NIR Light-, Temperature-, pH-, and Redox-Responsive Polymer

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NIR Light-, Temperature-, pH- and Redox-Responsive PolymerModified Reduced Graphene Oxide/Mesoporous Silica Sandwich-Like Nanocomposites for Controlled Release Panjun Wang, Shuo Chen, Ziquan Cao, and Guojie Wang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b07468 • Publication Date (Web): 10 Aug 2017 Downloaded from http://pubs.acs.org on August 12, 2017

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ACS Applied Materials & Interfaces

NIR Light-, Temperature-, pHand Redox-Responsive Polymer-Modified Reduced Graphene Oxide/Mesoporous Silica Sandwich-Like Nanocomposites for Controlled Release Panjun Wang, Shuo Chen, Ziquan Cao, Guojie Wang*

School of Materials Science and Engineering University of Science and Technology Beijing Beijing 100083, China E-mail: [email protected]

Keywords:

controlled

release; graphene

oxide; nanocarriers;

stimuli-responsive polymers

ACS Paragon Plus Environment

nanocomposites;


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ABSTRACT: Here a novel quadruple-responsive nanocarrier based on reduced graphene oxide/mesoporous silica sandwich-like nanocomposites (rGO@MS) modified by pHand temperature-responsive poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA) with a linker of disulfide was constructed via surface-initiated atom transfer radical polymerization. The polymer chains would be used as gatekeepers to control the release of the loaded cargo molecules under pH, temperature, NIR light and redox stimuli. The cargo

molecules

(rhodamine

B)

were

demonstrated

to

release

from

the

polymer-modified nanocomposites triggered by the quadruple-stimuli. It is noted that the release of the loaded rhodamine B from the nanocarriers could be enhanced greatly under the synergistic effect of multiple stimuli. The prepared quadruple-responsive polymer-modified nanocomposites show a bright prospect in the field of smart nanocarriers for controlled release.


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1. INTRODUCTION In the past few years, various nanocarriers such as polymeric micelles,1,2 nanogel,3,4 liposomes,5-7 and mesoporous silica nanoparticles,8-10 have got unprecedented development on cargo delivery. Currently, the stimuli-responsive nanocarriers have been a well-concerning focus for their site-specific and time-release controlled. Different stimuli have been employed for controlled release, such as pH, temperature, light, redox, enzyme,

and

magnetism.11-14

Poly(N,N-dimethylaminoethyl

methacrylate)

(PDMAEMA), a pH- and temperature-sensitive polymer with biocompatibility and antibacterial activity, has been widely studied as functional materials in medical and biomedical domains.15 In acidic conditions, PDMAEMA is protonated and becomes polycations; in alkaline conditions, the polymer is deprotonated and collapsed.16 PDMAEMA also possesses the lower critical solution temperature (LCST), above which the polymer is hydrophobic and collapsed, where the hydrogen bonding between the polymer chains and water is broken.17 Considering the advantages of remote control and minimal invasiveness, light activation is considered as the more promising way to control the release of cargo molecules from the nanocarriers.18,19 Compared to UV light and visible light, NIR light (wavelength between 750 and 1000 nm) possesses good tissue penetrability, high biocompatibility and lower scattering properties.20 Actually, NIR-responsive materials, such as upconverting nanoparticles (UCNPs), CuS, gold nanoparticles, and reduced graphene oxide (rGO), have been widely used in nanocarriers.21,22 However, the absorption of water at 980 nm leading to an overheating issue would limit the practical applications of UCNPs and CuS,23 while gold



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nanoparticles used in nanocarriers would face a problem of potential toxicity.24 Graphene oxide, which can absorb 808 nm NIR light without the overheating effect induced by 980 nm and possesses good biocompatibility, has been the most promising NIR light-responsive materials used in nanocarriers.25 Based on the π-π stacking and hydrogen interactions between PEGylated reduced graphene oxide and drug molecules, doxorubicin was loaded into the nanocarrier of PEGylated reduced graphene oxide and the photothermal heating changed the binding energy resulting in the desorption of doxorubicin from the nanocarrier.26 Nonetheless, the drug loading capacity would be dependent on the chemical structure of the drug, which could limit its application. To overcome the above disadvantage, the mesoporous silica-coated graphene oxide (GO@MS) has been prepared and used as nanocarriers to achieve high drug loading efficiency via pore adsorption.27 Yet most of the mesoporous silica based systems rely on a simple diffusion process that is promoted by a NIR-induced temperature difference without the utilization of a secondary temperature-sensitive process.28 Taking advantage of

the

stimuli-responsive

polymer

valve

capping

rGO@MS,

a

NIR-

and

temperature-responsive nanocarrier was prepared, in which the thermoresponsive poly(N-isopropylacrylamide-co-acrylamide) valve could be opened under NIR- and temperature-stimuli to release the drug doxorubicin from the silica pore channels of [email protected] Herein, we have successfully designed and synthesized a quadruple-responsive nanocarrier based on polymer-modified reduced graphene oxide/mesoporous silica sandwich-like nanocomposites, in which the pH- and temperature-sensitive PDMAEMA


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polymers were used as gatekeepers and redox-sensitive disulfide bonds were used as linkers between the rGO@MS and the polymer gatekeepers. In acidic conditions, the protonated polymers would adopt extended conformation with positive charges and attach to the surface of rGO@MS via ionic interaction with negative charges of MS to block the release of the loaded cargo molecules from the nanocarriers; in alkaline conditions, the polymers were deprotonated and collapsed, thus the ionic interaction would be weakened and the silica pore channels of rGO@MS were opened to release the loaded cargo molecules. When raising the temperature, the temperature-sensitive polymer became hydrophobic and collapsed leading to the silica pore channels opened for the release of cargo molecules. Upon near-infrared light irradiation, the rGO in the nanocomposites could absorb NIR irradiation and convert it to heat to release the loaded cargo molecules. Meanwhile, the disulfide bonds would be cleaved in the presence of reduction agents and the polymer chains would detach from the surface of rGO@MS leading to the silica pore channels opened and release of cargo molecules. It is noted that the release of the loaded Rh B from the nanocarriers could be enhanced greatly under the synergistic effect of multiple stimuli. The prepared quadruple-responsive polymer-modified nanocomposites show a bright prospect in the field of smart nanocarriers for controlled release.

2. EXPERIMENTAL SECTION Materials. Natural graphite flake (Alfa Aesar, -325 mesh, 99.8%), NaOH (96%), KMnO4 (99.5%), H2O2 (30%), NaCl (99.5%), HCl, H2SO4 (95%-98%) were obtained



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from Beijing Chemical Works. Hexadecyl trimethyl ammonium bromide (CTAB, aladdin, 99%), tetraethyl orthosilicate (TEOS, aladdin, 99%), 3-(triethoxysilyl)propyl isocyanate (TEPIC, aladdin, 95%), 2-hydroxyethyl disulfide (SS-DOH, Aldrich, 90%), 2-bromoisobutyl bromide (Br-iBuBr, Aldrich, 98%), and copper(I) bromide (CuBr, Alfa Aesar, 99.998%) were used without further purification. 2-(N,N-dimethylamino)ethyl methacrylate (DMAEMA, Aldrich, 99%) was dried over CaH2 and distilled under reduced pressure.

DL-dithiothreitol

(DTT, Sigma-Aldrich, 99%), rhodamine B (Rh B,

J&K, 95%). Triethylamine (Et3N) and organic reagents were purchased from Sinopharm Chemical Reagent Co. Ltd. Preparation of rGO@MS. The GO used in this work was prepared by a modified Hammer’s method (See Supporting Information).30 The prepared graphene oxide was broken by ultrasonic machine for two hours to obtain nano-sized graphene oxide sheets. The nano-sized graphene oxide (50 mg) was dispersed in 90 mL deionized water and the pH was adjusted to 12 with 2 M NaOH, then the mixture was magnetically stirred 12 hours at 80 oC to obtain mild reduced graphene oxide (rGO). Then CTAB (1.8 g) was added into the mixture and the pH was adjusted to 12 with 2 M NaOH. After stirred for 30 min, TEOS (0.9 mL) was added and stirred continuously for 24 hours at 80 oC. Finally, the product was collected by centrifugation, washed with deionized water and ethanol several times and dried by vacuum. Synthesis of Disulfide-Modified rGO@MS (rGO@MS-SS-OH). Firstly, TEPIC (2.5 mL) was added dropwise to the anhydrous toluene (50 mL) solution of rGO@MS (250 mg) and the mixture was magnetically stirred for 24 hours at 80 oC. The prepared


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rGO@MS-NCO was isolated via centrifugation and washed with toluene and N,N-dimethylformamide (DMF). Then 2-hydroxyethyl disulfide (3 mL) was added into the prepared rGO@MS-NCO in DMF (30 mL) and the mixture was magnetically stirred for 24 hours at 80 oC to obtain rGO@MS-SS-OH. The product (rGO@MS-SS-OH) was recollected by centrifugation, washed with deionized water and ethanol several times and dried by vacuum. The surfactant CATB in the silica pore channels was extracted by 0.6% (wt) NH4NO3 ethanol solution at 70 oC for 8 hours. Finally, the product (rGO@MS-SS-OH) was recollected by centrifugation, washed with deionized water and ethanol several times and dried by vacuum. Functionalization

with

ATRP

Initiating

Group

(rGO@MS-SS-Br).

rGO@MS-SS-OH prepared above was dispersed in 20 mL anhydrous THF. After the addition of distilled TEA (0.85 mL), the solution was placed in an ice-water bath and 2-bromoisobutyryl bromide (2.5 mL) was added. The mixture was stirred for 2 hours at 0 oC, and then stirred for another 24 hours at room temperature. After centrifugation, washed and dried, the resulting product modified with ARTP initiating agents was obtained (rGO@MS-SS-Br). Preparation

of

the

Polymer-Modified

Nanocomposites

rGO@MS-SS-PDMAEMA. Typically, rGO@MS-SS-Br (200 mg), DMAEMA (5 mL), CuBr (25 mg), Me6TREN (45 µl), DMF (10 mL) were placed in a 25 mL Schlenk flask, which was then sealed and degassed by eight freeze-pump-thaw cycles. Then the Schlenk flask was placed in oil bath at 80 oC for 48 hours and the reaction was terminated by exposure to air. After centrifugation, washed with ethanol and deionized



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water several times and dried by freeze-drying, the polymer modified nanocomposites were obtained. NIR-Induced Photothermal Effect. To investigate the NIR-induced photothermal effect, the aqueous solutions of GO, rGO, rGO@MS, rGO@MS-SS-PDMAEMA with different concentrations were irradiated by NIR laser (808 nm diode laser, 3 W cm-2) for 600 s. The temperature was measured using a digital thermometer every 60 s. Preparation of the Nanocomposite Loaded with RhB. Rh B, a cargo molecule, was encapsulated into the nanocomposite rGO@MS-SS-PDMAEMA as follows. The prepared rGO@MS-SS-PDMAEMA (100 mg) was added in 20 mL PBS (pH 7.4), followed by the addition of Rh B (50 mg). After stirred for 24 hours at 25 oC, the mixture was dialyzed against deionized water (pH 5.4) for 48 hours and centrifuged to remove free and surface-absorbed Rh B. Then rGO@MS-SS-PDMAEMA loaded with Rh B was obtained after freeze-dried. Controlled Release of the Loaded Rh B. Five aliquots (2 mg each) of rGO@MS-SS-PDMAEMA loaded with Rh B were respectively dispersed in 4 mL of PBS solution with different stimuli: 1) at pH 5.4 and 25 oC, 2) at pH 7.4 and 25 oC, 3) at pH 7.4 and 45 oC, 4) at pH 8.4 and 25 oC and 5) at pH 7.4, 25 oC, and with 20 mM DTT. The samples were transferred into dialysis bags (molecular weight cutoff = 3500) and the dialysis bags were kept in a 50 mL beaker with 30 mL of PBS solution with corresponding stimulus and stirred. As for NIR stimulus, rGO@MS-SS-PDMAEMA loaded with Rh B (2 mg) in 4 mL of PBS solution was transferred into the dialysis bag and kept in a 50 mL beaker with 30 mL of PBS solution, then the sample was taken out


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from the dialysis bag and subjected to NIR light irradiation (808 nm, 3 W cm-2) for 10 min at designed time point. At predetermined time intervals, 2 mL of the dialysate was extracted and then the same volume fresh PBS was added. The cumulative release of Rh B was measured by UV-Vis spectroscopy. For the temperature-controlled release, rGO@MS-SS-PDMAEMA loaded with Rh B (2 mg) was suspended in PBS (30 mL, pH 7.4) and the temperature increased to 65 oC with gentle stirring. At given time, the sample was taken out and centrifuged at 11000 rpm, then 2 mL of the supernatant was extracted to be characterized by UV-Vis spectroscopy and the same volume fresh PBS (pH 7.4) was added. Characterization. Transmission electron microscope (TEM) analysis was performed with JEM-2010 EX/S. UV-Vis absorption spectra were recorded on a JASCO V-570 spectrophotometer. The nitrogen adsorption isotherms of rGO@MS were measured on ASAP 2020 (Micromeritics, USA) at 77 K (liquid nitrogen temperature) using a 8 s equilibrium interval. Pore diameter was calculated by the Barrett–Joyner– Halenda (BJH) method. Thermogravimetry analysis (TGA) was performed using a METTLER TGDSC 1 analyser in an air flow at a heating rate of 10 oC min-1, from 25 to 1000 oC. Fourier transformed infrared (FT-IR) spectroscopy characterization was performed on a PerkinElmer spectrophotometer at room temperature. Dynamic light scattering (DLS) experiments were measured on a Zetasizer Nano ZS90 instrument (Malvern Instruments) equipped with a multipurpose autotitrator (MPT-2). X-ray photoelectric spectroscopy (XPS) was obtained with Thermo escalab 250XI. Molecular weight and molecular weight distribution (Mw/Mn) of PDMAEAM cleaved from the



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surface of rGO@MS-SS-PDMAEMA by DTT was determined by gel permeation chromatography (GPC) (Waters 1515) with styragel columns relative to polystyrene standards using THF as eluent. UV-vis absorption spectra were obtained on a JASCO V-570 spectrophotometer. NIR photoirradiation experiments were carried out using a continuous-wave diode laser system WG1233D3-808 nm (ANJ Laser, China) with wavelength of 808 nm and power density of 3 W cm-2.

3. RESULTS AND DISCUSSION Design

and

Fabrication

of

the

Stimuli-Responsive

Polymer-Modified

Nanocomposite rGO@MS-SS-PDMAEMA

Scheme 1. Schematic Outlines of the Fabrication Process of the Polymer-Modified Nanocomposite rGO@MS-SS-PDMAEMA and Controlled Release of the Loaded Rh B.

Scheme

1

outlines

the

fabrication

process


of

quadruple-responsive

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polymer-modified nanocomposites (rGO@MS-SS-PDMAEMA) and the controlled release of the loaded cargo molecules triggered by NIR light, temperature, pH and DTT. The graphene oxide was sonicated for 2 hours at 600 W to obtain the GO nanosheet with a final size of around 340 nm (Figure S1a), which was mildly reduced by NaOH at 80 oC for 12 hours with the change of color from brown to black and the change of chemical constitution (Figure S2).31,32 Then rGO@MS was prepared by sol-gel condensation of a silica precursor (TEOS) on the reduced GO under basic conditions with CTAB as the template, where CTAB filled the mesopores of the prepared rGO@MS. To introduce the stimuli-responsiveness: firstly, rGO@MS was functionalized with the isocyanate by reacting with silane coupling agent TEPIC; after the reduction-responsive disulfide linker was introduced on the surface of rGO@MS-NCO via the reaction between the isocyanate and hydroxyl groups of SS-DOH, the template CTAB inside the channels was removed by refluxing in ethanol solution of ammonium nitrate; then 2-bromoisobutyryl bromide was attached onto the surface of rGO@MS-SS-OH by esterification, which was used as initiator to trigger the polymerization of DMAEMA via surface-initiated atom transfer radical polymerization (Figure S3). The cargo molecules Rh B could be encapsulated into the rGO@MS-SS-PDMAEMA via physical adsorption. In acidic conditions, the protonated polymers would adopt extended conformation with positive charges and attach on the surface of rGO@MS with negative charges via ionic interaction to block the release of the loaded cargo molecules. In alkaline conditions, PDMAEMA would be deprotonated and the ionic interaction between the rGO@MS and the polymer valve would be weakened to release the loaded Rh B. When raising the



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temperature, the temperature-sensitive polymer became hydrophobic and collapsed leading to the silica pore channels opened and the release of Rh B. Upon near-infrared light irradiation, the rGO in the nanocomposites could absorb NIR irradiation and convert it to heat to release the loaded cargo molecules. Moreover, when the reduction agent existed, the disulfide bonds would be cleaved and the polymer chains would detach from the surface of rGO@MS to release the cargo molecules. Characterization of rGO@MS-SS-PDMAEMA. Figure 1 shows the TEM images of GO, rGO@MS without CTAB and rGO@MS-SS-PDMAEMA. The graphene oxide (GO) sheets were prepared by a modified Hammer’s method, the TEM image of which is shown in Figure 1a. The mesoporous silica shell with vertical pore channels was assembled onto the rGO by sol-gel condensation of a silica precursor (TEOS) to form a sandwich-like nanocomposite. The periodicity of the mesoporous channel structure on the rGO plate could be observed by TEM (Figure 1b). The mesoporous nature of rGO@MS was confirmed by nitrogen physisorption measurements and the pore diameter was determined to be 2.8 nm (Figure S4). The appearance of the polymer corona around rGO@MS could confirm the successful grafting of PDMAEMA (Figure 1c). The size distributions of the nanocomposites measured by dynamic light scattering are shown in Figure S1.


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Figure 1. TEM images of a) GO, b) rGO@MS, and c) rGO@MS-SS-PDMAEMA. Inset: high resolution image.

Figure 2a shows the FT-IR spectra of rGO@MS with or without CTAB, rGO@MS-SS-Br, and rGO@MS-SS-PDMAEMA, respectively. The strong peak at 1080 cm-1, corresponding to the stretching vibration of Si-O, demonstrated the assembly of the mesoporous silica shell. The absorption peaks at 2928 cm-1 and 2855 cm-1 and the peak at 1466 cm-1 respectively ascribed to the C-H stretching vibrations and the C-H deformation vibration of CTAB appeared in the rGO@MS with CTAB, shown in Figure 2a1, while the absorption peaks almost disappeared in the rGO@MS after removal of CTAB shown in Figure 2a2. The FT-IR spectrum of rGO@MS-SS-Br is shown in Figure 2a3. The clear absorption peaks at 1700 cm-1 and 1553 cm-1 are attributed to the C=O



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stretching vibration and the N-H bending vibration respectively, indicating the existence of the urethane formed from the isocyanate and hydroxyl groups of the disulfide. The peak at 671 cm-1 is attributed to the C-Br group, indicating the successful immobilization of initiator. The absorption peak at 1730 cm-1 was strengthened significantly in the FT-IR spectrum of rGO@MS-SS-PDMAEMA (Figure 2a4), resulted from the C=O stretching of the grafted PDMAEMA. Figure 2b shows the XPS patterns of rGO@MS and rGO@MS-SS-PDMAEMA, from which it can be seen that the N peak appeared and the C/O ratio increased in the spectrum of rGO@MS-SS-PDMAEMA, resulting

from

the

grafting

of

polymer

chains

onto the

rGO@MS.

The

thermogravimetric analysis (TGA) was performed to assess the mass ratio of different components in the rGO@MS-SS-PDMAEMA, shown in Figure 2c. When the samples were heated to 700

o

C, the weight losses of rGO@MS, rGO@MS-NCO and

rGO@MS-SS-PDMAEMA were about 27%, 40% and 63% respectively. The different weigh losses between rGO@MS-NCO and rGO@MS-SS-PDMAEMA indicated that the stimuli-responsive polymer valve took up ca. 23% weight of rGO@MS-SS-PDMAEMA. Figure 2d shows the transmittance of rGO@MS-SS-PDMAEMA in aqueous solution (pH 7.4) at different temperatures, from which it can be seen that the curve exhibited a sharp increase in transmittance around 63 oC. The polymer PDMAEMA would change between hydrophilic and hydrophobic along with the change of ambient temperature.17 Below the LCST of PDMAEMA, the polymer PDMAEMA would be hydrophilic for the intermolecular hydrogen bonds between the polymer and water, thus the nanocomposite rGO@MS-SS-PDMAEMA could be dispersed homogeneously in water. Above the


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LCST, the polymer PDMAEMA would become hydrophobic and collapse on the surface of rGO@MS, thus the nanocomposite could be precipitated and the transmittance would be increased. However, the transmittance of the polymer-modified nanocomposites at pH 5.4 changed little when the temperature was increased, shown in Figure S5, since the polymer PDMAEMA is protonated in acidic conditions and the LCST behavior disappeared .

Figure 2. a) FT-IR spectra of rGO@MS with CTAB (a1), rGO@MS without CTAB (a2), rGO@MS-SS-Br (a3), and rGO@MS-SS-PDMAEMA (a4), vertical lines indicating the location of the absorption peaks. b) XPS spectra of rGO@MS and rGO@MS-SS-PDMAEMA. c) TGA spectra of rGO@MS, rGO@MS-NCO and rGO@MS-SS-PDMAEMA. d) Transmittance results at λ= 500 nm for rGO@MS-SS-PDMAEMA in water (0.5 mg/mL, pH 7.4) at different temperature (Inset: optical images of the nanocomposites at 50 oC (left) and 70 oC (right).



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NIR-Induced Photothermal Effect. To investigate the photothermal effect of the nanocomposites, the temperature elevation after irradiation by NIR (808 nm, 3 W cm-2) was monitored. Figure 3a shows the NIR-induced photothermal effect of water (control group), GO, rGO, rGO@MS, and rGO@MS-SS-PDMAEMA. The elevation in temperature of water was less than 6 oC in 10 min, while the elevation for the aqueous solution of GO was up to 16 oC. It is worth noting that the aqueous solution of rGO, rGO@MS, or rGO@MS-SS-PDMAEMA showed an elevation in temperature above 50 o

C. The higher light absorption in the infrared region of rGO (Figure S2c) has indicated

its significant photothermal effect. Figure 3b shows the elevation in temperature of rGO@MS-SS-PDMAEMA with different concentrations under NIR irradiation. More heat could be generated by rGO@MS-SS-PDMAEMA with higher concentration and longer NIR irradiation time. For the nanocomposite rGO@MS-SS-PDMAEMA with concentration of 0.5 mg/mL, the temperature increased with the increase of NIR irradiation until the temperature reached a maximum level, where the polymer PDMAEMA would become hydrophobic and the nanocomposite could be precipitated and thus a maximum NIR-induced photothermal effect was obtained.


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Figure 3. Photothermal effects of: a) water (control group) and GO, rGO, rGO@MS, and rGO@MS-SS-PDMAEMA in water (0.5 mg/mL) under NIR irradiation (808 nm, 3 W cm-2); b) rGO@MS-SS-PDMAEMA in water with various concentrations under NIR irradiation (808 nm, 3 W cm-2).

NIR Light-, Temperature-, pH-, and Redox-Controlled Release of Rh B from the

Polymer-Modified Nanocomposites.

The

mesoporous

structures of

the

polymer-modified nanocomposites afford the system a high loading capacity for cargo molecules. The loading capacity of rGO@MS-SS-PDMAEMA for Rh B was determined to be 9.2% by UV-Vis spectroscopy (Figure S7). The stimuli-responsive components such as pH- and temperature-responsive PDMAEMA, NIR-responsive rGO and redox-responsive disulfide linkers in the system endow the polymer-modified nanocomposites with the ability to control the release of the loaded cargo molecules. The release of loaded Rh B was dialyzed and the cumulative release amount was calculated by its UV absorption. Figure 4a shows the controlled release of loaded Rh B under different pH. Less than 5% of the loaded Rh B was released from rGO@MS-SS-PDMAEMA after the continuous incubation at pH 5.4 for 24 h, indicating



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a good encapsulated capability of the grafted PDMAEMA valves. The cumulative release increased with the increase of pH and the release reached 37% at pH 8.4 for 24 h. The low cumulative release of Rh B at pH 5.4 for 24 hours and then a great release at pH 8.4 are shown in Figure S8a. In acidic conditions, tertiary amine groups of the PDMAEMA could be protonated and become positive.33 By means of the ionic interaction between PDMAEMA with positive charges and rGO@MS with negative charges (Figure S9), the pore channels would be blocked and the loaded Rh B could not be released. When in alkaline conditions, the polymers were deprotonated and collapsed, thus the ionic interaction would be weakened and the silica pore channels of rGO@MS were opened to release the loaded cargo molecules. The zeta potentials of the nanocomposites at pH 5.4, 7.4, and 8.4 were measured to be 35.7 mV, -15.2 mV, and -25.4 mV respectively, shown in Figure S10. Figure 4b shows the controlled release of the loaded Rh B under external temperature stimulus. When the ambient temperature was 25 oC, the cumulative release of the loaded Rh B was about 18% within 24 h. Compared with the release at 25 oC, the cumulative release of the loaded Rh B increased a little to 27% at 45 oC (below the LCST). However, when the temperature (65 oC) was more than the LCST, the cumulative release of the loaded Rh B had significantly improved up to 65%. At temperature above the LCST, the polymer shrank significantly leading to the pore channels opened to favor the release of the loaded Rh B. In addition, the elevated temperature would speed the diffusion of Rh B, which destroyed the π-π stacking and pore adsorption to promote the release of the loaded Rh B.28,29 Comparing the steep


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increase above LCST and the gradual increase below LCST, it can concluded that the release is dependent on the polymer collapse above LCST, not on acceleration of diffusion due to increased temperature. Figure 4c shows the controlled release of loaded Rh B under NIR irradiation. It is noted that there was a slow release process before NIR irradiation, while an abrupt release occurred when the NIR irradiation was performed for 10 min at the 4th hour. The release increased by 6.1%, which was comparable with that under the stimulation of temperature 65 oC for 10 min (7.5%) shown in Figure 4b. Then stimulated by another 10 min NIR irradiation performed at the 8th hour, the same result was observed. The 10 min NIR irradiation would increase the temperature above the LCST and then the polymer would become hydrophobic and collapse leading to the silica pore channels opened for the release of Rh B. Moreover, the NIR irradiation would facilitate the release of Rh B since the elevated temperature would speed the diffusion of Rh B. Figure 4d shows the controlled release of loaded Rh B in the absence or presence of DTT at pH 7.4. Only a little of Rh B (17%) could be released in the absence of DTT in 24 h, while more Rh B (28%) would be released in the presence of DTT. The disulfide linkers between rGO@MS and the polymer PDMAEMA would be cleaved in the presence of reduction agents and the polymer chains could detach from the surface of rGO@MS, leading to the silica pore channels opened and release of cargo molecules. The TGA curve of the nanocomposite rGO@MS-SS-PDMAEMA under 20 mmol DTT for 24 hours is shown in Figure S11, from which it can be seen that the weight loss of the nanocomposite was about 57%. Compared with 63% of the weight loss of the



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nanocomposite before DTT treatment, it is known that 6% of the nanocomposite was cleaved by DTT. The cleavage ratio of the grafting chains could be estimated to be 26%.

Figure 4. Cumulative release profiles of Rh B loaded in the nanocomposites under different stimuli in PBS buffer: a) at pH 5.4, 7.4 and 8.4 (at 25 oC); b) at different temperature (pH 7.4); c) with or without NIR irradiation at the defined time points indicated by arrows for 10 min (pH 7.4); d) with or without 20 mM DTT (pH 7.4, without NIR irradiation, 25 oC).

Since the controlled cargo release from the polymeric nanocomposites could be achieved under NIR light, temperature, pH and redox stimulation separately, it would be more desirable if two or three stimuli were combined to realize the efficient release of cargo at specific circumstances. Figure 5 shows the release profiles of Rh B from the nanocarriers under the successive combined stimulation. It can be seen clearly that the


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release of the loaded Rh B was 17% under a single stimulation at pH 7.4 (curve a), while the release rate has a great promotion and the cumulative release amount increased to 28% under combined stimulation of pH 7.4 and 20 mM DTT (curve b) and to 33% under combined stimulation of pH 7.4 and NIR irradiation (curve c). It should be noted that the release rate and the release amount would increase further under the combined stimulation of NIR, pH and DTT (curve d). The release amount triggered by the combination of the three stimuli could be enhanced to 39%. Comparing the release profile under the stimulation of pH 7.4 and NIR and that under the stimulation of pH 7.4, NIR and DTT, it should be noted that the cleavage of grafting polymers could erase the thermo sensitivity of the composite nanocarrier, since the NIR-thermo-controlled release rate decreased in the presence of DTT. The release of the loaded cargo molecules could be precisely controlled via the different combined stimulation of pH, DTT, and NIR light irradiation.



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Figure 5. Cumulative release profiles of Rh B loaded in the nanocomposites under the stimulation of: a) pH 7.4; b) pH 7.4 and 20 mM DTT; c) pH 7.4 and NIR; d) pH 7.4, 20 mM DTT and NIR. All the experiments were carried out at 25 oC.

4. CONCLUSION In summary, we have successfully designed and synthesized a quadruple-responsive nanocarrier based on polymer-modified reduced graphene oxide/mesoporous silica sandwich-like nanocomposites for controlled release. The prepared nanocarriers are composed of NIR-responsive reduced graphene oxide, pH- and temperature-responsive PDMAEMA and redox-sensitive disulfide linkers. Under acidic conditions, the protonated polymers would adopt extended conformation with positive charge and attached on the surface of rGO@MS with negative charge via ionic interaction to block the release of the loaded cargo molecules from the nanocarriers; under alkaline conditions, the ionic interaction would be weakened and the silica pore channels of


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rGO@MS were opened to release the loaded cargo molecules. When raising temperature, the temperature-sensitive polymer became hydrophobic and collapsed leading to the silica pore channels opened for the release of cargo molecules and the high temperature could promote the diffusion of cargo molecules. Upon near-infrared light irradiation, the rGO sandwiched into mesoporous silica shell could absorb NIR irradiation and convert it to heat to release the loaded cargo molecules. Meanwhile, when the reduction agent existed, the disulfide bonds would be cleaved and the polymer chains would detach from the surface of rGO@MS and thus led to the silica pore channels opened for the release of cargo molecules. In addition, it is noted that the enhanced release of the loaded cargo molecules from the nanocarriers could be achieved in combination of two stimuli and three stimuli, which would provide many new possibilities to release different release kinetics

of

the

loaded

molecules.

The

reported

multi-stimuli-responsive

organic-inorganic hybrid nanocarriers may exhibit promising application in controlled release of drug, gene delivery and catalysts in the future.34-36 ASSOCIATED CONTENT

Supporting Information. Dynamic light scattering, FT-IR spectra, UV-vis absorption spectra, the nitrogen adsorption-desorption isotherm, gel permeation chromatography, the cumulative release curves, zeta potential and thermogravimetry analysis.

AUTHOR INFORMATION Corresponding Author



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*(G.W.). Telephone: +86-10-62333619; e-mail: [email protected].

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We gratefully acknowledge financial support from the National Natural Science Foundation of China (Grant No. 51373025) and the Program for New Century Excellent Talents in University (NCET-11-0582).


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TOC


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NIR Light-, Temperature-, pH-, and Redox-Responsive Polymer

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