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NIR Light- and pH-Responsive Graphene Oxide Hybrid Cyclodextrin-Based Supramolecular Hydrogels panjun Wang, Chao Huang, Youmei Xing, Weihua Fang, Jie Ren, Haifeng Yu, and Guojie Wang Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b03689 • Publication Date (Web): 09 Jan 2019 Downloaded from http://pubs.acs.org on January 10, 2019

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NIR Light- and pH-Responsive Graphene Oxide Hybrid Cyclodextrin-Based Supramolecular Hydrogels Panjun Wang,† Chao Huang,† Youmei Xing,‡ Weihua Fang, ‡ Jie Ren,† Haifeng Yu,*,§ Guojie Wang*,† †

School of Materials Science and Engineering, University of Science and Technology Beijing,

Beijing 100083, China E-mail: [email protected] ‡

Hangzhou Greenda Electronic Materials Co., Ltd., Hangzhou 310051, China

§

Department of Materials Science and Engineering, College of Engineering and Key Laboratory

of Polymer Chemistry and Physics of Ministry of Education, Peking University, Beijing, 100871, China E-mail: [email protected] KEYWORDS: controlled release, cyclodextrin, graphene oxide, hydrogel, self-assembly

ACS Paragon Plus Environment

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ABSTRACT: Here a novel triple-responsive graphene oxide hybrid supramolecular hydrogel based on the electrostatic self-assembly between graphene oxide and a quaternized polymer and the host-guest inclusion between α-cyclodextrins and polyethylene glycol monomethylether (mPEG) was constructed. The quaternized polymer was synthesized by quaternization between pH sensitive poly(N,N-dimethylaminoethyl methacrylate) and bromine end-capped polyethylene glycol monomethylether. The supramolecular hydrogels prepared from the host-guest inclusion of polyethylene glycol monomethylether and α-cyclodextrins would turn into a mobile sol phase when the temperature increased above a certain temperature (Tgel-sol). Graphene oxide sheets not only acted as a core material to provide additional cross-linking, but also absorbed NIR light and converted NIR light into heat to trigger the gel-sol transition. The constructed graphene oxide hybrid cyclodextrin-based supramolecular hydrogels could respond to NIR light, temperature and pH, which could be beneficial for controlled release of cargoes and would hold great promise in the field of delivery systems.


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INTRODUCTION Supramolecular hydrogels formed from dynamic, intermolecular non-covalent interactions (e.g., ionic and dipolar interactions, electrostatic interaction, hydrogen bonds, van der Waals and π-π stacking) among molecular entities hold great promise in the field of delivery systems.1-3 αCyclodextrin (α-CD) is one of cyclic oligosaccharides, which consists of six glucopyranose units linked by α-1,4 glucosidic bonds and presents a truncated cone shape with a hydrophilic exterior consisted of hydroxyl groups and a hydrophobic interior that can accommodate non-polar compounds.4-5 Supramolecular hydrogels can be formed from α-CDs and PEG-based polymers, in which the PEG chains thread into the cavities of α-CDs to form pseudopolyrotaxanes (PPRs) via the well-known host-guest inclusion and then the strong hydrogen-bond interactions among adjacent PPRs provide a physical cross-linking effect resulting in the hydrogel formation.6-8 The supramolecular hydrogels of this type can change to the sol when activated by external or internal stimuli due to the disruption of interactions among PPRs or clearance of the cross-linkers. Up to present, the supramolecular hydrogels in response to diverse stimuli, such as temperature,9 pH,10 light,11 and redox12, have been extensively explored. An amphiphilic prodrug composed of anticancer drug camptothecin and PEG combined with α-CD would form temperature-sensitive supramolecular hydrogels, which exhibited a gel-sol transition at high temperature due to the disruption of interactions among PPRs.13 Karim et al. designed a pH and temperature dualresponsive micellized α-CD based supramolecular hydrogel system consisting of pH responsive poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA), in which the random tri-block polymer containing hydrophobic poly(L-lactide) and hydrophilic PDMAEMA and PEG synthesized by ATRP formed micelles and the micelle association with α-CD promoted selfassembly to form a supramolecular network.14 Reduction-sensitive supramolecular hydrogels


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could be fabricated by the inclusion of PEG-graft-(disulfide-linked polymer) with α-CD in aqueous solution, which would transform into sols with the addition of reducing agent.15 Considering the advantages of remote control and minimal invasiveness, light activation is considered as a more promising stimulating method.16-18 Recently, near infrared (NIR) light has been an attractive stimulus due to its minimal damage to normal body tissues and maximum penetration for the relevant tissues and organs.19-21 Actually, NIR-responsive materials, such as upconverting nanoparticles (UCNPs), gold nanoparticles (AuNPs), carbon nanotubes (CNTs) and graphene oxide (GO), have been widely used in NIR-responsive systems.22-23 Graphene oxide (GO), which can convert NIR light to heat efficiently and possesses good biocompatibility,24-25 has been a most promising NIR light-responsive material used in controlled release system.26 Based on the noncovalent interaction between the hydrophilic PEO segments of a star-like copolymer and the hydrophilic GO surface and the host-guest inclusion between α-CDs and PEO, a GO hybrid supramolecular hydrogel was constructed to manipulate the phase behavior of the hydrogel.27 Ha et al. reported a GO-based NIR-responsive supramolecular hydrogel constructed by the host-guest inclusion interactions between PEG and α-CD and the π-π stacking interactions between GO and prodrugs, which would undergo a gel-sol transition leading to the release of loaded drugs in an ondemand fashion under NIR light irradiation.28 The GO hybrid supramolecular hydrogels reported so far were prepared via non-covalent interaction such as hydrophilic effect or π-π stacking interactions and the host-guest inclusion interactions, which were sensitive to temperature and NIR light. Herein, the GO hybrid supramolecular hydrogel based on the electrostatic self-assembly and the host-guest inclusion, which were not only responsive to temperature and NIR but also responsive to pH, were explored. Firstly, a brush polymer (mPEG-QPDMAEMA) was synthesized


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by quaternization reaction between PDMAEAM and mPEG-Br. The supramolecular hydrogels were prepared based on the host-guest inclusion between mPEG chains of mPEG-QPDMAEMA and α-CD in aqueous solution, which would turn into a mobile sol phase when the temperature was increased above a certain temperature (Tgel-sol). Through the electrostatic self-assembly between GO and the quaternized polymer and the host-guest inclusion between α-CD and mPEG, GO hybrid supramolecular hydrogels were constructed, in which GO sheets would act as a core material to provide additional cross-linking leading to the increase of thermal stability of GO hybrid supramolecular hydrogels. The prepared GO hybrid supramolecular hydrogels consisted of NIR responsive GO, temperature responsive host-guest complexes and pH responsive PDMAEMA. Therefore, the system would response to NIR light, temperature and pH, which could be beneficial for the controlled release of cargoes under multiple stimuli. In addition, the prepared hydrogels would find diverse applications in inkjet printing for sensors and soft actuators.29-31

EXPERIMENTAL SECTION Synthesis of mPEG-Br. Bromine end-capped polyethylene glycol monomethylether (mPEG-Br) was synthesized by esterification of the terminal hydroxy group of mPEG with bromoacetyl bromide.32 Briefly, mPEG (5.0 g, 2.63 mmol), dry dichloromethane (DCM, 25 mL) and triethylamine (Et3N, 1.1 mL, 7.89 mmol) were added to a 100 mL round bottom flask at room temperature, and then the flask was placed in an ice-bath. When the mixture was cooled to 0 oC, bromoacetyl bromide (0.7 mL, 7.89 mmol) was added dropwise and kept the temperature at 0 oC for 2 h. Then the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was filtered and precipitated in cold diethyl ether to get the crude product. Finally, the crude product was recrystallized in absolute ethanol three times to obtain the final product. (4.2 g, yield: 84%) 1H NMR (400 MHz, CDCl3), δ (ppm): 4.34 (t, 2H, -COOCH2Br), 3.89 (t, 2H, -


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CH2CH2OOC-), 3.55-3.76 (m, repeating unit, -OCH2CH2-), 3.39 (s, 3H, -CH2OCH3). Synthesis of PDMAEMA. PDMAEMA was synthesized via atom transfer radical polymerization (ATRP).33 In a typical experiment, a Schlenk flask dried under vacuum with a magnetic

stirrer

was

charged

with

CuBr

(0.08

g,

0.58

mmol),

tris((N,N-

dimethylamino)ethyl)amine (Me6TREN, 0.015 mL, 0.58 mmol), anhydrous THF (10 mL), ethy 2bromoisobutyrate (EBIB, 0.083 mL, 0.58 mmol) and dimethylaminoethyl methacrylate (DMAEMA, 10 mL, 0.058 mol). The reaction mixture was deoxygenated by eight freeze-pumpthaw cycles and sealed. Then the reaction was allowed to proceed with constant stirring at 70 oC for 13 h. The reaction mixture was diluted with CH2Cl2 and passed through a column of neutral alumina to remove the copper salts. The polymer was precipitated three times from an excess of hexane, filtered and dried at 40 oC under vacuum for 24 h. (7.1 g, yield: 78%). 1H NMR (400 MHz, CDCl3) δ (ppm): 4.05 (t, 2H, -COOCH2CH2-), 2.55 (t, 2H, -CH2CH2N(CH3)2), 2.27 (s, 6H, CH2N(CH3)2), 1.75-2.0 (broad, 2H, aliphatic main chain), 0.80-1.30 (broad, 3H, -CH3 main chain). Quaternization reaction between PDMAEMA and mPEG-Br. Quaternization of the polymer PDMAEMA and mPEG-Br (0.25 mmol) with different molar feed ratio between DMAEMA and mPEG-Br was carried out at 65 oC in a mixture of ethanol (10 mL) and THF (10 mL), and stirred for 24 h. The reaction mixture was dialyzed (molecular weight cutoff = 10000) against water for 3 days to remove the unreacted mPEG-Br and then freeze-dried. The obtained mPEG-QPDMAEMA were denoted as P1, P2 and P3 with molar feed ratio of 5:1, 2.5:1 and 10:1 between DMAEMA and mPEG, respectively. 1H NMR (400 MHz, CDCl3) 4.05-4.35 (t, COOCH2CH2-; t, -COOCH2N+(CH3)2-), 3.55-3.76 (m, repeating unit, -OCH2CH2-; t, CH2CH2N+(CH3)2-; s, -CH2N+(CH3)2-), 3.39 (s, -CH2OCH3), 2.55 (t, -CH2CH2N(CH3)2), 2.27 (s, -CH2N(CH3)2), 1.75-2.0 (broad, aliphatic main chain), 0.80-1.30 (broad, -CH3 main chain).


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Preparation

of

mPEG-QPDMAEMA/α-CD

supramolecular

hydrogels.

The

supramolecular hydrogels were prepared based on the host-guest inclusion between mPEG chains of the mPEG-QPDMAEMA and α-CD in aqueous solution. In brief, the equal volume of the mPEG-QPDMAEMA aqueous solution and α-CD aqueous solution were blended and ultrasonicated for 10 min to generate a homogenous solution, and then the blended solution was left at room temperature for gelation and incubation for 48 h before measurements. The supramolecular hydrogels G1, G2 and G3 were prepared from P1 with a concentration of 12.5 mg/mL and α-CD with concentrations of 60 mg/mL, 70 mg/mL and 80 mg/mL, respectively. The supramolecular hydrogels G4, G5 and G6 were prepared from P2 with a concentration of 10.5 mg/mL and α-CD with concentrations of 60 mg/mL, 70 mg/mL and 80 mg/mL, respectively; The inclusion complexes IC1, IC2 and IC3 were prepared from P3 with a concentration of 15.5 mg/mL and α-CD with concentrations of 60 mg/mL, 70 mg/mL and 80 mg/mL, respectively. The gel-sol transition temperature was determined by a vial inversion method with the temperature increasing. Thus, the vials of hydrogel samples were immersed in a water bath at different temperature for 10 min; the gel-sol transition temperature was monitored visually on the basis of whether the hydrogel samples could flow after inverting the vials for 60 s. Preparation of GO hybrid supramolecular hydrogels (GO-P1/α-CD). GO sheets were prepared by a modified Hammer’s method as described in our previous work.34 Firstly, the aqueous solution of mixtures of mPEG-QPDMAEMA and GO (0.5 mL) was stirred for 2 h at room temperature. Then the equal volume of the aqueous solution α-CD was added and ultrasonicated for 10 min to generate a homogenous solution with mPEG-QPDMAEMA (12.5 mg/mL), GO (2 mg/mL) and α-CD (70 mg/mL). The final blended solution was left at room temperature for gelation and incubation for 48 h before measurements.


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NIR light-triggered supramolecular hydrogel Gel-Sol transition. GO hybrid supramolecular hydrogel and mPEG-QPDMAEMA/α-CD supramolecular hydrogel (1 mL) formed in vials were irradiated by NIR light (808 nm, 1.0 W cm-2) for 20 min, and then the vials were sloped to a certain angle to observe the gel-sol transition behavior. Loading and release of a cargo molecule 5-FU. The 5-FU loaded GO hybrid supramolecular hydrogels were prepared by an in situ formation method. Briefly, 5 mg of 5-FU and 70 mg of α-CD were dissolved in 0.5 mL of deionized water, and 12.5 mg of mPEGQPDMAEMA and 2.0 mg of GO were dispersed in 0.5 mL of deionized water. The two solutions were mixed by ultrasonication for 10 min and then the mixed solution was divided into five pieces in a cuvette and kept at room temperature for gelation and incubation for 48 h before measurements. The loading amount of 5-FU was determined to be 4.6 mg/g. Three pieces of 5-FU loaded GO supramolecular hydrogels were added 3 mL deionized water with pH 5.4, 7.4 and 9.4, respectively as released medium and kept at 37 oC. Two other pieces were added 3 mL deionized water with pH 7.4: one piece was irradiated by NIR laser (808 nm, 1.0 W cm-2) for 20 min; the other was kept at 55 oC for 20 min. At the desired time intervals, 0.1 mL of the released medium was extracted for analysis by UV-vis spectroscopy at 265 nm and the same volume of corresponding fresh deionized water was added to keep a constant volume.


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RESULTS AND DISCUSSION Synthesis and characterization of brush polymer mPEG-QPDMAEMA.

Figure 1. a) Synthetic route of the brush polymer mPEG-QPDMAEMA; b) 1H NMR spectra of PDMAEMA and mPEG-QPDMAEMA (P1) in CDCl3; c) FT-IR spectra of PDMAEMA and mPEG-QPDMAEMA (P1).

The strategy for the synthesis of the brush polymer mPEG-QPDMAEMA is presented in Figure 1a. Firstly, bromine end-capped polyethylene glycol monomethylether (mPEG-Br) was synthesized by esterification of the terminal hydroxy group of mPEG with bromoacetyl bromide. Its chemical structure was confirmed by the FT-IR spectrum (Figure S1) and 1H NMR analysis (Figure S2). Then PDMAEMA was synthesized via atom transfer radical polymerization. The SEC


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trace of PDMAEMA is shown in Figure S3. The molecular weight Mn and molar-mass dispersity (Đ) for PDMAEMA were determined to be 1.0 × 104 and 1.2, respectively. Finally, the quaternization reaction was carried out between mPEG-Br and PDMAEMA with feed ratio 5:1, 2.5:1 and 10:1 to obtain the desired brush polymer mPEG-QPDMAEMA (P1, P2 and P3). Figure 1b and 1c shows the 1H NMR and FT-IR spectra of PDMAEMA and mPEG-QPDMAEMA (P1) with feed ratio 5:1. The degree of quaternization of the brush polymer was calculated to be 11% by ratioing the integrals of the peaks at 3.39 ppm and at 0.80-1.30 ppm, corresponding to the methyl protons of the mPEG and the PDMAEMA, respectively. The 1H NMR and the FT-IR spectra of mPEG-QPDMAEMA with different degree of quaternization (P2 and P3) are shown in Figure S4 and Figure S5, respectively. Supramolecular hydrogels prepared based on the host-guest inclusion between mPEGQPDMAEMA and α-CD. The supramolecular hydrogels were prepared based on the host-guest inclusion between mPEG chains of mPEG-QPDMAEMA and α-CD in aqueous solution. The mPEG chains of mPEG-QPDMAEAM can thread into the cavities of a series of α-CDs to form PPRs via the well-known host-guest inclusion, and then the strong hydrogen-bond interactions among adjacent PPRs provide a physical cross-linking effect that result in the hydrogel formation (Figure 2a). The simple mixing of mPEG and α-CD in aqueous solution didn’t obtain a hydrogel but microcrystalline aggregates as a result of uncontrolled host-guest inclusion between mPEG and α-CD and subsequently hydrogen-bond interactions among PPRs.

35,36

In our work, mPEG

grafted PDMAEMA via quaternization was used to impede the uncontrolled host-guest inclusion between mPEG and α-CD. After blending the aqueous solution of mPEG-QPDMAEMA and αCD, ultrasonication for 10 min and incubating for 48 h, the supramolecular hydrogels were formed in a vial and didn’t flow when the glass vial was inverted, shown in Figure 2b. Figure 2c exhibits


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the SEM image of supramolecular hydrogels, from which it can be seen that the freeze-dried hydrogel clearly displays a loose sponge-like and connected network.

Figure 2. a) Schematic representation of the supramolecular hydrogels ( : mPEG-QPDMAEM； : α-CD), b) optical photo of the supramolecular hydrogels (G2) made of P1 (12.5 mg/mL) and α-CD (70 mg/mL), c) SEM image of the freeze-dried supramolecular hydrogels made of P1 (12.5 mg/mL) and α-CD (70 mg/mL).

The supramolecular hydrogels showed a gel-sol transition with increasing temperature. When the temperature was increased above Tgel-sol, the gel was converted into the sol phase and flowed down. Figure 3 shows the photographs of the supramolecular hydrogels made of P1 (12.5 mg/mL) and α-CD with different concentration at different temperature, from which it can be seen that all of the supramolecular hydrogels showed a gel-sol transition when increasing temperature. The gelsol transition temperatures of the supramolecular hydrogels G1, G2 and G3 prepared from α-CD with 60 mg/mL, 70 mg/mL and 80 mg/mL were 30 oC, 43 oC and 45 oC, respectively. It was noted that the transition temperature increased with the increase of the concentration of α-CD, which could be attributed to an enhanced physical cross-linking in the supramolecular hydrogels, resulting from an increase in the amount of the host-guest inclusion complexes of the mPEG chains


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and α-CD molecules.37 While the increase in the concentration of α-CD from 70 mg/mL to 80 mg/mL, where the molar ratio between α-CD and ethylene glycol units were 0.45 and 0.52 respectively, had little effect on the increase of the gel-sol transition temperature, since the stoichiometric ratio of the inclusion complexes of α-CD and ethylene glycol units is 0.5.38 The high molar ratio exceeding the stoichiometric ratio would have little effect on the increase of the amount of the host-guest inclusion complexes and the crosslinking density of PPRs. The photographs of the supramolecular hydrogels made of P2 (10.5 mg/mL) and α-CD with different concentration at different temperature shown in Figure S6. The gel-sol transition temperatures of the supramolecular hydrogels G4, G5 and G6 made of α-CD with 60 mg/mL, 70 mg/mL and 80 mg/mL were measured to be 40 oC, 47 oC and 50 oC, respectively. With the increase of concentration of α-CD, the changing trends of the gel-sol transition temperatures of G4, G5 and G6 were similar to those of complexes of P1 and α-CD shown in Figure 3. Interestingly, it is noted that the gel-sol transition temperature increased with the increase of degree of quaternization of the polymers when mixed with the same concentration of α-CD. High degree of quaternization results in high cross-linking densities leading to the increase of thermal stability of supramolecular hydrogels. When the polymer P3 with low quternization degree of 6.1% was mixed with α-CD, no hydrogels could be obtained due to the low degree of quaternization and cross-linking density (Figure S7). The characteristics of the synthesized polymers P1, P2 and P3 mixed with different concentrations of α-CD were summarized in Table 1.


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Figure 3. Photographs of the supramolecular hydrogels made of P1 (12.5 mg/mL) and α-CD with different concentration at different temperature. The concentrations of α-CD for G1, G2 and G3 are 60 mg/mL, 70 mg/mL and 80 mg/mL, respectively. Table 1. Characteristics of the synthesized polymers P1, P2 and P3 mixed with different concentrations of α-CD.

(mg/mL)

Degree of quaternization

P1

12.5

11%

P2

10.5

16%

P3

15.5

6.1%

Sample

mPEG-QPDMAEMA

(mol%)

Gels

Tgel-sol (oC)

60

G1

30

70 80

G2 G3

43 45

60

G4

40

70 80

G5 G6

47 50

60

IC1

--

70 80

IC2 IC3

---

mPEG

α-CD

(mg/mL)

(mg/mL)

7.0

X-ray diffraction (XRD) analysis was carried out to study the effect of temperature on hydrogel. Figure 4a shows the XRD patterns of the supramolecular hydrogel (G2) at different temperature. The supramolecular hydrogel shows two characteristic diffraction peaks at 2θ = 19.8° and 22.6° at 25 oC,39-41 which correspond to the crystalline PEG/α-CD inclusion complexes.13, 4243

When the temperature increased to 45 oC (Tgel-sol)), the supramolecular hydrogel exhibited a


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gel-sol transition, while the characteristic diffraction peaks changed little, which indicated that mPEG/α-CD inclusion complexes were not broken and the gel-sol transition was resulted from the destruction of the hydrogen-bond interactions among adjacent PPRs. When the temperature increased to 80 oC, the characteristic diffraction peaks almost disappeared since α-CD could be dethreaded from mPEG and the inclusion complexes were disassembled. The time sweep measurement was carried out to investigate the viscoelastic behavior of the supramolecular hydrogel (Figure 4b), in which the storage modulus (G′) and loss modulus (G″) were monitored as a function of time after mixing the polymer (P1) and α-CD solutions. As the gelation proceeded, both G′ and G″ increased and the increment speed of G′ was higher than that of G″ due to the formation of physical cross-linked networks by hydrogen-bond interactions among PPRs.44 Figure 4c shows the oscillatory frequency sweep from 0.01–100 rad s−1. The storage modulus (G′) values of the supramolecular hydrogels exhibited an essential elastic response, which were greater than the loss modulus (G″) values over the entire range of angular frequency, demonstrating the formation of hydrogels.45 The introduction of DMAEMA segments could make the supramolecular hydrogel pH-responsive, since the pKa value of PDMAEMA is about 7.5 and the change of pH value will result in the protonation/deprotonation of N,Ndimethylaminoethyl groups in PDMAEMA component.33 Figure 4d shows the oscillatory frequency sweep from 0.01–100 rad s−1 of the supramolecular hydrogel at different pH, from which it can be seen that the storage modulus (G′) decreased with the decrease of pH value. In acidic conditions, the protonation of the tertiary amine groups rendered PDMAEMA hydrophilic and highly stretching along the radial direction due to the geometrical constraint and the electrostatic repulsion between polymer chains, which could interrupt the formation of the microcrystalline domain and result in decrease of the cross-linking density.46


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Figure 4. a) Characteristics of the supramolecular hydrogels made of P1 (12.5 mg/mL) and α-CD (70 mg/mL). a) XRD patterns at different temperature, b) time sweep measurement: the storage modulus (G′) and loss modulus (G″) were monitored as a function of time at pH 7.4, c) storage modulus (G′) and loss modulus (G″) as a function of frequency for the supramolecular hydrogels at pH 7.4 and d) storage moduli (G′) as a function of frequency for the supramolecular hydrogels with various pH values.

Graphene oxide hybrid supramolecular hydrogels (GO-P1/α-CD). GO sheets, prepared by a modified Hammer’s method as described in our previous work (see Supporting Information), possess negative charges on the surface of the GO sheets,24,

47

which may interact with the

polycations mPEG-QPDMAEMA through electrostatic interaction. Figure 5a shows the schematic of the preparation of GO hybrid supramolecular hydrogels. Taking advantage of GO with negative charges and mPEG-PDMAEMA with positive charges, GO-P1 composites could be formed by electrostatic self-assembly. The synthesized polymer mPEG-QPDMAEMA (P1) and GO were mixed in aqueous solution and stirred for 2 h and then centrifuged and washed to remove the unbound polymer. The assemblies of P1 and GO were explored by the FT-IR spectra and the zeta


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potential analysis. Figure 5b shows the FT-IR spectra of GO, P1 and GO-P1. The peak at 3350 cm−1 attributed to the O-H stretching vibrations of GO and residual water between GO sheets, and the characteristic peaks of mPEG-QPDMAEMA could be seen: 2775-2947 cm-1, -N(CH3)2 stretch vibration; 3439 cm-1, a large carbon-nitrogen vibration peak (-N+(CH3)2-). The typical peaks corresponding to GO and P1 could be clearly observed in the FT-IR spectra of GO-P1. Figure 5c shows the zeta potential distributions of GO and GO-P1. The prepared GO sheets had a negative zeta potential of -30.5 mV, while the potential of the composite GO-P1 increased to +33.4 mV due to the introduction of the cationic mPEG-QPDMAEMA. When α-CD was added to the GO-P1 composite, the mPEG chains of mPEG-QPDMAEMA could thread into the cavities of a series of α-CDs to form PPRs via the host-guest inclusion, and then the strong hydrogen-bond interactions among adjacent PPRs would provide a physical cross-linking effect inducing the formation of supramolecular hydrogels, where the electrostatic interactions between GO and polycations would provide another physical cross-linking effect. Figure 5d shows the SEM image of GO hybrid supramolecular hydrogels, from which it can be seen that GO hybrid supramolecular hydrogels also possessed a loose sponge-like and connected network. Figure S8 shows the FT-IR spectra of P1, P1/α-CD and GO-P1/α-CD. Compared to P1, the peak at 1464 cm-1 (-CH2- deformation vibration of mPEG48) was weakened in the spectra of P1/α-CD and GO-P1/α-CD assemblies, indicating formation of the pseudopolyrotaxane structure in both of the assemblies. The typical peaks at 19.8° and 22.6° belonging to the crystalline PEG/α-CD inclusion complexes were clearly observed in the XRD patterns of GO hybrid supramolecular hydrogels (Figure S10), indicating that the introduction of GO had no effect on the formation of the inclusion complexes. In order to explore the effect of the concentration of GO on the supramolecular system, rheology measurements for the viscoelastic properties were carried out (Figure 6). Time sweep


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measurements for the viscoelastic behavior of GO hybrid supramolecular hydrogels with 1 mg/mL, 2 mg/mL and 4 mg/mL of GO were shown in Figure 6a, 6b and 6c, respectively. It was found that the gelation time decreased from 65 s to 35 s and then to 5 s when the concentration of GO increased correspondingly. Figure 6d shows the constant frequency oscillatory stress sweep for the supramolecular hydrogel with different concentration of GO. The storage modulus (G′) increased with the increase of the concentration of GO.

Figure 5. a) Schematic representation of GO hybrid supramolecular hydrogels. b) FT-IR spectra of P1, GO and GOP1. c) Zeta potential distributions of GO and GO-P1. d) SEM image of the freeze-dried GO hybrid supramolecular hydrogels.


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Figure 6. a), b) and c) Time sweep measurement for the viscoelastic behavior of the supramolecular hydrogels with different concentration of GO 1 mg/mL, 2 mg/mL and 4 mg/mL, respectively. d) Storage moduli (G′) as a function of frequency for the supramolecular hydrogels with different concentration of GO.

The prepared GO and GO hybrid supramolecular hydrogels both exhibited a good photothermal effect, shown in Figure S11. Upon NIR irradiation, the temperature of the samples could be increased from room temperature to 58 oC when irradiated for 20 min. It is expected that the GO hybrid supramolecular hydrogels would undergo a unique gel-sol transition under NIR irradiation. Figure 7a shows the schematic of NIR- and temperature-induced gel-sol transition of GO hybrid supramolecular hydrogels. GO sheets not only acted as a core material to provide additional cross-linking through electrostatic interaction, but also absorbed NIR light and converted NIR light into heat to trigger the gel-sol transition. Figure 7b shows the photographs of GO hybrid supramolecular hydrogels at different temperature, compared with those of G2 without GO. The gel-sol transition temperature of GO hybrid supramolecular hydrogels was found to be 52 oC, which was much higher than that of supramolecular hydrogels without GO (43 oC). Figure


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S12 shows that the gel-sol transition temperatures of GO hybrid supramolecular hydrogels increased from 50 oC to 52 oC and then to 55 oC when the concentration of GO increased from 1 mg/mL to 2 mg/mL and then to 4 mg/mL, respectively. The mPEG-QPDMAEMA modified GO sheets would act as a core material to provide additional cross-linking, which could lead to the increase of thermal stability of GO supramolecular hydrogels. Figure 7c shows the photographs of the supramolecular hydrogels with or without GO before and after NIR irradiation. It was worth noting that GO hybrid supramolecular hydrogels turned into a mobile sol phase after NIR irradiation, while the hydrogel without GO was still in the opaque gel phase.

Figure 7. a) Schematic of NIR- and temperature-induced gel-sol transition of GO hybrid supramolecular hydrogels. b) Photographs of temperature-induced gel–sol transition of supramolecular hydrogels with or without GO. c) Photographs of supramolecular hydrogels with or without GO before and after NIR light irradiation.

Controlled release of 5-FU from GO hybrid supramolecular hydrogels. The supramolecular hydrogels prepared by the host-guest inclusion between α-CDs and polyethylene glycol monomethylether (mPEG) could be used as a controlled release system. When the


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supramolecular hydrogels were dissociated, the loaded cargo molecules would be released.44 The prepared GO hybrid supramolecular hydrogels consisted of NIR responsive GO, temperature responsive physical cross-linker and pH responsive PDMAEMA, which would afford the system with great potential in the field of controlled release. The viscosity of the hydrogel as a function of shear rate is shown in Figure S15, from which it can be seen that the GO hybrid supramolecular hydrogel was thixotropic. Here, 5-FU, a hydrophilic anti-cancer drug, was used as cargo molecules encapsulated into GO hybrid supramolecular hydrogels for controlled release under temperature, NIR and pH stimulation. Figure 8a shows the controlled release of 5-FU under the stimulation of temperature. The cumulative release was less than 20% at 37 oC for 6 h; however, when the temperature was increased to 55 oC for 20 min at the 4th hour, there was an abrupt release and the release increased by 61.4%. When the temperature was increased to 55 oC for 20 min, GO supramolecular hydrogels turned into a mobile sol phase leading to a rapid release of 5-FU. Figure 8b shows the controlled release of loaded 5-FU under NIR irradiation, from which it can been seen that there was a slow release process before NIR irradiation, while an abrupt release occurred when the NIR light (808 nm, 1.2W cm-2) irradiation was performed for 20 min at the 4th hour. The release increased by 58.6% under NIR light irradiation for 20 min. The results indicated that the photothermal conversion of GO hybrid supramolecular hydrogels was highly efficient and the NIR light-induced photothermal effect was critical to induce the supramolecular hydrogel degradation and cargo release. Figure 8c shows the release behaviors of 5-FU under pH 9.4, 7.4 and 5.4 at 37 oC,

from which it can be seen that the cumulative release for 48 h was 64%, 73% and 95%

respectively, indicating that the cumulative release increased with the decrease of pH. In acidic conditions, the PDMAEMA segments would be protonated and become hydrophilic, thus the supramolecular hydrogels could show expanding conformation and be easier to be dissociated,


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resulting in more cargoes to be released. The release of 5-FU in P1/a-CD is shown in Figure S16, from which it can be seen that the release amount of 5-FU is more than that in GO hybrid supramolecular hydrogels at same time intervals under temperature and pH stimuli. GO sheets in the hydrogel would act as a core material to provide additional cross-linking, which could make the drug release slower. It is noted that the abrupt release in the hydrogel P1/a-CD did not occur upon NIR light irradiation due to the absence of photothermal GO. The controlled release of cargoes (5-Fu) stimulated by temperature, NIR light irradiation and pH demonstrated that the prepared GO hybrid supramolecular hydrogels could be expected to be a smart delivery system for conveniently controlled release with the advantages of multi-stimuli responsiveness.

Figure 8. Controlled release of 5-FU from GO hybrid supramolecular hydrogels (GO-P1/α-CD): a) at 37 oC for 6 h and at 37 oC first for 4 h and then increasing the temperature to 55 oC for 20 min (pH 7.4), b) with or without NIR irradiation at 4th hour for 20 min (pH 7.4) and c) at pH 5.4, 7.4 and 9.4 at 37 oC.


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CONCLUSION In summary, we successfully developed a strategy to construct GO hybrid cyclodextrin-based supramolecular hydrogels with NIR light-, temperature- and pH-responsive behaviors. Firstly, a brush polymer (mPEG-QPDMAEMA) was synthesized by quaternization reaction between pH sensitive PDMAEAM and mPEG-Br. Then the supramolecular hydrogels were prepared based on the host-guest inclusion between mPEG chains of the mPEG-QPDMAEMA and α-CD in aqueous solution. When the temperature was increased above Tgel-sol, the supramolecular hydrogels turned into a mobile sol phase. Taking advantage of the electrostatic self-assembly between GO and mPEG-QPDMAEMA and the host-guest inclusion between CDs and mPEG, we constructed GO hybrid supramolecular hydrogels. GO sheets not only acted as a core material to provide additional cross-linking, which could lead to the thermal stability of GO hybrid supramolecular hydrogels; but also absorbed NIR light and converted NIR light into heat to trigger the gel-sol transition. The constructed GO hybrid cyclodextrin-based supramolecular hydrogels did respond to NIR light, temperature and pH, and were used as a delivery system to release the loaded cargo molecules under the multiple stimuli. The NIR light-, temperature- and pH-dependent cargo release may afford the GO hybrid supramolecular hydrogels a great promise in the field of delivery systems.


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ASSOCIATED CONTENT Supporting Information. The Supporting Information is available fee of charge on the ACS Publications website. Materials, characterization methods and instruments, 1H NMR, SEC, FT-IR, XPS, XRD, Raman spectra, photothermal effects of GO and GO-P/α-CD, rheological properties, and release of 5-FU in P1/a-CD.

AUTHOR INFORMATION Corresponding Author *(G.W.). E-mail: [email protected] *(H.Y.). E-mail: [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (Grant No. 51373025) and the Program for New Century Excellent Talents in University (NCET-11-0582). H.Y. acknowledges financial supporting from the National Natural Science Foundation of China (Grant No. 51573005).


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TOC NIR Light- and pH-Responsive Graphene Oxide Hybrid Cyclodextrin-Based Supramolecular Hydrogels Panjun Wang,† Chao Huang,† Youmei Xing,‡ Weihua Fang, ‡ Jie Ren,† Haifeng Yu,*,§ Guojie Wang*,† NIR light-, temperature- and pH-responsive graphene oxide hybrid supramolecular hydrogels based on electrostatic self-assembly between graphene oxide and quaternized polymers and cyclodextrin/PEG host-guest inclusion were constructed for controlled release.


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NIR-Light- and pH-Responsive Graphene Oxide ... - ACS Publications

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