ARTICLE pubs.acs.org/JPCC
Preparation of pH-Responsive Mesoporous Silica Nanoparticles and Their Application in Controlled Drug Delivery Li Yuan,† Qianqian Tang,† Dong Yang,*,† Jin Zhong Zhang,‡ Fayong Zhang,§ and Jianhua Hu*,† †
Laboratory of Molecular Engineering of Polymers (Ministry of Education) & Laboratory of Advanced Materials, Department of Macromolecular Science, Fudan University, Shanghai 200433, China ‡ Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, United States § Department of Neurosurgery, Affiliated Huashan Hospital, Fudan University, Shanghai 200040, China ABSTRACT: Poly(acrylic acid) grafted mesoporous silica nanoparticles (PAA-MSNs) were prepared by a facile graftonto strategy, i.e., the amidation between PAA homopolymer and amino group functionalized MSNs. The resultant PAAMSNs were uniform spherical nanoparticles with a mean diameter of approximately 150 nm, and the graft amount of PAA evaluated by thermogravimetric analysis (TGA) was about 12 wt %. Due to the covalent graft of hydrophilic and pHresponsive PAA, the PAA-MSNs could be well dispersed in aqueous solution, which is favorable to be utilized as drug carriers to construct a pH-responsive controlled drug delivery system. N2 adsorptiondesorption isotherm results demonstrated that doxorubicin hydrochloride (DOX), a well-known anticancer drug, could be effectively loaded into the channels of PAA-MSNs through the electrostatic interaction. The loading content and the entrapment efficiency of DOX could reach up to 48% and 95%, respectively. The drug release rate of DOX@PAA-MSN was pH dependent and increased with the decrease of pH. The in vitro cytotoxicity test indicated that PAA-MSNs were highly biocompatible and suitable to use as drug carriers. The drug-loaded DOX@PAA-MSNs were distinctly cytotoxic to HeLa cells, due to the sustained release of drug, and showed higher clinical effects than free DOX. These results imply that the PAA-MSNs are promising platforms to construct pH-responsive controlled drug delivery systems for cancer therapy.
1. INTRODUCTION A controlled drug delivery system (CDDS) has been widely investigated and attracted increasing attention because it could offer many advantages, such as improved efficacy, reduced toxicity and side effects, reduced frequency of doses, and convenience.14 Up to date, many materials, e.g., liposomes,5 block copolymers,6 dendrimers,7 and various inorganic nanomaterials,8,9 have been utilized as drug carriers in CDDS. Among them, the mesoporous silica nanoparticle (MSN) has gained much importance due to its unique features, such as large surface area and pore volume, high chemical and thermal stability, excellent biocompatibility, and versatile chemistry for further functionalization.1015 Moreover, the MSN is composed of highly ordered mesoporous structures with uniform but adjustable pore size, which make it an excellent candidate for accommodating guest molecules, to provide a physical encasement that can protect the entrapped drugs from degradation and denaturization.1618 The earlier CDDS employing the MSN as a drug carrier was mainly based upon the physical and morphological properties of the MSN.1921 For instance, Vallet-Regi et al. have loaded ibuprofen into a series of MSNs with different pore sizes and found that the release rate of drug decreased with the decrease of pore size.22 However, in these systems, drug molecules were r 2011 American Chemical Society
simply physically adsorbed in the channels of MSNs and would be released immediately after administration,1921 which would cause undesirable side effects to normal cells and organs. Therefore, it is highly desirable to design a CDDS that can release the loaded drug in the specific environments by responding to external stimuli.23 To achieve this goal, a variety of stimuliresponsive MSN-CDDSs have been developed. Lin et al. have creatively used quantum dots,24 gold nanoparticles,25 iron oxide nanoparticles,26 and dendrimers27 as the gatekeepers to cap the pores of MSN and prevent the loaded drug from release. Thereafter, MSN-CDDSs based on various gatekeeper release mechanisms, such as the disulfide reduction mechanism,24 photochemistry mechanism,28 and redox mechanism,29 have been explored. However, most of these systems are complicated to synthesize, and the removed caps might induce toxic reaction to human bodies.2429 Besides the gatekeeper-controlled MSN-CDDSs, pH-responsive MSN-CDDSs have also attracted extensive research interest.3032 It is because the cancer cells have a more acidic environment compared with the normal cells,33,34 which Received: February 1, 2011 Revised: April 20, 2011 Published: May 04, 2011 9926
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The Journal of Physical Chemistry C provides an efficient way to control the drug release behavior by pH stimuli. Yang et al. have reported a smart pH-responsive CDDS based on carboxylic acid modified SBA-15 silica rods and poly(dimethyldiallylammonium chloride) for storage and release of vancomycin.35 Sun et al. have grafted a poly(2-diethylaminoethyl methacrylate) (PDEAEMA) shell onto the exterior surface of MSNs via surface-initiated atom transfer radical polymerization (ATRP), to produce a novel nanodevice with the MSN core as the drug carrier and the pH-responsive PDEAEMA shell as a smart nanovalve.11 To the best of our knowledge, most of the pH-responsive MSN-CDDSs are prepared by graft-from strategies, such as free radical polymerization and ATRP, which are either difficult to control the molecular weight of grafted polymers or need tedious processes to clean up the catalysts.35,36 Therefore, it is still a challenging work to explore a facile and efficient way to prepare pH-responsive MSN-CDDSs. Herein, we reported a facile graft-onto strategy to prepare a pH-responsive MSN-CDDS by the amidation reaction of poly(acrylic acid) homopolymer with amino groups modified MSNs. The resultant poly(acrylic acid) grafted MSNs (PAA-MSNs) were MCM-41 type of mesoporous materials, with a uniform diameter of about 150 nm. The covalently grafted PAA chains afforded not only hydrophilicity but also an abundance of carboxyl groups, to effectively load the drug by the electrostatic interactions. Doxorubicin hydrochloride (DOX), a well-known chemotherapeutic drug, was chosen as a model drug to assess the drug loading and releasing behaviors of PAA-MSN. The in vitro cellular cytotoxicity test was performed to evaluate the biocompatibility of PAA-MSN, and the cytotoxic effect of drug-loaded DOX@PAA-MSN to HeLa cells was also investigated.
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overnight in a vacuum at 45 °C for 12 h to give APS-MSN as white powder. APS-MSN (30 mg) was dispersed in 10 mL of DMF, and then 10 mg of PAA (Mw = 1800) was dissolved into the mixture. The reaction mixture was stirred at 140 °C for 2 h. After the reaction, the mixture was centrifuged and washed with copious ethanol. To ensure that the PAA physically adsorbed on MSN was removed completely, the washing procedure was repeated until the weight loss of PAA-MSN (calculated by TGA) did not change. The resultant product was dried overnight in a vacuum at 45 °C. The graft ratio of PAA was about 12 wt % evaluated by TGA. 2.3. Drug Loading and in Vitro Release. DOX was chosen as a model drug to assess the drug loading and controlled release behavior of MSN and PAA-MSN. Typically, MSN, PAA-MSN, and DOX were dispersed in deionized water to form 5 mg 3 mL1 solutions, respectively. Then, 2 mL of DOX solution was mixed with 2 mL of PAA-MSN solution, followed by diluting to 10 mL with pH = 7.4 PBS. The mixture was stirred at room temperature for 24 h to reach the equilibrium state. The DOX loaded PAAMSN (DOX@PAA-MSN) was collected by centrifugation at 12 000 rpm for 10 min. A similar procedure was conducted for MSN to give DOX@MSN. Both the DOX@PAA-MSN and DOX@MSN were washed five times with 2 mL of pH = 7.4 PBS to remove the physically absorbed DOX. The amount of loaded drug for PAA-MSN and MSN was determined by a UVvis spectrophotometer at 480 nm. The drug loading content and entrapment efficiency were calculated by the following equations Loading content ð%Þ ¼
Entrapment efficiency ð%Þ ¼
2. EXPERIMENTAL SECTION 2.1. Chemicals. Doxorubicin hydrochloride (DOX) was purchased from Beijing Huafeng United Technology Co., Ltd. Cell Counting Kit-8 (CCK-8) was purchased from Dojindo Molecular Technologies, Inc. Poly(acrylic acid) (PAA, Mw = 1800) was purchased from Aladdin. 3-Aminopropyltriethoxysilane (APS), tetraethyl orthosilicate (TEOS), N-cetyltrimethylammonium bromide (CTAB), and mesitylene (TMB) were purchased from Shanghai Chemical Reagent Co., Ltd. All the chemicals were analytical grade and used without further treatment. 2.2. Preparation of PAA-MSN. 1.0 g of CTAB and 7.0 mL of TMB were successively added into a solution containing 480 mL of deionized water and 3.5 mL of 2 mol 3 L1 NaOH(aq). After vigorous stirring at 80 °C for 4 h, 5.0 mL of TEOS was quickly added into the mixture. Then, the reaction was vigorously stirred at 80 °C for another 2 h. The resultant white precipitate was separated by filtration, washing with copious ethanol, and drying overnight in a vacuum at 45 °C. The structure-template CTAB and TMB were removed by refluxing in ethanol solution of ammonium nitrate (NH4NO3/C2H5OH, 10 mg 3 mL1) for 6 h at 80 °C. The template-removed product was filtrated and dried in a vacuum at 45 °C for 12 h to give MSN as a white powder. MSN (0.1 g ) was dispersed in 20 mL of anhydrous ethanol, and then the solution was heated to 80 °C. APS (1 mL) was added into the solution to functionalize MSN with amino groups. The reaction mixture was refluxed for 6 h, and followed by centrifugation, washing with ethanol for several times, and drying
Weight of drug in MSNs Weight of drug loaded MSNs Weight of drug in MSNs Initial weight of drug
In the in vitro drug release experiment, a certain amount of DOX@PAA-MSN powder was dispersed into 2 mL of deionized water. The dispersion was transferred into a dialysis bag (cut off molecular weight 7000 g 3 mol1), and then the bag was immersed into 100 mL of PBS solution with different pHs (5.6, 6.8, and 7.4) at room temperature with magnetic stirring. An amount of 1.0 mL of solution was withdrawn at a given time interval, followed by supplying the same volume of fresh PBS solution. The amount of released drug was measured by a UVvis spectrophotometer at 480 nm. 2.4. Cytotoxicity Assay. A human cervical cancer cell line (HeLa cells) was used to evaluate the cytotoxicity of PAA-MSN, DOX@PAA-MSN, and free DOX by a WST-8 assay. Cancer cells were seeded in 96-well plates at a density of 5000 cells per well and cultured in 5% CO2 at 37 °C for 24 h. Then, the cells were washed with PBS, and the medium was changed to fresh PBS mediums containing the indicated concentrations of PAA-MSN, DOX@PAA-MSN, and free DOX, respectively. At the end of the incubation (12 or 24 h), the cells were washed with fresh PBS to remove the DOX and PAA-MSN that were not taken up by the cells. After adding 10 μL of CCK-8 solution, the mixture was incubated for another 2 h. The absorbance of each well was measured at 450 nm with a plate reader. Cell viability was determined by the following equation Cell viability ð%Þ ¼ 9927
Isample Iblank Icontrol Iblank
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The Journal of Physical Chemistry C where Isample, Icontrol, and Iblank represent the absorbance intensity at 450 nm determined for cells treated with different samples, for control cells (nontreated), and for blank wells without cells, respectively. 2.5. Characterization. Transmission electron microscopy (TEM) images were obtained on a JEOL JEM 2100 F transmission electron microscope, and samples for TEM measurements were made by casting one drop of the sample’s ethanol solution on
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carbon-coated copper grids. The surface analysis was performed by nitrogen sorption isotherms at 77 K with a micromeritics ASAP2020 sorptometer. The surface areas were calculated by the Brunauer EmmettTeller (BET) method, and the pore size distributions were calculated by the BarrettJoynerHalenda (BJH) method. Powder X-ray patterns (XRD) were recorded on a Bruker D4 X-ray diffractometer with Ni-filtered Cu KR radiation (40 kV, 40 mA). The size distribution of the nanoparticles was measured by dynamic light scattering (DLS) using a Malvern autosizer 4700. Thermogravimetric analysis (TGA) was performed on a Perkin-Elmer Pyris 1 TGA instrument at a heating rate of 20 °C 3 min1 in a nitrogen flow from 100 to 750 °C. Fourier transform infrared (FT-IR) spectra were recorded on Nicolet Nexus 470. The UVvis absorbance spectra were measured with a Perkin-Elmer Lambda 35 spectrophotometer. The zeta potentials were measured by a Malvern Nano-HT Zetasizer.
3. RESULTS AND DISCUSSIONS
Figure 1. Schematic preparation process of PAA-MSN.
3.1. Graft-onto Strategy to Prepare PAA-MSN. The schematic preparation process of PAA-MSN was illustrated in Figure 1. To get MSN with pore size large enough to accommodate PAA chains and drug molecules, a widely used poreexpanding agent, TMB, was added along with CTAB. Subsequently, MSN was functionalized with amino groups both on the internal and external surfaces by reaction with APS, which would afford targets to the consequent functionalization with PAA. Finally, PAA chains were covalently grafted onto the internal and
Figure 2. (A) TEM images and (B) XRD pattern of MSNs.
Figure 3. Size distribution of (A) MSN and (B) PAA-MSN. 9928
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Figure 4. (A) N2 adsorptiondesorption isotherms and (B) pore-size distribution of MSN and PAA-MSN.
Figure 6. TGA curves of MSN, APS-MSN, and PAA-MSN.
Figure 5. FT-IR spectra of MSN-CTAB, MSN, APS-MSN, and PAAMSN.
external surfaces of MSNs by the amidation between the amino groups of MSN and the carboxyl groups of PAA. As shown in the TEM images (Figure 2A), the prepared MSNs were uniform spherical nanoparticles with a mean diameter of approximately 150 nm. In the highly magnified TEM image (Figure 2A, inset), a highly ordered mesoporous network with a hexagonal array could be clearly seen, which is the characteristic of MCM-41 type MSN. This is also confirmed by XRD measurement (Figure 2B), and four well-resolved diffraction peaks, assigned as (100), (110), (200), and (210) planes, respectively, are clearly observed in the XRD pattern of MSN, which is consistent with the characteristic diffraction pattern of MCM-41 type MSN.36,37 In addition, the hydrodynamic diameter and size distribution of MSN and PAA-MSN were measured by DLS. As shown in Figure 3, the diameter of MSN was 317 nm with a polydispersity index (PDI) of 0.31, larger than that observed from TEM because of the hydrate layer in aqueous environment. PAA-MSN showed a smaller diameter of 282 nm and a narrower PDI of 0.03, indicating that PAA-MSN possessed better dispersibility in water than MSN, due to the graft of hydrophilic PAA chains. The total surface areas and the average pore diameters of MSN and PAA-MSN were analyzed by the N2 adsorption/desorption
measurement. As shown in Figure 3, the BET isotherms of these two materials (Figure 4A) both exhibited the characteristic type of IV N2 adsorption/desorption patterns according to the IUPAC classification, with well-defined steps at relative pressures P/Po of 0.40.8, which indicated that both of them possess uniform mesoporous channels and narrow pore size distributions. Despite that the adsorbed nitrogen amount of PAA-MSN was reduced, the shape of the hysteresis loop remained unchanged, which indicated that the pore shape was not significantly changed after grafting with PAA. It could be calculated that the MSNs are with high specific surface area (SBET, 907 m2/g) and large cumulative pore volume (Vp, 1.461 cm3/g). After grafting with PAA, the SBET and Vp of PAA-MSNs were decreased to 552 m2/g and 0.623 cm3/g, respectively. This is because some of the channel entrances were covered by the PAA chains in the drying treatment process. Furthermore, the average pore size was also decreased from 3.9 nm for MSN to 3.0 nm for PAA-MSN (Figure 4B), which suggested that a portion of the PAA chains was grafted onto the internal surface of MSNs. The FT-IR spectra of MSN without removing CTAB (MSNCTAB), MSN, APS-MSN, and PAA-MSN were shown in Figure 5. Due to the large amount of CTAB present in the channels, MSN-CTAB gave the characteristic CH stretching vibrations at 2926 and 2859 cm1 and CH deformation vibration around 1473 cm1. After removal of CTAB, these CH peaks derived from CTAB all disappeared, and the broad adsorption peak in the range of 37503000 cm1 was due to the stretching vibration of the silanol group. After reacting with APS to form a SiOSi bond, this broad band was obviously reduced. Moreover, a new peak assigned to NH asymmetric bending vibration at 1555 cm1 and two peaks assigned to CH 9929
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stretching vibrations at 2940 and 2880 cm1 appeared, which confirmed the successful functionalization of MSNs with amino groups. After grafting with PAA, several new adsorption peaks appeared at 1553, 1654, and 1718 cm1, which could be assigned to the NH bending vibration, the CdO stretching vibration in the amide group, and the CdO stretching vibration in the carboxyl group, respectively, which indicated the successful grafting of PAA. This was also confirmed by the zeta potential characterization. As the existence of silanol groups on MSN, the zeta potential of MSN was 6.7 mV. Due to the successful functionalization with amino groups, the zeta potential of APSMSN was increased to 8.1 mV. After grafting with PAA, the zeta potential of PAA-MSN was decreased to 46.3 mV, which indicated the existence of a great amount of carboxyl groups. All these results suggested that the PAA chains were successfully grafted onto MSN. The grafted amount of PAA on MSN was estimated by TGA. As was shown in Figure 6, after heating to 750 °C, MSN, APSMSN, and PAA-MSN showed a weight loss of 12.3 wt %, 21.2 wt %, and 33.2 wt %, respectively. Thus, the graft ratio of PAA could be calculated to be about 12 wt %. In a control dispersion
experiment, 2 mg of MSN and PAA-MSN were dispersed in 2 mL of deionized water under sonication to form 1 mg 3 mL1 dispersion solutions, respectively. After standing for 1 week, most of the MSN was precipitated from the solution; however, no obvious precipitation was found in the PAA-MSN solution. Due to the covalent graft of hydrophilic PAA chains, the dispersibility of PAA-MSN in aqueous solution was evidently enhanced, which is a critical factor in biomedicine applications. 3.2. High Drug Loading Efficiency. As it was known, the pKas of DOX and PAA were 8.6 and 4.8, respectively.24,25 At pH 7.4, the positively charged DOX will bind with the negatively charged PAA to form the DOX@PAA-MSN complex by the electrostatic interaction. When DOX was just added into the PAA-MSN dispersion solution, the concentration of DOX was higher outside the PAA-MSNs than that inside the PAA-MSNs. Thus, the DOX would diffuse from the outside to the channels of PAAMSNs driven by the diffusion effect. This was supported by the nitrogen adsorption measurement. The SBET and Vp of DOX@ PAA-MSNs were drastically reduced, and the BET isotherm curve of DOX@PAA-MSN (Figure 7) demonstrated that the mesopores were inaccessible to nitrogen. The BJH analysis showed that all the pore sizes were bigger than 10 nm, which might be the interstices between nanoparticles. All these results suggested that the DOX was successfully encapsulated into the channels of PAA-MSN. The drug loading capacity of PAA-MSN at different weight ratio of DOX/PAA-MSN was listed in Table 1. The loading content and the entrapment efficiency of drug increased quickly
Figure 7. N2 adsorptiondesorption isotherms of DOX@PAA-MSN.
Table 1. DOX Loading Content and Entrapment Efficiency of PAA-MSNs DOX/PAA-MSN
loading content (%)
entrapment efficiency (%)
1
47.98
95.0
0.5
32.25
95.2
0.2 0.1
15.33 7.86
90.5 87.0
Figure 9. pH dependence of the zeta potentials of MSN.
Figure 8. pH-dependent release kinetics of (A) DOX@PAA-MSN and (B) DOX@MSN. 9930
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Figure 10. Relative cell viabilities of HeLa cells incubated with different concentrations of (A) PAA-MSNs for 12 and 24 h and (B) DOX and DOX@PAA-MSN for 24 h.
with the increase of DOX/PAA-MSN and could reach up to 48% and 95%, respectively, at DOX/PAA-MSN = 1. These results indicate that PAA-MSNs possess high drug loading efficiency to DOX. 3.3. pH-Responsive Drug Release Property. The in vitro drug release behaviors of DOX@PAA-MSN and DOX@MSN were studied in PBS buffers with different pHs (5.6, 6.8, and 7.4) at room temperature. It could be seen from Figure 8A that the drug release rate of DOX@PAA-MSN was obviously pH dependent and increased with the decrease of pH. The cumulative release amount of DOX could reach up to 70% after 24 h at pH 5.6, much higher than that at pHs 6.8 and 7.4, which was 42% and 13%, respectively. This is because with the decrease of pH more of the PAA was protonized, which would lead to the dissociation of electrostatic interaction between PAA and DOX, so that more of the incorporated DOX was released. Figure 8B demonstrated that the drug release of DOX@MSNs was also slightly pH dependent. This is because the zeta-potential of MSN is slightly pH dependent due to the existence of silanols on the surface of MSN (Figure 9). However, compared to DOX@PAA-MSNs, the released drug amount of DOX@MSNs could reach only 20%, 10%, and 5% in corresponding PBS buffer after 24 h, respectively, which indicated that the release amount is quite small and that the difference in release amount between different pH is not significant. It was apparent that DOX@PAA-MSN exhibited a more pronounced pH-dependent drug release behavior than DOX@MSN. Although a little DOX leached out based on a diffusion-controlled release mechanism similar to DOX@MSN at higher pH, most DOX had been effectively confined inside the channels of PAA-MSN. 3.4. In Vitro Cell Assay. The in vitro cell cytotoxicity of PAAMSN, DOX, and DOX@PAA-MSN to HeLa cells was investigated by WST-8 assay. It could be seen from Figure 10A that the PAA-MSNs showed no obvious cytotoxic effect on the HeLa cells at 0.1100 μg 3 mL1 after incubation for 12 and 24 h. As the concentration of PAA-MSNs was as high as 100 μg 3 mL1, the cell viability was about 90% after incubation for 24 h. These results demonstrated that the PAA-MSNs are nontoxic at low concentrations and slightly toxic at high concentrations. It was reported that the concentration of the mesoporous nanoparticles as drug platforms to kill cancer cells effectively was lower than 10 μg 3 mL1.38 Therefore, PAA-MSNs are highly biocompatibile and suitable to use as the drug carriers in CDDS. Figure 10B showed the in vitro cellular cytotoxicity of DOX and DOX@PAA-MSN to HeLa cells at different concentrations. The cytotoxicity of DOX and DOX@PAA-MSN increased with
the increase of their concentrations. It also can be seen that the cytotoxicity of DOX@PAA-MSN is almost the same as the free DOX in most tested concentrations. After 24 h incubations with free DOX and DOX@PAA-MSN, the cell viabilities were 80% and 64% at the concentration of 1 μg 3 mL1 and 18% and 13% at the concentration of 10 μg 3 mL1, respectively. It is interesting to note that the cytotoxicity of DOX@PAA-MSN was very similar to that of free DOX. The IC50 value (the concentration of drugs required to reduce cell growth by 50%) of DOX@PAA-MSN and free DOX was 1.9 and 3.0 μg/mL, respectively. In consideration of the above drug release results (minimal leakage at pH 7.4), these results suggest that DOX@PAA-MSN could be efficiently transferred into HeLa cells by a positive endocytosis mechanism.39
4. CONCLUSION In summary, PAA-MSNs were successfully prepared by a facile graft-onto strategy, i.e., the amidation between PAA homopolymers and amino group functionalized MSN. The resultant PAAMSNs were MCM-41 type of mesoporous materials, with a mean diameter of 150 nm. The loading and releasing behaviors of DOX were investigated. PAA-MSNs exhibited a high drug loading efficiency, due to the strong electrostatic interaction between PAA and DOX. The release rate of DOX was pH dependent, increasing with the decrease of pH. The in vitro cellular cytotoxicity test demonstrated that the PAA-MSNs are highly biocompatible and suitable to utilize as drug carriers in CDDS. Furthermore, DOX@PAA-MSNs showed a more efficient cytotoxicity than free DOX to HeLa cells. It can foresee that PAAMSNs are promising platforms to construct pH-responsive CDDS for cancer therapy. ’ AUTHOR INFORMATION Corresponding Author
*Dr. Dong Yang. Fax: þ86-21-65640293. Tel.: þ86-21-65642385. E-mail:
[email protected]. Dr. Jianhua Hu. Fax: þ86-21-65640293. Tel.: þ86-21-55665280. E-mail: hujh@ fudan.edu.cn.
’ ACKNOWLEDGMENT The authors thank the financial support from the National Natural Science Foundation of China (50873029 and 51073042), Shanghai Scientific and Technological Innovation Project 9931
dx.doi.org/10.1021/jp201053d |J. Phys. Chem. C 2011, 115, 9926–9932
The Journal of Physical Chemistry C (08431902300), and Shanghai Nano Special Project (1052 nm03702). Prof. J. Z. Zhang thanks the financial support from the Laboratory of Molecular Engineering of Polymers (Ministry of Education) of Fudan University.
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