Article pubs.acs.org/cm
A Polydopamine Nanoparticle-Knotted Poly(ethylene glycol) Hydrogel for On-Demand Drug Delivery and Chemo-photothermal Therapy Xing Wang,† Changping Wang,† Xinyu Wang, Yitong Wang, Qiang Zhang,* and Yiyun Cheng* Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, P.R. China S Supporting Information *
ABSTRACT: Hydrogels have exhibited remarkable benefits in drug delivery such as local delivery, days or even weeks of continuous drug release with improved bioavailability, and minimized adverse effects. Here we report a polydopamine (PDA) nanoparticle-knotted poly(ethylene glycol) (PEG) hydrogel for on-demand drug delivery and combined chemo-photothermal therapy. Anticancer drugs such as 7-ethyl-10-hydroxycamptothecin (SN38) loaded on PDA nanoparticles via π−π interaction in the gel exhibit minimal leakage at physiological conditions and could be released in an on-demand fashion upon near-infrared light exposure. The hydrogel shows excellent biocompatibility and does not induce any foreign-body reaction over a four-month implantation. The in vivo results demonstrate that the PDA nanoparticle-knotted PEG hydrogel loaded with SN38 could efficiently suppress tumor growth by a combined chemo-photothermal therapy. This smart hydrogel would benefit a series of local treatments for diverse diseases.
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ity,20−22 resulting in reduced safety of the PEG hydrogels. The second issue is related to the control of drug release. Therapeutic agents are commonly physically entrapped in the network of PEG hydrogels,23,24 which complicates regulation of drug release with highly temporal resolution and is characterized by burst release at the beginning and slow leakage during the long time of implantation in the body.25,26 A third problem is that many PEG hydrogels are generally nondegradable.27,28 Although PEG is highly biocompatible, a permanent retention of PEG hydrogels in the body even after the complete release of drugs or the cure of diseases increases the risk of foreign-body reactions and other unexpected adverse effects. Therefore, additional research efforts are in demand to address these problems for the clinical translation of PEG hydrogels. Nanocomposite hydrogels that incorporate nanoparticles in their network via chemical or physical interactions might provide a new opportunity for the performance improvement of PEG hydrogels. Polydopamine (PDA), a major component of melanin, possesses excellent biocompatibility and is biodegradable in the body.29−31 Polydopamine nanoparticles (PDANPs) were reported to have high drug loading capability and photothermal effect.32−34 Additionally, chemicals with thiol or amine groups can be feasibly conjugated on the surface of PDANPs.35,36 In this study, we used PDANPs as a cross-linking agent to cross-link a thiol-terminated four-arm PEG (4-arm-
INTRODUCTION There are diverse clinical indications such as cancers, central nervous diseases, diabetes, and skeletal diseases that require a long-term performance of therapeutics.1−4 An ideal drug treatment to manage these diseases is to maintain the drugs locally for a long period and to control the drug release in an on-demand fashion. Hydrogels, mostly composed of hydrophilic polymers to form a three-dimensional network, have been well used as a matrix scaffold for local drug delivery.5−7 Stimuli-responsive hydrogels not only provide a spatial control of the release of therapeutics8 but also offer a temporal management of the release of drugs in response to different stimuli.9−11 Recent development of stimuli-responsive nanoscale systems, which are able to control the drug release in response to either exogenous stimuli such as light, magnetic field, and ultrasound or endogenous ones including pH, enzymes, and redox potential,12−14 provides materials and principles for the fabrication of stimuli-responsive hydrogels for drug delivery. Poly(ethylene glycol) (PEG) has been widely used as a polymer basis to fabricate hydrogels due to its unique properties including great biocompatibility, no adhesiveness to proteins and cells, and excellent hydrophilic nature.15 PEGbased hydrogels have been used to deliver diverse therapeutic agents such as chemical drugs, proteins, oligonucleotides, and polysaccharides.16−19 Although PEG hydrogels are promising for clinical applications, they still have some problems that need to be addressed. The first problem involves hydrogel fabrication. Cross-linking agents used to cross-link the PEG chains and the related chemical reactions might cause unexpected toxic© 2017 American Chemical Society
Received: December 8, 2016 Revised: January 11, 2017 Published: January 11, 2017 1370
DOI: 10.1021/acs.chemmater.6b05192 Chem. Mater. 2017, 29, 1370−1376
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Figure 1. Preparation and characterization of the PDA-knotted PEG hydrogel. (a) Preparation of PDA/PEG hydrogel. PDANPs were used as a cross-linking agent to cross-link 4-arm-PEG-SH. (b) Fabrication of a star-shaped PDA/PEG hydrogel. (c, d) SEM images of PDA/PEG hydrogel. (e) Dynamic G′ and G″ moduli of PDA/PEG hydrogel. The mixture of 4-arm-PEG-SH and PDANPs was blended by a Vortex mixer for 10 min. After that, the rheology of the mixture was measured by a hybrid rheometer. (f) The shear-thinning behavior of PDA/PEG hydrogel. (g) Photothermal effect of PDA/PEG hydrogel irradiated with NIR light at 3.6 W cm−2 for 10 min.
Figure 2. NIR-triggered drug release from PDA/PEG hydrogel. (a) Schematic represents SN38 loaded on PDANPs via π−π stacking and released from PDA/PEG hydrogel upon NIR irradiation. (b) UV−vis spectra of PDANPs loaded with different amounts of SN38. (c) NIR light-triggered drug release from PDA/PEG hydrogel (8.3% drug loading). The hydrogel was intermittently irradiated by NIR light at 3.6 W cm−2 for 10 min each time.
PEG-SH) to form a PDA/PEG hydrogel. The hydrogel was injectable and could be fabricated into different shapes. It also
exhibited excellent biocompatibility and did not induce any foreign-body reaction over a 4-month implantation. Owing to 1371
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Figure 3. In vitro and in vivo toxicity of PDA/PEG hydrogel. (a, b) Cytotoxicity of PDANPs (a) and 4-arm-PEG-SH (b) on NIH3T3 cells. (c) Cytotoxicity of PDA/PEG hydrogel on NIH3T3 cells. The culture media immersed with PDA/PEG hydrogel were collected and incubated with cells for 48 h. (d) The body weight changes of mice subcutaneously injected with PBS and PDA/PEG hydrogel. (e) The hematological parameters of mice analyzed 4 months after injection of PDA/PEG hydrogel and PBS. (f) Collagen formation around the tissues injected with PBS and PDA/PEG hydrogel. The tissues were stained with Masson’s trichrome.
the existence of PDANPs, the hydrogel could load anticancer drugs such as 7-ethyl-10-hydroxycamptothecin (SN38) and maintain the drug in the gel network for a long period, and further controlled the drug release in an on-demand manner upon near-infrared (NIR) irradiation. PDANPs also endowed the hydrogel excellent photothermal effect. A combined chemophotothermal therapy mediated by the prepared hydrogel was conducted to ablate solid tumors.
hydrogel was further analyzed for the evolution of its viscosity along with the shear rate at a strain of 0.1%. The data suggest that it represented a typical shear-thinning behavior (Figure 1f).37 Because PDANPs can efficiently convert NIR irradiation into heat,38 the hydrogel also exhibited an excellent photothermal effect (Figure 1g). We previously demonstrated that chemical drugs such as doxorubicin could be loaded on PDANPs via π−π stacking and/or hydrogen bonding interactions,39 and that the loaded drugs could be released by exposure to NIR light.32,40 Therefore, the prepared PDA/PEG hydrogel should also have the capability for light-responsive drug release. To identify this possibility, anticancer drug SN38 was primarily loaded on PDANPs. The drug loading ratio of SN38 on PDANPs was determined according to the unique absorbance of SN38 in the ultraviolet-visible (UV−vis) spectra (Figure 2b and SI Figure S2), and the loading capability was tailorable (Figure 2b). Although the transmission electron microscopy (TEM) image reveals that there was no obvious morphology change for PDANP−SN38 compared with the fresh PDANPs (SI Figure S3a), the hydrodynamic size of PDANP−SN38 was significantly increased by ∼17 nm (SI Figure S4a,b), indicating that SN38 was successfully loaded on the PDANPs. The zeta potential of the PDANPs was minimally changed after SN38 loading (SI Figure S4c). PDANP−SN38 was then used to fabricate the PDA−SN38/PEG hydrogel (Figure 2a). The SEM image reveals that polymer-like matter coated individual PDANPs in the prepared hydrogel (SI Figure S3b), which confirms that SN38 was loaded on PDANPs in the hydrogel. PDA−SN38/PEG hydrogel was further immersed in a phosphate-buffered solution (PBS) for a long period. During the incubation, there was minimal SN38 released from the hydrogel (SI Figure S5), indicating that the hydrogel could
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RESULTS AND DISCUSSION The hydrogel was prepared by simply mixing PDANPs and 4arm-PEG-SH together in aqueous solution (Figure 1a). The catechol groups on PDANPs can be oxidized into quinones,29,35 which can further react with nucleophiles such as thiol and amine groups via Michael addition and/or Schiff base reactions.29 Therefore, 4-arm-PEG-SH can react with PDANPs to form a hydrogel. We synthesized spherical PDANPs with uniform size of 78.1 ± 11.2 nm in diameter (Supporting Information (SI) Figure S1), and 4-arm-PEG-SH with a molecular weight of ∼20 kDa was used for the hydrogel preparation. The cross-linking reaction between 4-arm-PEG-SH and PDANPs lasted for about 30 min to form a solid gel, resulting in a mixture of the two components as injectable and able to be fabricated into different shapes (Figure 1b). The scanning electron microscopy (SEM) images reveal that the microstructure of the hydrogel was composed of a high density of PDANPs (Figure 1c,d), which was a reasonable observation because PDANPs have a relatively larger size compared with 4arm-PEG-SH. The dynamic rheological behavior of the hydrogel was further investigated. As shown in Figure 1e, the storage modulus (G′) and the loss modulus (G″) were recorded along with time, and the result indicates that it took approximately 12 min for the sol transformation to the gel. The 1372
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Figure 4. In vivo chemo-photothermal treatment of tumors by PDA−SN38/PEG hydrogel. (a) Therapeutic procedure: Mice bearing PC-9 tumors in six groups were treated with PBS, PBS+NIR, PDANP−SN38, PDA/PEG hydrogel+NIR (gel+NIR), PDA−SN38/PEG hydrogel (Gel−SN38), and PDA−SN38/PEG hydrogel+NIR (gel−SN38+NIR), respectively. (b) Tumor-site temperature changes during each NIR irradiation. NIR irradiation was performed at 0.58 W·cm−2 for 5 min each time. (c) The evolution of tumor volume in different groups. (d, e) Photograph of the excised tumors (d) and their average weight (e).
vitro. Furthermore, we subcutaneously injected the hydrogel in the back of mice and then raised the mice over 120 days. During the period of breeding, there was no significant body weight change between the mice injected with hydrogel and PBS (Figure 3d). The hematological parameters including red blood cell (RBC), hemoglobin (Hb), white blood cell (WBC), lymphocyte (LY#), and neutrophil granulocyte (NE%) were further determined after the sacrifice of mice. The data reveal that the hematological parameters of mice injected with hydrogel had a value similar to those of mice treated with PBS (Figure 3e). Acute and chronic inflammatory responses to hydrogel would lead to the formation of a collagen capsule around the hydrogel.44 Masson’s trichrome stain, which stains collagen blue, cytoplasm red, and nuclei black, was used to identify the formation of collagen capsules in the tissues around the hydrogel.45 As shown in Figure 3f, there was no observed formation of collagen capsules around the hydrogel over a 4month implantation, which indicates that PDA/PEG hydrogel did not arouse a foreign-body reaction. Finally, the histological examination of the main organs including heart, liver, spleen, lung, and kidney reveals that there was no detectable pathological change in these organs (SI Figure S7), indicating minimal systemic toxicity induced by the PDA/PEG hydrogel. All the results from in vitro and in vivo studies suggest that PDA/PEG hydrogel was biocompatible. Previous reports in the literature suggest that PDANPs were slowly oxidized by reactive oxygen species in the body and further degraded,46 which indicates that the PDA/PEG hydrogel might also
effectively retain chemical drugs at physiological conditions. When the hydrogel was irradiated by an NIR laser, SN38 was released in an “off-on” fashion (Figure 2c). However, only a small amount of SN38 was released from the nonirradiated hydrogel (Figure 2c). A problem that exsisted in many previous studies in drug delivery with hydrogels is that a burst release of the drug commonly occurs at the beginning.41,42 This is attributed to the drugs being physically entrapped in the hydrogel network and the concentration gradient-directed drug diffusion from the hydrogel. In our case, the chemical drug was loaded on PDANPs via strong π−π stacking interaction,29 which could effectively retain the drugs in the hydrogel at physiological conditions. Therefore, no burst release occurred at the beginning. These data suggest that the PDA/PEG hydrogel could effectively retain chemical drugs and then release them in response to NIR light in an “off-on” manner. We further systematically investigated the biocompatibility of PDA/PEG hydrogel in vitro and in vivo. The two components of the hydrogel, PDANPs and 4-arm-PEG-SH, were first incubated with the normal NIH3T3 cells at different concentrations. The results suggest that both of them had no observable cytotoxicity (Figure 3a,b), which is consistent with the previously reported literature.29,43 Because PEG was nonadhesive toward proteins and cells,15 we immersed the hydrogel in culture media for a period and then treated NIH3T3 cells with the culture media for 48 h. No reduction of the cell viability was detected (Figure 3c and SI Figure S6). These results suggest that the hydrogel had no cytotoxicity in 1373
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Preparation of PDANPs. PDANPs were synthesized according to a previously reported method. In a typical synthesis, 0.335 mL of ammonia aqueous solution (28−30%) was added to a mixture of 4 mL of ethanol and 9 mL of deionized (DI) water in a water bath at 40 °C under mildly magnetic stirring. 50 mg dopamine hydrochloride dissolved in 1 mL of DI water was then injected into the reaction solution. The reaction proceeded for 8 h, and then the product was collected via centrifugation at 15000 rpm for 15 min and subsequently washed with DI water three times. The final product was suspended in DI water for use, and its concentration was determined via weighing after lyophilization. Fabrication of PDA/PEG Hydrogel. In a standard fabrication, 10 mg of 4-arm-PEG-SH in 0.1 mL of DI water was mixed with 0.1 mL of PDANPs (45 mg·mL−1), and then the mix was blended on a Vortex mixer for 10 min. After that, the mixture stood without disturbance to form the hydrogel. Dynamic and Steady Rheology Measurement of PDA/PEG Hydrogel. The rheology measurement was carried out via a hybrid rheometer (Discovery Hibrid Rheometer-3, TA Instruments, New Castle, DE). A 40 mm parallel plate was used for the measurement. The mixture of PDANPs and 4-arm-PEG-SH blended on a Vortex mixer for 10 min. After that the mixture was placed on the parallel plate and was sealed by using silicon oil to prevent evaporation. The measurement was conducted at 37 °C with the strain set as 0.1% and the angular frequency as 10 rad/s. For the shear-thinning measurement, the viscosity of the hydrogel (1.5 cm3) was measured along with the shear rate at a strain of 0.1% and an angular frequency of 10 rad· s−1. Photothermal Effect of PDA/PEG Hydrogel. PDA/PEG hydrogel (0.1 cm3) formed in a glass bottle was irradiated with an 808 nm NIR laser (Changchun New Industries Optoelectronics Technology Co., Ltd., China) at a power density of 3.6 W cm−2 for 10 min, and the temperature was recorded by using an infrared thermal camera (Magnity Electronics, China). Drug Loading of SN38 on PDANPs. Different amounts of SN38 (2, 4, and 6 mg) were mixed with 4 mL of 1.9 mg·mL−1 PDANPs suspended in a mixture of water and DMSO (10:1, v/v). The mixed solution was incubated for 12 h at room temperature under magnetic stirring. The undissolved SN38 was first removed by centrifugation at a relatively low speed (2000 rpm) for 5 min, and then the supernatant was collected and centrifuged at a high speed of 15000 rpm for 10 min to precipitate SN38-loaded PDANPs (PDANP−SN38). The obtained PDANP−SN38 was then washed three times with DI water. The drug loading capacity of PDANPs was determined by a UV−vis spectrometer. The typical absorption at 380 nm for SN38 was used to determine the amount of drug loaded on PDANPs. The absorbance of PDANPs was deducted from the spectra of PDANP−SN38. The drug loading ratios were calculated according to the formula: drug loading ratio = drug mass × 100%/(drug mass + PDANPs mass). Preparation of PDA−SN38/PEG Hydrogel. For the preparation of PDA−SN38/PEG hydrogel, PDANP−SN38 with different drug loading ratios (2.9%, 8.3%, and 11.8%) were used instead of PDANPs, and the preparation followed the same procedure as in the above fabrication of PDA/PEG hydrogel. NIR Light-Triggered Drug Release from PDA−SN38/PEG Hydrogel. PDA−SN38/PEG hydrogel (0.1 cm3, 8.3% drug loading for PDANPs) was immersed in 1 mL of DI water in a cuvette. The hydrogel was irradiated with an 808 nm NIR laser at a power density of 3.6 W·cm−2 for 10 min followed by an interval of 30 min. The procedure was performed four times. The solution was analyzed by using a UV−vis spectrometer to determine the drug release. In contrast, another hydrogel not irradiated by NIR laser was used as control. Cell Culture. The mouse embryonic fibroblast cell line (NIH3T3) and the nonsmall-cell lung cancer cell line (PC-9) were obtained from American Type Culture Collection. NIH3T3 cells were cultured at 37 °C under humidified 5% CO2 in DMEM medium (GIBCO) supplemented with 10% fetal bovine serum (Wisent, Nanjing, P. R. China), 100 units/mL penicillin, and 100 mg/mL streptomycin. PC-9 cells were cultured at 37 °C under humidified 5% CO2 in RPMI 1640
depolymerize following the degradation of PDANPs and then eliminated out of the body. This possibility would enhance the safety of PDA/PEG hydrogel implanted in the body. PDA−SN38/PEG hydrogel was then used for the combined chemo-photothermal treatment of tumors in vivo. Mice bearing PC-9 tumors in six groups were intratumorally administered PBS (two groups), PDANP−SN38, PDA/PEG hydrogel (gel group), and PDA−SN38/PEG hydrogel (two groups, gel− SN38 group), following with or without NIR irradiation every 2 days for five times (Figure 4a). The tumor-site temperature in the PBS+NIR group was measured to be ∼35 °C after NIR irradiation, while the ones in the gel+NIR group and gel− SN38+NIR group reached ∼44 °C (Figure 4b and SI Figure S8). After treatment, the tumor growth in the gel−SN38+NIR group was completely inhibited, while that in PDANP−SN38, gel+NIR, and gel−SN38 groups was only partially depressed (Figure 4c). The tumors in each group were further excised and weighed. The results confirm that tumors in the gel− SN38+NIR group were more efficiently depressed compared with the ones in control groups (Figure 4d,e). The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay reveals that tumor cells in the gel−SN38+NIR group were mostly apoptotic, while the ones in control groups were minimally apoptotic (SI Figure S9). The body weight of mice in each group had no detectable difference during the therapeutic period (SI Figure S10), and the histological examination reveals no detectable pathological change in the main organs (SI Figure S11), both of which confirm that PDA/ PEG hydrogel had minimal systemic toxicity. These results together demonstrate that PDA−SN38/PEG hydrogel-mediated chemo-photothermal therapy could efficiently ablate the tumor growth in vivo.
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CONCLUSION In summary, we successfully prepared a PDA nanoparticleknotted PEG hydrogel by mixing PDANPs with 4-arm-PEGSH. PDANPs in the hydrogel not only served as a cross-linking agent to connect 4-arm-PEG-SH to form hydrogel but also played a crucial role to load the chemical drugs such as SN38 and to release the drugs in response to NIR light. Upon NIR irradiation, SN38 was released from the hydrogel in an “off-on” fashion, allowing the control of drug release in highly spatial and temporal resolutions. Furthermore, the hydrogel demonstrated excellent biocompatibility and did not elicit inflammatory responses in the body, and the hydrogel-mediated chemophotothermal treatment efficiently depressed the tumor growth.
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EXPERIMENTAL SECTION
Materials. Dopamine hydrochloride was obtained from SigmaAldrich (St. Louis, MO). 4-arm-PEG-SH (molecular weight 20 kDa) was purchased from JenKem Technology Co., Ltd. (Beijing, China). Ethanol (AR, > 99.7%), ammonia (28−30%, weight percentage), and SN38 were bought from Aladdin Industrial Co., Ltd. (Shanghai, China). Dimethyl sulfoxide (DMSO) was obtained from Sinopharm Chemical Reagent Co., Ltd. (Beijing, China). Instruments and Characterization. TEM images were taken using a Hitachi microscope (HT7700, Hitachi, Japan) operating at an acceleration voltage of 100 kV. The hydrodynamic diameters of nanoparticles were measured by dynamic light scattering instrument (Zetasizer Nano ZS90, Malvern Instruments, UK). UV−vis spectra were recorded by using a UV−vis spectrometer (Cary60, Agilent Technologies, Santa Clara, CA). SEM images were collected via a scanning electron microscope (S4800, Hitachi, Japan) operated at 10 kV. 1374
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medium (GIBCO) supplemented with 10% fetal bovine serum, 100 units/mL penicillin, and 100 units/mL streptomycin. In Vitro Cytotoxicity Assay. Cytotoxicity of the components of PDA/PEG hydrogel including PDANPs and 4-arm-PEG-SH was analyzed on NIH3T3 cells. The cells were seeded in 96-well plates with a density of 10000 cells per well and incubated overnight at 37 °C. PDANPs of different concentrations (0, 0.06, 0.09, 0.12, 0.16 mg· mL−1) and PEG of different concentrations (0, 1, 3, 5, 10 mg·mL−1) were added into the cell media and then were incubated with the cells for 24 h at 37 °C. After that, a standard 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was carried out to determine the cell viability. Furthermore, PDA/PEG hydrogel (0.4 cm3) was immersed in DMEM medium (4.148 mL) for 24 h. The immersion solution was collected to culture cells for 48 h, and then the standard MTT assay and acridine orange/ethidium bromide staining assay were conducted to evaluate the cytotoxicity. In Vivo Toxicity of PDA/PEG Hydrogel. Male BALB/c nude mice (three months) with an average weight of 25 g were purchased from SLAC Laboratory Animal Co., Ltd. (Shanghai, China). The animal experiments were conducted following the National Institutes of Health guidelines for care and use of laboratory animals and approved by the ethics committee of East China Normal University. The mice were randomly divided into two groups (five mice in each group) and then were subcutaneously injected with PBS (30 μL) and PDA/PEG hydrogel (30 μL) into the back of mice, respectively. The mice were raised for 4 months. The body weights of mice were recorded every day. Finally, the mice were sacrificed. The blood was collected for hematology analysis, and the main organs including heart, liver, spleen, lung, and kidney were collected to conduct the histological examination. The tissues around the PDA/PEG hydrogel were also collected for Masson’s trichome staining assay. In Vivo Chemo-photothermal Treatment of Tumors. Male BALB/c nude mice (three months) with an average weight of 25 g were purchased from SLAC Laboratory Animal Co., Ltd. (Shanghai, China). PC-9 cells (1−2 × 106 cells suspended in 200 μL of PBS) were injected into the right back of nude mice to establish the PC-9 xenograft model. Two weeks later, the mice were randomly divided into six groups with five mice in each group and then were intratumorally injected with PBS (30 μL, two groups), PDANP− SN38 (30 μL, 2.9% drug loading), PDA/PEG hydrogel (30 μL), and PDA−SN38/PEG hydrogel (30 μL, 2.9% drug loading for PDANPs, two groups). Twenty-four hours later, the mice in one of the PBS groups, the PDA/PEG hydrogel group, and one of the PDA−SN38/ PEG hydrogel groups were treated with NIR irradiation at a power density of 0.58 W·cm−2 for 5 min every 2 days. The tumor-site temperature and the thermographic images of the mice were recorded for each NIR irradiation by using an infrared thermal camera, and the tumor volumes and the body weights of mice were recorded every day. After NIR irradiation five times, the mice were sacrificed, and the tumors were isolated and then weighed. The apoptosis of tumor cells in each group was further analyzed by a TUNEL assay. The main organs of the mice in each group including heart, liver, spleen, lung, and kidney were also harvested and analyzed by hematoxylin and eosin staining.
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Article
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Xinyu Wang: 0000-0002-9167-2077 Yiyun Cheng: 0000-0002-1101-5692 Author Contributions †
X.W. and C.W. contributed equally on the manuscript.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (81671822), the Basic Research Program of Science and Technology Commission of Shanghai Municipality (14JC1491100), the Fok Ying Tong Education Foundation (151036), and the Shanghai Pujiang Program (14PJD016). We also acknowledge the electron microscopy center of East China Normal University for nanoparticle and hydrogel characterization.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemmater.6b05192. TEM images, hydrodynamic sizes, and zeta potentials of PDANPs and PDA−SN38, calibration curve of SN38, SEM image of PDA−SN38/PEG hydrogel, drug stability in the hydrogel, cytotoxicity of the hydrogel, thermographs of mice, histological examination of main organs, TUNEL staining of tumors, and evolution of mice body weight (PDF) 1375
DOI: 10.1021/acs.chemmater.6b05192 Chem. Mater. 2017, 29, 1370−1376
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DOI: 10.1021/acs.chemmater.6b05192 Chem. Mater. 2017, 29, 1370−1376
