identical polymers even in binary polymer blends containing copolymers with different composition and/or alkyl pendants to form discrete micelles via selective interpolymer association. (b) Self-healing yet selectively adhesive hydrogels obtained from ABA-triblock copolymers comprising amphiphilic random copolymers as the A segment and a hydrophilic poly(ethylene glycol) chain as the B segment.

Table 1. Characterization of Random Copolymers and Their Micelles in Water

Result and Discussion Polymer Design To investigate self-sorting behavior, i.e., selective inter-polymer association and its dynamic nature, we employed fluorescence spectroscopy using naphthalene and pyrene probes.32,33 The two fluorophores afford fluorescence resonance energy transfer (FRET) in close proximity (Förster radius is 2.86 nm).33 We designed naphthalene (Np)- or pyrene (Py)-labeled amphiphilic random copolymers for micelles with different sizes and cores in water. Two types of hydrophobic monomers (RMA: n-butyl or n-dodecyl methacrylate) were utilized, while composition (RMA: 30, 40, 50, and 70 mol%) and chain length (degree of polymerization: DP = 50 - 100, Figure 1) were also tuned. Well-controlled random copolymers with narrow molecular weight distribution (Mw/Mn = 1.1 – 1.3) were synthesized by ruthenium-catalyzed living radical copolymerization of hydrophilic PEG methyl ether methacrylate (PEGMA: Mn = 475, 8.5 of average oxyethylene units), n-butyl (B) or n-dodecyl (D) methacrylates, and naphthalene or pyrene-bearing methacrylates with ethyl 2-chloro-2phenylacetate as a chloride initiator (Table 1, Supporting Information, Scheme S1, Figures S1 and S2). The degree of polymerization and composition (m/n/p) of the copolymers were determined by 1H nuclear magnetic resonance (NMR) spectroscopy. The polymer samples are encoded as Rx-Np or Py: R means alkyl pendant B (n-butyl) or D (n-dodecyl) and x does R content, while non-labeled copolymers were shown as Rx-U). Non-labeled copolymers (Rx-U) were also designed to investigate self-sorting properties by FRET and size exclusion chromatography (SEC).

Polymer

Mn a

Mw/Mna

(SEC) (SEC)

m/n/pb

Mw,DMFc

Mw,H2Oc

(MALLS) (MALLS)

Naggd

Rh,H2Oe (nm)

B50-Np 16,700 1.16

27/28/1.0 20,500

41,700

2.0 3.5

B50-Py

17,200 1.17

28/29/1.0 22,000

42,400

1.9 3.5

B50-U

17,600 1.18

29/30/-

38,100

1.7 3.5

22,400

B70-Np 22,300 1.20

31/73/1.1 28,700

235,000

8.2 6.2

B70-Py

20,400 1.22

29/69/1.0 27,700

244,000

8.8 6.4

B70-U

21,800 1.21

31/71/-

216,000

7.3 6.3

29,500

D30-Np 20,100 1.23

39/17/1.1 26,100

49,100

1.9 3.9

D40-Np 17,700 1.18

33/21/1.0 25,000

95,100

3.8 4.5

D50-Np 13,100 1.29

28/27/1.1 24,100

196,000

8.1 6.3

D50-Py

13,900 1.32

29/29/1.1 26,100

218,000

8.3 6.3

D50-U

15,200 1.21

32/31/-

227,000

7.8 6.4

29,200

a

Determined by SEC in DMF (10 mM LiBr) with PMMA standard calibration. b

The number (i.e., degree of polymerization) of PEG (m), alkyl (n), or Np or Py (p)-bearing methacrylates in the copolymers and Mn of the copolymers determined by 1H NMR. c

Absolute weight-average molecular weight (Mw) determined by SECMALLS in DMF (10 mM LiBr) or H2O. d

Aggregation number in H2O: Nagg = Mw, H2O (MALLS)/Mw, DMF (MALLS). Hydrodynamic radius determined by DLS in H2O at 25 oC: [polymer] = 10 mg/mL. e


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a

D50-Np

B70-Np

Nagg: 8

Nagg: 8

c

Compositionand PendantSelective

FRET

Number (mol)

FRET

D50-Py Nagg: 8

b

800

D30-Np

B50-Np

Nagg: 2

Nagg: 2

IPy

600

D50-Np D40-Np D30-Np B70-Np B50-Np

D30 D40 D50 0.1

0

1

500

550

20

40 60 80 DMA Content (mol%)

Composition

100

Pendant & Composition Composition Overlap

0.5

0 450 400 Wavelength (nm)

0

+ D50-Py

200

350

D50+D40: 47%

d

INp

Composition Overlap

D50+D30: 18%

PendantSelective

400

0 300

0.2

Relative IPy/INp

CompositionSelective

Emission Intensity (a.u.)

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


D30-Np D40-Np D50-Np B70-Np B50-Np Np-Copolymers with D50-Py

Figure 2. Self-sorting of amphiphilic random copolymers in water. (a) The binary blends of amphiphilic random copolymers (D50-Py + D50-, D30-, B70-, and B50-Np), after dissolved in water, readily induce self-recognition dependent on composition and/or pendant structures to form discrete or hybrid micelles. (b) Fluorescence spectra of the aqueous solutions of D50-Py and various Np-bearing copolymers [D50- (black), D40- (green), D30(blue), B70- (red), B50-Np (orange)] monitored from 300 to 550 nm with 290 nm excitation at 25 ºC. Concentration: [D50-Py] = 0.10 mg/mL + [D30-Np] = 0.10 mg/mL, [D40-Np] = 0.10 mg/mL, [D50-Np] = 0.080 mg/mL, [B50-Np] = 0.072 mg/mL, [B70-Np] = 0.10 mg/mL (naphthalene in [Rx-Np] = 5 x 10-6 mol/L). (c) Composition distribution of PEGMA/DMA random copolymers (D: 30, 40, and 50 mol%, DP = 50) calculated with binomial distribution. (d) Relative IPy/INp of the aqueous solutions of the binary copolymers against IPy/INp of the aqueous solution of D50-Np and D50-Py. Black symbols: the overlap of the calculated composition distribution.

All of the copolymers easily dissolved in water to form quite small and size-controlled micelles (Mw/Mn < 1.2 by SEC in water, size: ~10 nm). The absolute weight-average molecular weight (Mw), aggregation number (Nagg), and hydrodynamic radius (Rh) of the micelles were determined by size-exclusion chromatography coupled with multi-angle light scattering (SEC-MALLS) and dynamic light scattering in water (Table 1).25-29 In copolymers comprising dodecyl pendants (DP: ~50), Mw and Nagg increased with increasing D contents from 30 to 40 to 50 mol%: Mw (Nagg) = 49100 g/mol (1.9), 95100 g/mol (3.8), and 196000 g/mol (8.1). Rh in water also increased from 4 nm to 6 nm with increasing D contents. The copolymers with 70 mol% butyl units (DP: ~100) formed micelles with almost the same size and Nagg as those with 50 mol% dodecyl units (DP: ~60): Mw = ~220000, Nagg = ~8. To evaluate self-sorting behavior into discrete micelles under diluted conditions, critical micellization concentration (cmc) of all the copolymers was determined by fluorescence measurement using pyrene (Figure S4).27 All the copolymers had low cmc values: cmc = 1 – 2 x 10-3 mg/mL. In this paper, we examined all self-sorting experiments of the copolymers in water above the cmc.

Self-Sorting of Polymers in Water Self-sorting of two copolymers with different R content and/or R structures (D50 vs. D50, D40, D30, B50, B70) was examined by FRET in water at 25 oC (Figure 2). Fluorescence spectra of the aqueous solutions of the binary blends were recorded with 290 nm excitation; the ratio of IPy (emission intensity at 396 nm) and INp (emission intensity at 336 nm) was monitored. Here, we fixed D50-Py as a Py-labeled copolymer and changed Np-labeled copolymers (RxNp: D50, D40, D30, B50, B70-Np). The aqueous solutions of RxNp and D50-Py were prepared as follows: Each Np-labeled copolymer and D50-Py were mixed in dichloromethane, followed by the evaporation; resulting blends were dissolved in water. For comparison, INp of all Np-labeled copolymers was set at constant arbitrary unit (constant concentration of naphthalene: [naphthalene] = 5 ´ 10-6 mol/L); the mixing molar ratio of Np-polymer and Py-polymer was 1/1. The concentration of each polymer (~0.1 mg/mL) is much higher than cmc of the copolymers. The fluorescence spectra (obtained after 1 h from the sample preparation) and relative IPy/INp ratio are shown in Figure 2b and d, respectively. The aqueous solution of D50-Np and D50-Py (black line in Figure 2b) resulted in the decrease of naphthalene emission around 320 – 360 nm and the dramatic increase of pyrene emission around 380 – 450 nm. The spectral change by FRET indicates the co-micellization via the intermolecular assembly of the two



a

b D50-Py

B50-U

D50-Py

Mw,H2O 218,000 Nagg 8.3

B50-U

38,100 1.7

H 2O rt, 1 h

Evaporation

Blend

Blendaq

in CH2Cl2

106

c

d

D50-U

105 104 MW (PEO)

103

B50-Py

D50-U

Mw,H2O 227,000 Nagg 7.8

B50-Py

42,400 1.9

H 2O rt, 1 h

Evaporation

Blend

Blendaq

in CH2Cl2

106

105 104 MW (PEO)

103

Figure 3. Self-sorting of binary blend copolymers characterized by SEC coupled with RI (solid lines) and UV (blue or red dashed lines, l = 345 nm) detectors using PEO calibration in water at 25 ºC: (a) D50-Py alone (blue) and B50-U alone (black), (b) the binary blend of D50-Py and B50U, (c) D50-U alone (black) and B50-Py alone (blue), and (d) the binary blend of D50-U and B50-Py. Mw,H2O values were determined by a MALLS detector equipped with the SEC system (see Table 1). a

b

D50-Np SI15

1000 1000

I(q) / arb.unit I(q) / arb.unit

I(q) / arb.unit

100 100

1010 11

0.1 0.1

c

B70-Np SI14

1000 1000

100 100

I(q) / arb.unit

4

80 80

5

6

7 8 9

0.1 0.1

2

3

4

-1 -1 qq // nm nm

r = 5.9 nm

5

6

7 8 9

11

d D50-Np

r=5.9nm

10 10

11

0.1 0.1

2

4

40 40

60 60

P(r)x10

40 40

20 20

00 0 0

5

6

7 8 9

0.1 0.1

2

3

4

-1 -1 q /q nm / nm

50 50

SI15

9 P(r) x 10 9

Given that, relative IPy/INp values of different composition pairs (D30-Np + D50-Py, D40-Np + D50-Py) were calculated against the IPy/INp,50 value of an identical composition pair (D50-Np and D50Py): 100 x [IPy/INp]/[IPy/INp,50]. Surprisingly, the relative IPy/INp values were almost consistent with the overlap of composition distribution of their copolymers (Figure 2d, e.g., in D40-Np + D50-Py: relative IPy/INp = 47%, composition overlap: 47%). Additionally, we changed the blend ratio of D50-Py and Dx-Np (mol/mol) from 1/1 to 1/4 or 1/9 in FRET experiments to increase the overlap area of composition distribution of copolymers (Figure S5). IPy/INp for the blend of D30 and D50 clearly increased with increasing the overlap of the composition distribution. This finding importantly suggests that each polymer chain can self-recognize polymer chains with identical composition in the presence of multiple different polymers. Additionally, binary polymer blends with different alkyl pendants R (B50-Np + D50-Py or B70-Np + D50-Py) also exhibited quite small relative IPy/INp (Figure 2d), indicative of pendant and/or composition-selective self-sorting into not only different-size micelles (for B50% + D50%) but also same-size micelles (for B70% + D50%). We further investigated effects of sample preparation time and temperature on self-sorting of binary copolymer blends in water to reveal the following facts (Figure S6): (1) Self-sorting of those copolymers immediately took place at least in one hour after dissolving polymer blends in water. (2) Self-sorting is virtually independent of temperature between 25 and 40 oC. Furthermore, micelles of D50Py and B70-Np formed their inherent and discrete structures even after the treatment of the micelle mixture at 70 oC above the cloud point temperature. Self-sorting behavior of the micelles can be also confirmed by SEC measurement of Py-labeled copolymers and non-labeled

counterparts, coupled with RI (solid lines) and UV (blue or red dashed lines, l = 345 nm) detectors in H2O (Figures 3 and S7). Typically, the binary blend of D50-Py and B50-U showed a bimodal SEC curve by the RI detector whose peak tops were consistent with those

P(r)x10

copolymers; the polymer chains came closer enough to induce energy transfer within the micelles. In contrast, pyrene emission gradually decreased with decreasing D content of Np-labeled copolymers; the mixture of D30-Np and D50-Py showed little pyrene emission. This importantly suggests that, owing to large difference of composition (~20%), D30 and D50 copolymers hardly co-assembled, i.e., self-recognized via the dissolving process in water, to form discrete micelles comprising respective polymers. To understand the composition-dependent self-sorting behavior, we evaluated composition distribution of the random copolymers.34 The copolymers have statistical distribution of PEGMA and dodecyl methacrylate, so that D40 or D30 random copolymers inevitably have overlap of composition distribution with D50 counterparts. PEGMA and DMA were simultaneously consumed during living radical random copolymerization, independent of the feed ratio of the monomers (Figures S1 and S2). This indicates that the monomer reactivity ratios of PEGMA and DMA (r1, r2) are equal to 1. Thus, composition distribution of PEGMA/DMA random copolymers (D: 30, 40, and 50 mol%, DP = 50) was calculated with binomial distribution [nCk pk (1 – p)n-k] as r1 =1 and r2 = 1, where n and p are degree of polymerization and composition, respectively.34 Figure 2c shows binomial distributions for PEGMA/DMA copolymers with 50 monomer units; n is 50. Blue, green, and black histograms correspond to “average” D30 (PEGMA/DMA = 35/15), D40 (30/20), and D50 (25/25) copolymers, respectively. For example, black histograms indicate that the D50 copolymer includes only 11% of exactly 25/25 copolymer among all copolymer chains. Additionally, overlapping area between blue and black histograms (D30 and D50) is 18%, thus 18% of D50 and D30 should be potentially identical and hybridized to form co-micelles in water.

9 P(r) x 10 9

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

11

2

B70-Np

rr=5.5nm = 5.5 nm

SI14

30 30

20 20

10 10

5

5

10

15

10 15 nm r r// nm

20

20

25

25

00 0 0

5

5

10

15

10 15 nm r r/ /nm

20

20

25

25

Figure 4. SAXS profiles of (a) D50-Np or (b) B70-Np micelles in water at 25 o C ([polymer] = 1 mg/mL) and pair-distance distribution functions [P(r)] of the (c) D50-Np or (d) B70-Np micelles.


Page 5 of 10 a

D50-Npaq

D50-Py + B70-Uaq

B70-Npaq

FRET

No Exchange

between D50-Py & D50-Np

between D50-Py & B70-Np

c 10 h 5h 3h 2h 1h 30 min

600 400

d 800

Time

200

B70-Npaq

600 400

Time

6

10 h 5h 3h 2h 1h 30 min

Addition of D50-Npaq Addition of B70-Npaq

4

®® ®® ®® ®® ® ®®

IPy/INp

D50-Npaq



800

2

200

®

0 300

No FRET

Selective Chain Exchange

b


0 300

500

e

D50-Npaq

350

450 400 Wavelength (nm)

D50-U + B70-Pyaq

®

®

®

®

®

®®

®

®® ® ® ® ® ® ® ® ® ® ® ® ® ® ® ® ® ® ® ® 0 ® 0 6 8 10 2 4 Time, h

500

B70-Npaq FRET

No Exchange

Selective Chain Exchange

between B70-Py & D50-Np

between B70-Py & B70-Np

g

f D50-Npaq

10 h 90 min 40 min 20 min 10 min 5 min

600 400 200 0 300

350

450 400 Wavelength (nm)

h 800

Time

500


800

B70-Npaq

10 h 90 min 40 min 20 min 10 min 5 min

600 400 200 0 300


500

Addition of B70-Npaq Addition of D50-Npaq

6

Time

®

4

®

®

® ®®®®®®® ®®®® ® ®®

® ® ® ®

IPy/INp

No FRET


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


2

® ® ® ®®®®®®®®®®®®®®®®®®®® 0 ®

0

2

6 4 Time, h

8

10

Figure 5. (a) Selective chain exchange of D50 micelles in the presence of B70 micelles. (b, c) Fluorescence spectra and (d) IPy/INp of the aqueous solutions of D50-Py and B70-U ([D50-Py] = [B70-U] = 0.20 mg/mL, 1 mL) after adding the aqueous solution of (b) D50-Np or (c) B70-Np (0.20 mg/mL, 1 mL) at 25 ºC (excitation: 290 nm). (e) Selective chain exchange of B70 micelles in the presence of D50 micelles. (f, g) Fluorescence spectra and (h) IPy/INp of the aqueous solutions of D50-U and B70-Py ([D50-U] = [B70-Py] = 0.20 mg/mL, 1 mL) after adding the aqueous solution of (f) D50-Np or (g) B70-Np (0.20 mg/mL, 1 mL) at 25 ºC (excitation: 290 nm).

of respective polymers (Figure 3a,b). In contrast, the polymer blend just exhibited a unimodal SEC curve by the UV detector (red dash line) whose peak corresponded to that of Py-labeled D50-Py alone (blue dash line). This result indicates that these copolymers efficiently induce self-sorting in water even under diluted and flow conditions of SEC. Additionally, the apparent molecular weight of the polymer micelles determined by the RI detector with poly(ethylene oxide) (PEO) calibration is much smaller than the absolute weightaverage molecular weight by MALLS (e.g., D50-Py: SEC peak MW = ~20,000; Mw,H2O by MALLS = 218,000). This importantly means that the polymer micelles have much more compact structure than linear PEO used as a calibration standard.26-29 In self-sorting process, polymer chains initially self-folds in water, followed by inter-chain assembly, to form multichain micelles without hybridization of distinct polymers. Folded polymer chains tend to form stable and inherent conformation, dependent on composition and alkyl pendants. Therefore, both the gain of entropy of water molecules (due to collapse of hydration around hydrophobic segments into free water) and the decrease of enthalpy (due to avoiding

non-matching association of distinct polymers) would effectively compensate for the loss of mixing entropy of polymers. B70 or D50 copolymer micelles had almost the same size and Nagg but effectively induced self-sorting in water. To understand the origin of the self-soring behavior, the structure of the two micelles was analyzed by SAXS in water (Figure 4). Both of the micelles formed globular structure in water, while the detail was distinct. The SAXS profile of the dodecyl-bearing D50-Np had a minimum and a maximum at ca 0.9 nm-1 and 1.2 nm-1, respectively, whereas that of butyl-bearing B70-Np did not show such peaks. D50-Np micelle has a hydrophobic core comprising the dodecyl pendants with low electron density.26,35,36 In contrast, B70-Np micelle has a relatively loose hydrophobic core; the butyl pendants are more loosely assembled within folded polymer chains than the dodecyl pendants. Thus, owing to the difference of the micelle structures, the two micelles are non-matching during inter-chain self-assembly process, resulting in self-sorting into discrete micelles.22


Journal of the American Chemical Society Dynamic Self-Recognition via Selective Chain Exchange Efficient self-sorting of amphiphilic copolymers involves dynamic, reversible, but selective chain exchange process between self-assembled micelles. We first evaluated chain exchange properties of D50 or B70 copolymer micelles in water by FRET experiments (Figure S8). Here, IPy/INp was monitored upon mixing of the aqueous solution of Py-labeled copolymers and that of Np-labeled copolymers at various temperatures (5 - 40 ºC). The FRET experiments revealed that D50 or B70 copolymer micelles (Mw,H2O ~ 220K, Rh ~ 6 nm, Nagg ~ 8) were “not kinetically frozen” to effectively induce polymer chain exchange above 25 oC. Chain exchange between their micelles was promoted upon heating to 40 oC, while both micelles hardly induced chain exchange at 5 oC to be almost kinetically frozen. Additionally, chain exchange for B70 micelles was much faster than that for D50 micelles at over 25 oC. Given these results, we further investigated selective exchange of polymer chains between identical polymer micelles in the presence of different micelles (Figure 5). Here, the aqueous solutions of D50Np or B70-Np were added into the aqueous mixture of D50-Py and non-labeled B70-U at 25 ºC, followed by fluorescence measurement. The addition of D50-Np gradually increased pyrene emission via FRET as a function of time, whereas that of B70-Np did not change original weak pyrene emission at all (Figure 5a-d). This importantly indicates chain exchange exclusive among D50 copolymer micelles without chain exchange between D50 micelles and B70 ones. Such dynamic but selective chain exchange was also observed in B70 copolymer micelles. This was confirmed by the addition of the aqueous solutions of D50-Np or B70-Np into the aqueous mixture of nonlabeled D50-U and B70-Py (Figure 5e-h). B70-Np micelles induced chain exchange exclusively with B70-Py micelles to increase the emission of the Py, while D50-Np micelles did chain exchange with D50-U not to increase the emission around 400 nm. Even under a D50-Py + B70-Np THF solution

FRET

b

No FRET Dynamic Self-Correcting

Kinetically Frozen

H 2O (5 ºC)

5 ºC

Thermodynamically Stable

25 ºC

1 5 ºC

Relative IPy/INp

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

25 ºC

0.5 ¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿ ¿ 1 week 1 week 1 h ¿ ¿ ¿¿¿ ¿¿¿¿¿¿¿¿¿¿¿¿¿¿ ¿ ¿ ¿

25 ºC 0

0

2

4

5 ºC

40 ºC

6 Time, h

Figure 6. (a) Self-correction of hybrid micelles comprising different copolymers into discrete micelles upon heating from 5 oC to 25 oC. (b) Time-dependent IPy/INp of the aqueous solution of D50-Py and B70-Np obtained by adding the THF solution of D50-Py and B70-Np into ice water: Effects of temperature and time on the self-correcting and self-sorting behavior.

Page 6 of 10

such competitive conditions, the chain exchange of B70 copolymers was much faster than that of D50 copolymers. In the self-sorting systems developed herein, two copolymers should be partially hybridized at an initial state immediately after adding water into polymer blends. Thus, the polymer chains dynamically and reversibly interchange among the hybridized micelles to eventually form separate counterparts. To elucidate the self-sorting mechanism, we examined temperature-dependent chain exchange of D50 and B70 copolymers (Figure 6). Because the copolymer micelles do not induce chain exchange at 5 ºC (Figure S8), we prepared the aqueous solution of D50-Py and B70-Np by adding the THF stock solution of the polymer blend (kept at 5 ºC) into ice-water. Interestingly, the solution at 5ºC showed larger pyrene emission (higher IPy/INp) by FRET than that at 25 ºC and maintained the intensity at 5 oC for 3 h. However, upon heating to 25 ºC, the pyrene emission immediately decreased. Thus, kinetically trapped, thermodynamically metastable, and hybridized micelles (Rh = ~6 nm by DLS, Figure S9) were initially formed at 5 ºC and began self-correcting into discrete micelles beyond energy barrier upon heating to 25 o C. The final self-sorting state was maintained for long time (over two weeks at least), independent of temperature (5-40 oC). The chain exchange process between self-sorted random copolymer micelles potentially involves (1) dissociation and insertion of polymer chains as unimer and/or (2) fusion and fission of micelles.37-39 The detailed mechanism of the selective chain exchange is now under investigation. Self-Sorting within Hydrogels Dynamic self-sorting of amphiphilic copolymers is further applicable to the design of self-sorting and self-healing hydrogels with selective gel recognition properties.40 For this, we synthesized two kinds of ABA-triblock copolymers comprising B70 or D50 random copolymers as A and a long hydrophilic poly(ethylene glycol) chain (Mn = 28,200 by SEC in DMF, oxyethylene unit: l = 641) as B via Rucatalyzed living radical polymerization with a bifunctional PEG macroinitiator (Scheme S1, Figure S3, Table S1): B70-PEG-B70 (Mw = 74,300 by SEC-MALLS in DMF, A-segment: PEGMA/BMA = 25/58) or D50-PEG-D50 (Mw = 76,000 by SEC-MALLS in DMF, A-segment: PEGMA/DMA = 26/25). The hydrogels were prepared with the triblock copolymers as follows: The dichloromethane solution of B70-PEG-B70 or D50-PEGD50 was added into a vial, and the solvent was evaporated under vacuum overnight at 25 ºC. Distilled water was added into the vial (polymer concentration: 1 - 10 wt%); the mixture was kept or stirred at 25 ºC for 1 day, kept at 40 ºC for 1 - 2 days, then stored at 25 ºC. The triblock copolymers afforded transparent, elastic, and self-standing hydrogels above 3 wt% concentration in water (Figures 7 and S10). Here, the A segments self-assemble to construct quite small and dynamic micelles (~10 nm) as physical crosslinking points for network structures. Thus, the resulting hydrogels turn to be transparent and the physical properties depend on the structure and dynamic nature of the A segments. Confirmed by rheology measurement, the storage moduli (G’) of B70-based gels were larger than the loss moduli (G’’) above 3 wt% concentration (Figure S10); G’ and G’’ increased with increasing the polymer concentration from 3 to 10 wt%. More importantly, the A segments further demonstrated self-sorting even within hydrogels. The binary blend of B70-PEG-B70 and a B70-U random copolymer in water (4 wt%/4.6 wt%) provided a hydrogel much softer than B70-PEG-B70 alone (4 wt%, Figure 7a,b):


Page 7 of 10


a

e

Cl O

O 25 O

O

Chain Exchange between Micelles

O 58 O

8.5

3

Dynamic Physical Crosslinking

l

H 2O

B70-PEG-B70 Triblock

f

Contact Cut

b + B70-PEG-B70 Triblock

B70 Random

Contact

1 day

H 2O

on Surface

Cl O

O 26 O

O 25 O

8.5

D50-PEG-D50

c

11

Self-Healing

+ B70-PEG-B70 Triblock

d

D50 Random

g Cut

2h

¿

¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿

¿ ¯ ¿¯ ¯¯¯ ¯¯ ¯¯¯¯ ¯¯ ¯ ¯¯¯ ¯¯ ¯¯ ¯¯¯ ¯¯ ¯¯ ¯¯ ¯¯ ¯¯ ¯¯ ¯¯ ¯¯ ¯¯¯¯ ¯

10-1

100 101 Angular Frequency (rad/s)

on Surface

Cl

G’ G’’

O

B70-PEG-B70

101

Contact

Self-Sorting ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿

102

Contact

H 2O

103

Modulus (Pa)

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

O 25 O 8.5

B70-PEG-B70

O 58 O 3

Self-Healing

B70-PEG-B70 + D50 B70-PEG-B70 + B70

h

Contact Contact

B70-PEG-B70 D50-PEG-D50 Gel Gel

102

2 days

No Adhesion

No Exchange

Figure 7. Self-sorting and self-healing hydrogels via the self-assembly of ABA triblock copolymers comprising D50 or B70 random copolymer A segments and a poly(ethylene glycol) B segment in water. A hydrogel of (a) B70-PEG-B70 alone (4 wt%) and binary hydrogels of (b) B70-PEG-B70 and B70 (4 wt%/4.6 wt%) or (c) B70-PEG-B70 and D50 (4 wt%/4.6 wt%). (d) Frequency dependent oscillatory rheology measurement at a strain of 1% for the B70-PEG-B70 gel (black) and the binary hydrogels of B70-PEG-B70 and B70 (blue) or B70-PEG-B70 and D50 (orange) at 25 ºC. Filled or open symbols indicate storage (G’) or loss (G’’) modulus, respectively. Self-healing properties of (f) a D50-PEG-D50 gel (10 wt%) and (g) a B70-PEGB70 (10 wt%) via (e) the dynamic exchange of the random copolymer segments between the self-assembly micelles as physical crosslinking units. (h) No adhesion properties between a D50-PEG-D50 gel and a B70-PEG-B70 gel.

The binary hydrogel flowed in 40 minutes after tilting the vial, because the average aggregation number of B70-PEG-B70 chains in physical crosslinking points decreased from 8 to 3. In contrast, the binary blend of B70-PEG-B70 and a dodecyl-bearing random copolymer (D50, Mn,NMR = 31,300) in water (4 wt%/4.6 wt%) gave a hydrogel with almost the same rheological properties as that of B70PEG-B70 alone (4 wt%, Figure 7a,c): The binary hydrogel did not flow in 1 day after tilting the vial. This is because B70-PEG-B70 and D50 efficiently self-sorted to form crosslinking networks and independent micelles, respectively, within the hydrogel. The physical properties of the self-sorting hydrogels were also confirmed by rheology measurement (Figures 7d and S11): the binary hydrogel of B70-PEG-B70 and B70-U exhibited storage modulus (G’) lower than that of B70-PEG-B70 alone, whereas the binary hydrogel of B70-PEG-B70 and D50 had almost the same G’ as that of B70-PEGB70 alone. The binary hydrogel of B70-PEG-B70 and B70-U further exhibited shear-thinning properties (Figure S11). Self-Healing Hydrogels with Selective Adhesiveness Focusing on selective chain exchange properties of amphiphilic random copolymer micelles, we examined self-healing and selectively adhesive properties of hydrogels (Figure 7e). For this, 10 wt% gels of D50-PEG-D50 (stained with Rhodamine B for clarity) or

B70-PEG-B70 were cut into three pieces (centimeter scale) and again contacted at 25 ºC (Figure 7f,g). Both the cut D50-PEG-D50 gels and the cut B70-PEG-B70 gels tightly adhered and self-healed at least in 1 day and in 2 hours, respectively, owing to chain exchange of the A segments between micelles as physical crosslinking points on the gel surfaces. The faster self-healing for the B70 gel is due to faster chain exchange of B70 segments than D50 ones, as similarly observed in micelles (Figure S8). Additionally, D50-PEG-D50 gels never adhered with B70-PEG-B70 ones even after 2 days (Figure 7h), importantly indicating that those gels can macroscopically selfrecognize and self-sort each other. Conclusion In conclusion, it was revealed that amphiphilic random copolymers can find target polymers comprising identical composition and pendant structures via dynamic and reversible chain association and exchange process universally in water, within hydrogels, and on the gel surfaces. Namely, the amphiphilic copolymers can recognize themselves in aqueous media. The dynamic self-sorting systems, as artificial models, reproduce the orthogonal and hierarchical formation of self-assembly objects from nano to macroscopic level under complex media in living organisms (e.g., proteins, viruses, cells, tissue, organs). The discovery of self-sorting polymers surly not only



achieves breakthrough in polymer, material, and bio-science but also provides innovative technologies to tailor-make dynamic, reversible, functional materials applicable to various research fields.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental details, characterization by SEC-MALLS, DLS, FRET experiments, and rheology measurement (PDF)

AUTHOR INFORMATION Corresponding Author * [email protected]

Notes The authors declare no competing financial interest

ACKNOWLEDGMENT This work was supported by Japan Society for the Promotion of Science KAKENHI Grant (JP17H03066 and JP17K19159), by Sekisui Chemical through “Innovations Inspired by Nature" Research Support Program, by The Mazda Foundation, by The Sumitomo Electric Group Social Contribution Foundation, by The Ogasawara Foundation for the Promotion of Science & Engineering, and by The Noguchi Institute. The SAXS measurement was performed at BL45XU in SPring-8 with the approval of RIKEN (Proposal No. 20160005, and 20170020).

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Self-Sorting of Amphiphilic Copolymers for Self-Assembly Materials in Water: Polymer Can Recognize Itself ABA-Triblock Copolymers

Amphiphilic Random Copolymers

H 2O

Self-Sorting Dynamic

Selective

on Surface

Self-Healing

H 2O Binary Polymer Blends

Discrete Micelles


Hydrogels

10

Self-Sorting of Amphiphilic Copolymers for Self-Assembly Materials in

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