Supramolecular Gelation of a Polymeric Prodrug for Its Encapsulation

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Supramolecular Gelation of a Polymeric Prodrug for Its Encapsulation and Sustained Release Dong Ma and Li-Ming Zhang* DSAPM Lab and PCFM Lab, Institute of Polymer Science, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China ABSTRACT: A polymeric prodrug, PEGylated indomethacin (MPEG-indo), was prepared and then used to interact with Rcyclodextrin (R-CD) in their aqueous mixed system. This process could lead to the formation of supramolecular hydrogel under mild conditions and simultaneous encapsulation of MPEG-indo in the hydrogel matrix. For the formed supramolecular hydrogel, its gelation kinetics, mechanical strength, shear-thinning behavior and thixotropic response were investigated with respect to the effects of MPEG-indo and R-CD amounts by dynamic and steady rheological tests. Meanwhile, the possibility of using this hydrogel matrix as injectable drug delivery system was also explored. By in vitro release and cell viability tests, it was found that the encapsulated MPEG-indo could exhibit a controlled and sustained release behavior as well as maintain its biological activity.

’ INTRODUCTION During the past few years, physical hydrogels have received much attention in the biomedical field, especially for the delivery of therapeutic drugs because of their useful properties.13 Such hydrogels can be obtained by noncovalent cohesive interactions including hydrophobic association, charge condensation, hydrogen bonding, stereocomplexation, or supramolecular self-assembly. Among them, the supramolecular hydrogels resulting from the inclusion complexation between R-cyclodextrin (R-CD) and various guest polymers have sparked growing interest in recent years. For example, Li et al.4 used poly(ethylene oxide)s and R-CD to form the supramolecular hydrogels as injectable drug delivery systems; Wang et al.5 used R-CD and poly(ethylene oxide)-b-poly(epsilon-caprolactone) diblock copolymer to prepare the supramolecular hydrogel for the local sustained intramyocardial delivery of recombined human erythropoietin; Ma et al.6 used the heparin-conjugated poly(ethylene glycol) methyl ether and R-CD to fabricate bioactive supramolecular hydrogels with controlled dual drug release characteristics; and Zhu et al.7 used the cisplatin-loaded block copolymer nanoparticles and R-CD to obtain the supramolecular hydrogels with a stepwise delivery property for cancer therapy. Compared with other physical hydrogels, these supramolecular hydrogels loaded with various therapeutic drugs are easier to be formed and modulated under mild conditions. Polymeric prodrugs are the conjugates of drug molecules with hydrophilic polymers such as poly(ethylene glycol), acrylic polymers, or polysaccharides.811 The drug molecules to be conjugated suffer generally from the following physicochemical properties: (1) lower water solubility, (2) instability at varied r 2011 American Chemical Society

physiological pH values, (3) higher systemic toxicity, and (4) reduced cellular entry. Up to now, numerous polymeric prodrugs have received regulatory approval and found practical applications.8,12 In particular, when poly(ethylene glycol) is covalently attached to paclitaxel, doxorubicin, camptothecin, adenosine deaminase, or aspartic acid, it can transfer many of this polymer’s favorable characteristics to the resulting prodrugs, such as increased circulating half-life in blood, enhanced proteolytic resistance, reduced immunogenicity and aggregation, as well as increased bioavailability and water solubility.13,14 For the improvement of further therapeutic efficacies and pharmaceutical properties of polymeric prodrugs, recent effort has been given to develop hydrophilic hydrogel matrices for their encapsulation and delivery. For example, Varghese et al.15 prepared in situ cross-linkable high-molecular-weight hyaluronanbisphosphonate conjugate to create a hydrogel-linked prodrug approach for localized delivery and cell-specific targeting; Gustafson et al.16 prepared silk-elastin-like hydrogel for improving the safety of adenovirus-mediated gene-directed enzyme-prodrug therapy; Mehrdad17 prepared novel pH-sensitive hydrogels for the colon-specific delivery of methacrylic-type polymeric prodrugs. In this work, we explored the supramolecular gelation of a polymeric prodrug, PEGylated indomethacin (MPEG-indo), for its encapsulation and sustained release. For this purpose, R-CD was used to interact with MPEG-indo in their aqueous mixed system. To understand and modulate this gelation process, Received: December 25, 2010 Revised: July 8, 2011 Published: July 24, 2011 3124

dx.doi.org/10.1021/bm101566r | Biomacromolecules 2011, 12, 3124–3130

Biomacromolecules we investigated not only the gelation kinetics but also the mechanical strength, shear-thinning behavior, and thixotropic response of resultant supramolecuar hydrogels by dynamic and steady rheometry under various amounts of MPEG-indo and R-CD. In addition, the in vitro release behavior and biological activity were also studied for this polymeric prodrug encapsulated in the supramolecular matrix.

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Scheme 1. Synthetic Route to PEGylated Indomethacin (MPEG-indo)

’ EXPERIMENTAL SECTION Materials. Indomethacin was purchased from Tokyo Chemical Industry Company and dried in vacuo at 45 °C for 24 h before use. Poly(ethylene glycol) methyl ethers (MPEG) with molecular weight of 5000 were purchased from Sigma and dried in vacuo at 60 °C for 24 h before use. R-CD was purchased from Tokyo Chemical Industry Company in Japan and used directly. N,N0 -Dicyclohexyl carbodiimide (DCC) and 4-dimethylamiopryidine (DMAP) were purchased from Sigma-Aldrich and used directly. Other organic solvents used for the synthesis were dried by CaH2 and distilled under reduced pressure. The human laryngocarcinoma (Hep-2) cells were provided by Animal Lab Center of SYSU (China). Synthesis of MPEG-indo and Its Characterization. In a round-bottomed flask, 0.358 g indomethacin (1 mmol) was dissolved in 10 mL of anhydrous DMSO to obtain a clear solution. To this, 0.309 g DCC (1.5 mmol) and 0.122 g DMAP (1.0 mmol) were added. After being stirred for 30 min, MPEG solution (4.5 g MPEG dissolved in 20 mL of DMSO) was added, and the resultant reaction mixture was then stirred at room temperature for 24 h. It was then filtered to remove side products to obtain a clear filtrate. The filtrate was added to diethyl ether to precipitate the product. After being dried under vacuum, MPEG-indo was obtained with a yield of 87.5%. Its chemical structure was characterized by 1H NMR spectrum with the help of a 300 MHz Bruker Avance DPX-300 spectrometer (using CDCl3 as the solvent). Supramolecular Gelation and Its Characterization. For the formation of supramolecular hydrogels, required concentrations of aqueous MPEG-indo and R-CD solutions were, respectively, prepared by using distilled water as the solvent. Depending on the amount of used MPEG-indo or R-CD, a gelation occurred at room temperature due to the hostguest interaction between MPEG-indo and R-CD in their aqueous mixed system. In this study, three MPEG-indo amounts (2.0, 3.0, and 4.0 wt % in the mixed system) and three R-CD amounts (6.0, 7.0, and 8.0 wt % in the mixed system) were used. For the investigation of supramolecular gelation mechanism, X-ray diffraction (XRD) measurements were performed by using a Rigaku D/max-2200 type X-ray diffractometer. The radiation source used was the Ni-filtered Cu KR radiation with a wavelength of 0.154 nm. The voltage was set to 40 kV, and the current was 30 mA. The proportional counter detector collected data at a rate of 2θ = 2°/min over the range 2θ = 550°. Differential scanning calorimetry (DSC) measurements were carried out using a DSC-200 PC (Netzsch, Germany) differential scanning calorimeter. The DSC thermograms covered a temperature range from 20 to 100 °C at a scanning rate of 20 °C/min. For the investigation of the gelation kinetics for aqueous MPEGindo/R-CD systems, time-sweep rheological analyses were performed by an advanced rheometric extended system (ARES, TA) in oscillatory mode with parallel plate geometry (50 mm diameter, 1.0 mm gap) at 25 °C. In this case, the samples were placed on the plate immediately after the mixing, and the measurement began after 2 min. The viscoelastic parameters were measured as a function of time within the linear region previously determined by a strain sweep. To investigate the mechanical property of resultant hydrogels, dynamic frequency sweep tests were conducted. In this case, the hydrogel samples were allowed to consolidate for 12 h before the measurements. The frequency applied to

hydrogel sample increased from 0.1 to 100 rad/s. In addition, steady rate sweep tests were carried out to investigate the shear thinning and thixotropic properties of resultant hydrogels. In this case, the hydrogel samples were also allowed to consolidate for 12 h before the measurements. In Vitro Release Test. For each release system, a total of 1.0 mL of solution formulation was injected into a 10 mL tube and then set overnight for hydrogel formation. Phosphate buffer saline (PBS, 4.0 mL, 0.01 mol/L, pH 7.4) was added to the tube as the release medium. The tube was incubated in a shaking water bath with a 60 stroke/min at 37 °C during the test. At a given time point, 2.0 mL of supernatant was collected from each tube, which was then replaced by the same amount of fresh prewarmed PBS. The time for each sampling was determined to be ∼30 s, in which the mixture did not approach the equilibrium. The amount of released MPEG-indo was determined by a UV spectrophotometer (S52, China) at the absorbance wavelength of 320 nm. All release studies were carried out in triplicate. Cell Viability Test. The viability of human laryngocarcinoma (Hep2) cells was determined by a methyl thiazol tetrazolium (MTT) bromide assay to evaluate the biological activity of released MPEG-indo. Hep-2 cells were seeded onto a 96-well plate at a density of 4000 cells per well and then cultured at 37 °C in a humidified 5% CO2 atmosphere for a determined time. Then, the encapsulated MPEG-indo released at different time points from the resultant hydrogel sample was added to the plate. The cells were then incubated for 24 h. The MPEG-indo concentration for each well was kept to be 8.0 μmol/L. After that, 20 μL of MTT solution (5 mg/mL in PBS) was added to each well, followed by 4 h of incubation. After the culture medium was suctioned completely, 150 μL per well of DMSO was added to dissolve the formed formazan crystals. The absorbance that correlated with the number of viable cells in each well was measured by an MRX-microplate reader at 490 nm. 3125

dx.doi.org/10.1021/bm101566r |Biomacromolecules 2011, 12, 3124–3130

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Figure 1. 1H NMR spectrum of PEGylated indomethacin (MPEGindo) in CDCl3 (25 °C).

Figure 3. XRD patterns (a) and DSC curves (b) of R-CD, MPEG-indo, and freeze-dried hydrogel sample formed in situ from 3.0 wt % MPEGindo and 7.0 wt % R-CD.

Figure 2. Photographs for the formation of a supramolecular hydrogel sample from 3.0 wt % (in the mixed system) of MPEG-indo and 7.0 wt % (in the mixed system) of R-CD at room temperature. The absorbance of the test group treated with the released MPEG-indo was compared with that of the control group to obtain the percentage of cell viability. For comparison study, the cell viabilities of Hep-2 incubated with the PBS media without and with free MPEG-indo were also evaluated under the same experimental conditions.

’ RESULTS AND DISCUSSION The polymeric prodrug, MPEG-indo, could be prepared through an esterification reaction between the hydroxyl group from MPEG and the carboxylic acid group from indomethacin accoding to the synthetic route indicated in Scheme 1. Its chemical structure could be characterized by 1H NMR analysis. As seen from Figure 1, the 1H NMR spectrum of MPEG-indo shows not only the characteristic proton peaks of conjugated indomethacin at 2.38 ppm (CH3 for j) and 6.727.66 ppm (Ar-H for f, h, g, l, and k)18 but also the characteristic proton peaks of conjugated MPEG at 4.25 ppm (CH2CH2O of MPEG end unit for d) and 3.64 ppm (CH2CH2O of MPEG homosequence units for b).19 By calculating the peak area ratio of methylene protons from conjugated MPEG (δ 4.25, d) and methyl protons from conjugated indomethacin (δ 2.38, j), 100 MPEG molecules were found to be conjugated with 96 indomethacin molecules. For such a polymeric prodrug, we observed that it could be dissolved in water to form homogeneous solution. In particular, aqueous MPEG-indo solution could be transformed into the invertable hydrogel in some cases when R-CD was introduced, as

shown in Figure 2. Depending on MPEG-indo or R-CD amount, this gelation could occur under mild conditions without high temperature and the use of chemical emulsifier or cross-linker. This phenomenon may be attributed to the formation of inclusion complexes between MPEG-indo and R-CD in their aqueous mixed system. To confirm this, we measured the XRD patterns and DSC curves of R-CD, MPEG-indo, and freeze-dried hydrogel sample formed in situ from 3.0 wt % of MPEG-indo and 7.0 wt % of R-CD, as shown in Figure 3. From Figure 3a, the hydrogel sample was observed to have two characteristic diffraction peaks at 2θ = 19.8° (d = 4.44 Å) and 22.6° (d = 3.94 Å), which were not observed in the patterns of MPEG-indo and R-CD. These two peaks could represent the channel-type structure of MPEG-indo/R-CD complex.20,21 From Figure 3b, a distinct endothermic peak at 60.9 °C was observed for MPEG-indo, corresponding to the melting point of poly(ethylene glycol) chain crystalline.22 After the gelation, this melting point was shifted to a lower temperature (58.6 °C), implying that poly(ethylene glycol) chain was included in the channel of R-CD so as to impede the crystalline phase formation. Similar phenomenon was also observed by Wei et al.22 when they investigated the self-assemblies of R-CD threaded onto the amphiphilic copolymer containing poly(ethylene glycol) chain. Therefore, MPEG-indo/R-CD inclusion complexes were formed in the hydrogel sample, which might act as physical cross-links and then result in the supramolecular hydrogel networks. To confirm that indomethacin did not participate in the complex formation, we also carried out the XRD analysis for the free indomethacin/R-CD system in the melting state and did not find any characteristic diffraction peaks or a decrease in the relative crystallinity. Similarly, Wulff and Alden23 investigated the complex formation of indomethacin with R-, β-, and γ-CD in the presence of polyethylene glycol (PEG) 6000 by XRD, DSC, and 3126


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Figure 4. Effects of MPEG-indo and R-CD amounts on the supramolecular gelation kinetics. Test conditions: frequency, 1.0 rad/s; strain, 1.0%; temperature, 25 °C.

dissolution tests. As a result, no complexation of indomethacin with R-CD could be detected. To investigate the effects of MPEG-indo and R-CD amounts on the supramolecular gelation, we carried out time sweep measurements for the viscoelastic properties of each system, in which the storage modulus (G0 ) and loss modulus (G00 ) were monitored as a function of time. Figure 4 shows the time dependences of G0 and G00 for various MPEG-indo/R-CD systems. In each case, a crossover point between G0 and G00 was observed, which implied that there was a solgel transition.24 Beyond the crossing, the G0 value becomes larger than the G00 value, indicating that the system becomes more elastic. The corresponding time of the crossover from a viscous behavior to an elastic response could be regarded as the gelation time.23 From Figure 4, the gelation time was found to decrease with the increase in MPEG-indo or R-CD amount. When the amount of MPEG-indo increased from 2.0 to 4.0 wt %, the gelation time decreased from 48.7 to 25.8 min. When the amount of R-CD increased from 6.0 to 8.0 wt %, the gelation time decreased from 74.5 to 15.7 min. These results indicate that a higher MPEG-indo or R-CD amount would be favorable for the supramolecular gelation, which may be attributed to an enhanced inclusion complexation between MPEG-indo and R-CD in this case. For the resultant supramolecular hydrogels, their elastic moduli (G0 ), shear-dependent viscosity, and thixotropic property were also investigated with respect to the effects of MPEG-indo and R-CD amounts. Figure 5 shows the changes of G0 with the amounts of MPEG-indo and R-CD. As seen, the G0 value of resultant hydrogel increased with the increase in MPEG-indo or R-CD amount. At a frequency of 1.0 rad/s, for example, the G0 value increased from 127 to 401 kPa when MPEG-indo amount increased from 2.0 to 4.0 wt % and increased from 6.2 to 425 kPa

Figure 5. Effects of MPEG-indo and R-CD amounts on the elastic moduli (G0 ) of the in situ formed supramolecular hydrogels. Test conditions: strain, 1.0%; temperature, 25 °C.

when the R-CD amount increased from 6.0 to 8.0 wt %. Moreover, all G0 values showed a weak dependence on frequency except for those in the case of low R-CD amount (6.0 wt %). These facts confirm that the hydrogels were well cross-linked with insignificant sol fraction. It is well known that remarkable shear-thinning and thixotropic properties are required and important for the development 3127


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Figure 6. Change of steady shear viscosity as a function of shear rate for the supramolecular hydrogels formed in situ under various MPEG-indo and R-CD amounts. Test conditions: 1.0% strain, 25 °C.

Figure 7. Thixotropic responses of the supramolecular hydrogels formed in situ under various MPEG-indo and R-CD amounts. Test conditions: 1.0% strain; 25 °C.

of injectable drug delivery systems, which have recently drawn much attention because of the elimination of sugical implantation and retrieval.2528 To explore the possibility of using the resultant supramolecular hydrogel as injectable drug carrier, we carried out steady rate sweep tests for the hydrogel samples. Figure 6 gives steady shear viscosity as a function of shear rate for the supramolecular hydrogels formed in situ under various MPEG-indo and R-CD amounts. It was found that all of the hydrogel samples exhibited a shear-thinning behavior, regardless of MPEG-indo or R-CD amount. In other words, the viscosity of

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the hydrogel sample greatly diminished as it was sheared. This rheological property may render the resultant supramolecular hydrogel injectable through a hypodermic needle. Further investigation was dealt with the thixotropic property of these hydrogel samples at 25 °C. For this purpose, the flow curves were measured by increasing the shear rate from a minimum of 0.83 s1 to a maximum of 50 s1 and then decreasing the shear rate in the same equal steps. The duration of shear at each step was 60 s. This method is similar to that adopted by Saunders29 when he studied the thixotropic behavior of thickened polystyrene latexes. If the supramolecular hydrogels investigated exhibit the thixotropy, then a hysteresis loop could be obtained from these “upward” and “downward” curves developed during reversible shear stressshear rate paths, and the corresponding enclosed area could be used to evaluate the magnitude of the thixotropy. Figure 7 shows the thixotropic responses of the supramolecular hydrogels formed under various MPEG-indo and R-CD amounts in aqueous systems (pH 7.4). It was found that the thixotropic property of the resultant supramolecular hydrogel could build up with the increase oin MPEGindo or R-CD amount. As listed in Table 1, the hysteresis loop area increased from 85.59 to 179.56 kPa s1 when MPEG-indo amount increased from 2.0 to 4.0 wt % and increased from 2.45 to 256.78 kPa s1 when the R-CD amount increased from 6.0 to 8.0 wt %. It is known30 that the thixotropy of a material is quantified by its ability to regain its gel structure when it is allowed to rest for a period of time after the sol phase is attained. Therefore, the supramolecular hydrogel in this study has an ability to build up its structure from sol to gel, especially in the case of higher MPEG-indo and R-CD amounts. This may become an advantage when such a hydrogel is used as injectable drug delivery system. From the viewpoint of practical application, more investigations should be done with respect to this supramolecular gelation and thixotropy under physiologically relevant conditions (in 0.9% NaCl at 37 °C), which will be our next work. For the encapsulated MPEG-indo, its in vitro release profiles from the supramolecular hydrogels formed under various MPEG-indo and R-CD amounts were measured in pH 7.4 PBS at 37 °C, as shown in Figure 8. In each case, there was a sustained release behavior without initial burst release. Moreover, the release kinetics was dependent on the hydrogel composition. As seen, the hydrogels with lower amounts of MPEG-indo and R-CD resulted in much faster release kinetics (Figure 8A, 2.0 wt % MPEG-indo; Figure 8B, 6.0 wt % R-CD), and the hydrogels with higher amounts of MPEG-indo and R-CD resulted in much slower release kinetics (Figure 8A, 4.0 wt % MPEG-indo; Figure 8B, 8.0 wt % R-CD). These facts indicated that the complexation between MPEG-indo and R-CD played a key role in the formation of a stable supramolecular hydrogel. To understand better the effects of MPEG-indo and R-CD amounts on the release rate of encapsulated MPEG-indo, we fitted the data from the curves of Figure 8 to the following Higuchi equation31 Q ¼ kH t 1=2 (1)where Q is the cumulative amount of drug release at time t and kH is the Higuchi constant that can be considered to be a measure of drug release rate.32 By plotting log (Q) versus log (t), we obtained the kH values as well as the corresponding determination coefficients (R2), as listed in Table 2. It was found that all release profiles were well-fitted to the Higuchi equation with 3128


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Table 1. Effects of MPEG-indo and r-CD Amounts on the Hysteresis Loop Area for the Resultant Supramolecular Hydrogel integrating area for down curve

hysteresis loop area (kPa 3 s-1)

hydrogel compositions

integrating area for up curve

2.0% MPEG-indo + 7.0% R-CD

207.99

122.40


401.75

312.70

89.05


771.43

591.87

179.56

6.0% R-CD + 3.0% Hep-MPEG

88.40

85.95

2.45


401.75

312.70

89.05


623.97

367.19

256.78

Effect of MPEG-indo Amount 85.59

Effect of R-CD Amount

Figure 9. Photographs (20) and viability of Hep-2 cells incubated in the PBS media without and with free MPEG-indo as well as the media containing the encapsulated MPEG-indo released from the supramolecular hydrogel (3.0 wt % MPEG-indo + 7.0 wt % R-CD) at various time points. Figure 8. Cumulative release profiles of encapsulated MPEG-indo from the supramolecular hydrogels formed under various MPEG-indo amounts (A) and R-CD amounts (B). Test conditions: pH 7.4 PBS; 37 °C.

Table 2. Release Kinetics Constants Obtained by Fitting with Higuchi Model for Supramolecular Hydrogels with Different Compositions hydrogel compositions

kH/(day)1/2

R2

Effect of MPEG-indo Amount 2.0% MPEG-indo + 7.0% R-CD

0.150

0.991


0.134

0.993


0.126

0.993

Effect of R-CD Amount 6.0% R-CD + 3.0% Hep-MPEG

0.186

0.996


0.134

0.993


0.118

0.998

R2 > 0.99, and the kH values decreased with the increase in MPEG-indo or R-CD amount. These results implicate that the release properties of the supramolecular hydrogels can be finetuned by the amount of MPEG-indo or R-CD. In addition, we

also observed that the hydrogels gradually disintegrated and dissolved in the release medium during the release of MPEGindo. Therefore, it is thought that the release of encapsulated MPEG-indo is controlled mainly by the dissolution and dissociation of the supramolecular hydrogel rather than by a diffusion mechanism. According to a previous study,33 indomethacin polyoxyethylene esters as the prodrugs had a notable stability in phosphate buffer at pH 7.4 but could reconvert into the parent drug in the presence of human plasma. Because of mild encapsulation by the supramolecular gelation, the released MPEG-indo is expected to maintain its biological activity. To confirm this, we measured the viability of Hep-2 cells before and after the treatment with the release media containing the encapsulated MPEG-indo by MTT assay. In this case, the supramolecular hydrogel matrix was formed from 3.0 wt % MPEG-indo and 7.0 wt % R-CD, and the release media were collected at 1st, 3rd, 7th, and 14th day, respectively. Meanwhile, two control tests were also performed using PBS media without and with free MPEG-indo. Figure 9 gives the photographs and viability of Hep-2 cells incubated with various culture media. As seen, the cell viability in the PBS medium without prodrug was close to 100%. In contrast, the cell viability in the medium with free prodrug or released prodrug has an obvious decrease. In particular, no significant difference in the cell viability was 3129


Biomacromolecules observed for free prodrug and released prodrug. Moreover, the release time of encapsulated prodrug did not induce an obvious change in the cell viability. It is known34,35 that indomethacin as a nonsteroidal anti-inflammatory drug can reduce or inhibit the proliferation rate of tumor cells. Some investigations36 have shown that R-CD used for the formation of supramolecular hydrogel is noncytotoxic. Therefore, a decrease in the viability of Hep-2 cells after the treatments implies that the released MPEGindo has the biological activity similar to free MPEG-indo. In other words, the biological activity of MPEG-indo could be maintained after its supramolecular gelation. Moreover, the encapsulation time of MPEG-indo did not affect obviously its biological activity.

’ CONCLUSIONS The PEGylation of indomethacin provides this hydrophobic drug with good water solubility and the supramolecular gelation property in the presence of R-CD. This gelation process could be carried out under mild conditions without high temperature and the use of chemical emulsifier or cross-linker. In particular, PEGylated indomethacin (MPEG-indo) could be encapsulated in the supramolecular hydrogel matrix. Moreover, the encapsulated MPEG-indo has a controlled and sustained release behavior and could maintain its biological activity. Depending on MPEGindo and R-CD amounts, the resultant supramolecular hydrogel has an adjustable gelation time, mechanical strength, shear thining, and thixotropic properties. This study provides a novel drug-entrapment strategy for hydrophilic hydrogel-based carriers to deliver poorly soluble drugs. Because other therapeutic agents such as cells, drugs, and growth factor drugs could be incorporated into the supramolecular hydrogel matrix by simple premixing, this study also provides a new route for the development of controlled dual- or multidrug delivery systems. ’ AUTHOR INFORMATION Corresponding Author

*Tel/Fax: (+86) 20-84112354. E-mail: [email protected].

’ ACKNOWLEDGMENT This work is supported by National Natural Science Foundation of China (21074152 and 20874116), Natural Science Foundation of Guangdong Province in China (8151027501000004 and 9151027501000105), Doctoral Research Program of Education Ministry in China (20090171110023), and China Postdoctor Foundation (20100480802).

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Supramolecular Gelation of a Polymeric Prodrug for Its Encapsulation

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