Redox-Sensitive Nanoscale Coordination Polymers for Drug Delivery

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Redox-Sensitive Nanoscale Coordination Polymers for Drug Delivery and Cancer Theranostics Jiayue Zhao,† Yu Yang,‡ Xiao Han,† Chao Liang,† Jingjing Liu,† Xuejiao Song,† Zili Ge,*,§ and Zhuang Liu*,† †

Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, 199 Ren’ai Road, Suzhou, 215123 Jiangsu, China ‡ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidad, Taipa, Macau 999078, China § Department of Stomatology, The First Affiliated Hospital of Soochow University, Suzhou 215000, China S Supporting Information *

ABSTRACT: Nanoscale coordination polymers (NCPs), with inherent biodegradability, chemical diversities, and porous structures, are a promising class of nanomaterials in the nanomedicine field. Herein, a unique type of redox-sensitive NCPs is constructed with manganese ions (Mn2+) and dithiodiglycolic acid as the disulfide (SS)-containing organic bridging ligand. The obtained Mn-SS NCPs with a mesoporous structure could be efficiently loaded with doxorubicin (DOX), a chemotherapeutics. The yielded MnSS/DOX nanoparticles are coated with a layer of polydopamine (PDA) and then modified by poly(ethylene glycol) (PEG). In such a Mn-SS/DOX@PDA-PEG NCP structure, the disulfide linkage (SS) within dithiodiglycolic acid can be cleaved in the presence of glutathione (GSH), leading to efficient redox-responsive dissociation of NCPs and the subsequent drug release. Meanwhile, Mn2+ in Mn-SS/DOX@PDA-PEG NCPs would offer a strong T1 contrast in magnetic resonance (MR) imaging, Upon intravenous injection, these Mn-SS/DOX@PDAPEG NCPs show efficient tumor homing, as revealed by MR imaging, and offer an obviously improved in vivo therapeutic outcome compared to that achieved with free DOX. KEYWORDS: nanoscale coordination polymers (NCPs), drug delivery, chemotherapy, redox-responsive release, theranostics

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INTRODUCTION Nanoscale metal-organic frameworks (NMOFs) and nanoscale coordination polymers (NCPs) both are coordination networks of metal ions and organic polydentate ligands.1−11 During the past decades, NMOFs and NCPs have been extensively studied in many different fields, including catalysis,12−14 energy research,15 and biomedicine,16 because of their various interesting inherent physicochemical properties.17 In the area of biomedicine, NMOFs and NCPs have found promising applications as multifunctional nanocarriers for delivering imaging agents,18 genes,19 photosensitizers,20 and anticancer chemotherapeutic drugs.21 For instance, many types of anticancer drugs, such as cisplatin,22,23 methotrexate,24 and 5fluorouracilor,25−27 have been successfully incorporated into NMOFs and NCPs to realize cancer chemotherapy. Photosensitizer-integrated NMOFs have been demonstrated to be promising agents for photodynamic therapy.28−31 We recently also discovered that NMOFs constructed by metal ions and near-infrared (NIR) absorbing molecules could be employed for imaging guided photothermal therapy of cancer.32,33 Importantly, it has been demonstrated that unlike those © 2017 American Chemical Society

conventional inorganic nanostructures that are often not biodegradable, many NCPs show inherent biodegradability and can be excreted from the body without long-term retention, minimizing concerns of their potential long-term toxicity. To realize specific and effective cancer treatment, many types of drug delivery systems responsive to external or internal stimuli have been extensively explored in recent years.34−40 In particular, considering the intrinsic reducing microenvironment inside solid tumors, in which the concentrations of glutathione (GSH) are much higher than those in normal tissues, redoxsensitive drug delivery systems, often by incorporating disulfide bonds that can be cleaved by excessive GSH, have attracted tremendous attention.41−43 Notably, although employing reducing-responsive disulfide bonds to fabricate redox-sensitive drug delivery systems has been extensively explored for antitumor drug delivery, to our best knowledge, constructing Received: May 27, 2017 Accepted: June 21, 2017 Published: June 21, 2017 23555

DOI: 10.1021/acsami.7b07535 ACS Appl. Mater. Interfaces 2017, 9, 23555−23563

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ACS Applied Materials & Interfaces

Figure 1. Synthesis and characterization of Mn-SS NCPs. (a) Schematic illustration to show the fabrication process of Mn-SS nanoparticles. (b) TEM images of Mn-SS. (c) N2 adsorption/desorption isotherm curves of Mn-SS samples. (d) TGA measurements of the Mn-SS sample from 25 to 800 °C.

mide (DMF)/ethanol (v/v = 5/3) solution at 150 °C for 24 h. The synthetic procedure of Mn-SS nanoparticles is illustrated in Figure 1a. The product was obtained by centrifugation and then redispersed in ethanol. According to transmission electron microscopy (TEM) images, Mn-SS/DOX@PDA-PEG showed spherical structures and a narrow size distribution from 30 to 50 nm (Figure 1b). The composition of Mn-SS NCPs was confirmed by thermogravimetric analysis (TGA) (Figure 1d). By Brunauer−Emmett−Teller (BET) measurements, the surface area, pore volume, and adsorption average pore width of Mn-SS NCPs were measured to be 53.7 m2 g−1, 0.117 cm3 g−1, and 8.75 nm, respectively (Figure 1c). Next, DOX, a typical chemotherapy drug, was used to demonstrate the use of Mn-SS NCPs as a drug delivery carrier. Mn-SS nanoparticles were loaded with DOX through hydrophodic interaction. Then, the obtained Mn-SS/DOX nanoparticles were modified with PDA by in situ polymerization of DA on the surface of these nanoparticles and further coated with C18PMH-PEG (Figure 2a). After PEGylation, such MnSS/DOX@PDA-PEG nanoparticles showed great stability in the cell culture medium (Dulbecco’s modified Eagle’s medium) and phosphate-buffered saline (PBS). Whereas Mn-SS nanoparticles without PEGylation would aggregate within PBS, the Mn-SS@PDA-PEG sample showed excellent stability in different physiological buffers (Figure S1). After being coated with PDA and C18PMH-PEG, the average size of Mn-SS/ DOX@PDA-PEG NCPs showed a slight increase compared to that of the Mn-SS nanoparticles. The TEM image of Mn-SS/ DOX@PDA-PEG showed the diameter of these nanoparticles to be about 100 nm (Figure 2b). Consistently, the average hydrodynamic diameter of these nanoparticles was measured by

redox-sensitive NCPs as drug carriers using disulfide-containing organic linkers has not yet been reported. In this study, we designed a new type of redox-sensitive NCPs, which consist of manganese ions (Mn2+), as the metal connecting points, and dithiodiglycolic acid, as the organic bridging ligands. Doxorubicin (DOX), a chemotherapy drug, can be loaded into the obtained Mn-SS NCPs with a mesoporous structure. Subsequently, the formed Mn-SS/ DOX nanoparticles are coated with polydopamine (PDA) and further modified with an amphiphilic polymer, poly(ethylene glycol) (PEG)-grafted poly(maleic anhydride-alt-1octadecene) (C18PMH-PEG), obtaining Mn-SS/DOX@PDAPEG nanoparticles with excellent physiological stability and biocompatibility. Interestingly, such Mn-SS/DOX@PDA-PEG NCPs with the presence of GSH would be rapidly decomposed, owing to the cleavage of disulfide linkers, resulting in a GSHresponsive release of DOX. Meanwhile, Mn2+ in such NCPs can serve as a T1-contrast agent under magnetic resonance (MR) imaging, which proves efficient tumor accumulation of Mn-SS/DOX@PDA-PEG NCPs after intravenous (i.v.) injection. Importantly, an increased tumor growth inhibition effect is observed for Mn-SS/DOX@PDA-PEG nanoparticles in comparison to that from the free DOX formulation in our in vivo experiments. Our study thus presents a new type of redoxsensitive NCPs, promising for imaging-guided drug delivery in cancer theranostics.

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RESULTS AND DISCUSSION In our experiments, redox-responsive NCPs were synthesized by heating the mixture of MnCl2, poly(vinylpyrrolidone) (PVPK30), and dithiodiglycolic acid (SS) in a N,N-dimethylforma23556


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Figure 2. Drug loading and release. (a) Scheme showing the preparation of DOX-loaded NCPs, as well as the GSH-triggered nanoparticle decomposition and drug release. (b) TEM image of Mn-SS/DOX@PDA-PEG nanoparticles. (c) Ultraviolet−visible (UV−vis)−NIR spectra of DOX-loaded Mn-SS with different concentrations of added DOX, varying from 0 to 1.5 mg/mL. (d) Quantification of DOX loadings at different feeding DOX concentrations. (e) TEM image of Mn-SS@PDA-PEG 0.25 h post incubation with 10 mM GSH. (f) Hydrodynamic diameters of MnSS/DOX@PDA-PEG before and after incubation with GSH. (g) Cumulative release profiles of DOX from Mn-SS/DOX@PDA-PEG in PBS with different pHs without or with 10 mM GSH.

dynamic light scattering (DLS) to be ∼100 nm (Figure 2f). As expected, a typical absorption peak of DOX at 490 nm was

observed for Mn-SS/DOX@PDA-PEG samples (Figure 2c), in which the DOX loading capacities increased as more DOX was 23557


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Figure 3. In vitro experiments with Mn-SS/DOX@PDA-PEG NCPs. (a) Relative viabilities of 4T1, HeLa, and K7M2 cells after being incubated with various concentrations of Mn-SS@PDA-PEG (no DOX loading) for 24 h. (b) Confocal fluorescence images of 4T1 cells incubated with MnSS/DOX@PDA-PEG or free DOX ([DOX] = 25 μM) for different periods of time. The red and blue colors represent DOX fluorescence and DAPIstained cell nuclei, respectively. Scale bar: 20 μm. (c) Relative viabilities of 4T1 cells treated with various concentrations of Mn-SS/DOX@PDA-PEG or free DOX for 24 h.

added during sample preparation (Figure 2d). A moderate DOX loading (DOX/Mn-SS = 1:1 in the final product) was chosen for later experiments. In our Mn-SS/DOX@PDA-PEG system, DOX was loaded in the interior of Mn-SS NCPs containing redox-sensitive disulfide linkers, which could be cleaved by excessive GSH, so as to trigger the disassembly of nanoparticles and thus the release of DOX. The TEM image of Mn-SS/DOX@PDA-PEG nanoparticles before and after incubation with GSH (10 mM) clearly showed the GSH-triggered decomposition of these nanoparticles (Figure 2e). Moreover, the hydrodynamic sizes of these nanoparticles also showed a significant decrease after GSH treatment, as revealed by DLS (Figure 2f), further evidencing the disassembly of such NCPs. We next tested the DOX release behaviors from Mn-SS/DOX@PDA-PEG nanoparticles at different pH values and different concentrations of GSH (Figure 2g). As expected, the DOX release could be significantly accelerated in the presence of GSH as a result of

GSH-induced disassembly of such NCPs. Meanwhile, because of the protonation of the amino group on DOX, the release of DOX from Mn-SS/DOX@PDA-PEG nanoparticles appeared to be faster under reduced pH, similar to that in other nanoscale DOX delivery systems.44,45 Next, in vitro experiments were conducted for drug-loaded NCPs. 4T1 murine breast cancer cells, HeLa human cervical cancer cells, and K7M2 murine osteosarcoma cells were first chosen to test the potential cytotoxicity of Mn-SS@PDA-PEG without drug loading by the cell viability assay. No obvious cytotoxicity was observed when different types of cells were incubated with Mn-SS@PDA-PEG at various concentrations (up to a high Mn2+ concentration of 100 μg/mL) for 24 h, indicating the excellent biocompatibility of Mn-SS@PDA-PEG (Figure 3a). We then tracked the cellular uptake of Mn-SS/DOX@PDAPEG by confocal fluorescence imaging. 4T1 cells were incubated with the DOX-loaded nanoparticles (Figure 3b). At 23558


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Figure 4. In vivo behaviors of Mn-SS/DOX@PDA-PEG nanoparticles. (a) T1-MR images of nanoparticles with different Mn2+ concentrations. (b) T1-weighted MR images and T1 relaxation rates (R1) of Mn-SS/DOX@PDA-PEG solutions at different manganese ion concentrations. (c) In vivo T1-weighted MR images of 4T1-tumor-bearing mice taken at 0, 12, 24, and 48 h after i.v. injection of Mn-SS/DOX@PDA-PEG. (d) T1-weighted MR signals in the tumor at different time points after injection of Mn-SS/DOX@PDA-PEG. (e) Blood circulation data of Mn-SS/DOX@PDA-PEG after i.v. injection. Mn2+ levels (in the unit of %ID/g) in the blood were measured by inductively coupled plasma atomic emission spectroscopy (ICP-AES). (f) Biodistribution of Mn-SS/DOX@PDA-PEG in 4T1-tumor-bearing mice based on ICP-AES measurements of Mn2+ levels in different organs at 24 h post injection.

an earlier time point (1 h), most of the DOX fluorescence signals were observed in the cell cytoplasm without significant entry into nuclei. Interestingly, at later time points, strong DOX fluorescence was observed inside cell nuclei. Such a phenomenon may be explained by the GSH-induced gradual disassembly of NCPs once inside the cells to release DOX, which in its free form would bind to double-strand DNA inside cell nuclei. Furthermore, both free DOX and Mn-SS/DOX@ PDA-PEG showed significant concentration-dependent cytotoxicity to cells (Figure 3c), although DOX loading inside these nanoparticles showed slightly reduced in vitro cytotoxicity, which would be probably due to the sustained release of DOX from these nanoparticles.46,47

In many studies, it has been demonstrated that Mn2+ ions could provide a strong contrast in T1-weighted MR imaging.48,49 As expected, in our experiments, Mn-SS/DOX@ PDA-PEG samples showed a concentration-dependent lightening under T1-weighted MR imaging (Figure 4a). The corresponding longitudinal relaxivity (r1) value of Mn-SS@ DA-PEG was determined to be 9.947 mM−1 S−1 (Figure 4b), which is higher than that of Magnevist (4.25 mM−1 S−1), a commercial Gd-based agent.50 Next, Mn-SS/DOX@PDA-PEG was intravenously injected into mice bearing 4T1 tumors. A strong brightening effect showed up in the tumor region according to in vivo MR imaging, indicating high tumor accumulation of Mn-SS/DOX@PDA-PEG nanoparticles after 23559


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Figure 5. In vivo therapy by Mn-SS/DOX@PDA-PEG. (a) Tumor growth curves of different groups after various treatments. The arrows indicate the time points at which various agents were injected. (b) Body weight changes of different groups of mice after various treatments. The p values in (a) and (b) were calculated by Tukey’s post-test (***p < 0.001, **p < 0.01, or *p < 0.05). (c) Hematoxylin and eosin (H&E) and triphosphatebiotin nick end labeling (TUNEL) stained tumor slices collected from mice after various treatments on day 12. Scale bar: 200 μm.

obviously better inhibitory effect on tumor growth compared to that achieved with free DOX at the same dose. The body weight change of mice from different groups showed that treatment with Mn-SS/DOX@PDA-PEG resulted in less significant body weight loss compared to that with the free DOX group, although the body weights in both treatment groups appeared to be lower compared to those in untreated mice, owing to the toxicity of DOX (Figure 5b). H&E staining of tumor slices showed that the tumor cells in the control group maintained normal morphology and complete cell structure, whereas most tumor cells were destroyed in the Mn-SS/DOX@PDA-PEG group (Figure 5c). On the other hand, as revealed by transferase-mediated deoxyuridine TUNEL staining, a high level of apoptosis was observed in tumors of mice treated with Mn-SS/DOX@PDAPEG compared to that in other groups (including the free DOX group) (Figure 5c). These results were consistent with the tumor growth data presented earlier. All these results evidenced that chemotherapy with Mn-SS/DOX@PDA-PEG showed improved antitumor therapeutic efficacy as well as less significant in vivo side effects compared to those of free DOX.

systemic i.v. administration (Figure 4c). As illustrated by the quantitative analysis of MR imaging data, the tumor T1 signals increased significantly after i.v. injection of Mn-SS/DOX@ PDA-PEG (Figure 4d). In addition to in vivo MR imaging, we also quantitatively tested the in vivo behaviors of Mn-SS/DOX@PDA-PEG by measuring Mn2+ levels in various organs using ICP-AES. The blood levels of Mn-SS/DOX@PDA-PEG nanoparticles showed a gradual decrease over time but remained at a relatively high level of ∼4% ID/g even at 24 h post injection (Figure 4e). We further investigated the biodistribution of Mn-SS/DOX@PDAPEG by ICP-AES measurements of Mn2+ levels in various organs. At 24 h post injection, the tumor uptake of NCPs was found to be relatively high, at a level of ∼5% ID/g. Such passive tumor accumulation of nanoparticles could be attributed to the enhanced permeability and retention effect of tumor tissues (Figure 4f). Similar to other types of nanoparticles, such NCPs also showed high accumulation in the liver and spleen due to macrophage clearance of nanoparticles in these reticuloendothelial systems. Moreover, the high Mn2+ level in the mouse kidney indicated that these NCPs after decomposition into small ions and molecules could be excreted by renal excretion, a behavior observed for many types of NCPs or NMOFs.28,33 To test the antitumor efficacy of the Mn-SS/DOX@PDAPEG nanoparticles, we monitored tumor volume changes of different treatment groups of the 4T1 tumor-bearing mice, including the untreated control group, Mn-SS@PDA-PEG free carrier group, free DOX group, and Mn-SS/DOX@PDA-PEG group. Mice in each group were injected with three doses at days 0, 4, and 8 as shown by the arrows in Figure 5a. The tumor sizes were measured starting from day 0. Remarkably, the treatment with Mn-SS/DOX@PDA-PEG showed an

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CONCLUSIONS In conclusion, we present a new kind of redox-sensitive NCPs by a solvothermal method based on Mn2+ and dithiodiglycolic acid for applications in drug delivery and MR imaging. With DOX loading and surface PEGylation, these nanoparticles showed excellent stability in the physiological environment and exhibited long blood circulation time as well as high tumor homing after i.v. injection. Owing to the cleavage of disulfide bond triggered by GSH, Mn-SS/DOX@PDA-PEG nano23560


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Cellular Experiment. The 4T1, HeLa, and K7M2 cells were originally obtained from the American Type Culture Collection and cultured under standard conditions. The cells with various treatments were observed under a Leica SP5 laser scanning confocal microscope. Animal Experiments. Balb/c mice were obtained from Nanjing Peng Sheng Biological Technology Co. Ltd. All animal experiments were performed under the protocols approved by the Soochow University Laboratory Animal Center. 4T1 tumors were generated by subcutaneous injection of 1 × 106 cells in 30 μL of PBS onto the back of each mouse. Blood circulation and biodistribution measurements were conducted following our previously reported protocols, using ICP-AES to quantitatively measure (Vista Mpx 700-ES) Mn2+ in solubilized blood and tissue samples.

particles in the reducing environment would show a decomposed structure and accelerated drug release to enable chemotherapy, which offers obviously improved in vivo tumor growth inhibition effect compared to that of free DOX at the same dose. Our work is the first to incorporate disulfide linkages in the formulation of NCP structures to fabricate NCP-based redox-sensitive theranostic platforms. Similar strategies may be applied to the design of other NMOFbased or NCP-based smart nanomedicine responsive to different environmental stimuli, such as pH, reactive oxygen species, and even light and temperature. Moreover, compared with conventional polymer-based drug delivery nanoparticles, the metal ions within NCPs could be utilized for imaging (e.g., MR imaging as demonstrated in this work) and other potential therapeutic functions (e.g., enhanced radiotherapy, as demonstrated in our previous studies).51,52,28 On the other hand, unlike many nonbiodegradable inorganic nanoparticles explored in drug delivery, the inherent biodegradability of NCPs is a significant advantage for their potential clinical translation.

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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/acsami.7b07535. Hydrodynamic diameters of Mn-SS/DOX@PDA-PEG nanoparticles (Figure S1) (PDF)

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EXPERIMENTAL SECTION

Materials. All chemicals were purchased from Sigma-Aldrich unless specified. Dithiodiglycolic acid (SS) was from TCI, Shanghai, China. Manganese(II) chloride tetrahydrate (MnCl2) was from Alfa Aesar. PEG polymers were products of Jiaxin Bomei, Inc., China. All cellculture-related reagents were ordered from Hyclone. Preparation of Mn-SS Nanoparticles. MnCl2 solution (107 μL, 50 mg/mL in DMF), dithiodiglycolic acid (347 μL, 15 mg/mL in DMF), PVP (300 mg, PVP-K30), triethylamine (200 μL), and the solvent of DMF/ethanol (v/v = 5/3) were added to a 15 mL centrifuge tube until the volume was 13 mL. Then, the reaction mixture was ultrasonically dispersed and transferred to a 20 mL hydrothermal synthesis reactor, which reacted for 24 h at 150 °C. Finally, the product was collected by centrifugation, washed with ethanol, and redispersed in ethanol for further use. Drug Loading and Surface Modification of Mn-SS NCPs. First, 100 μL of an ethanol solution of Mn-SS (Mn2+ concentration is 7 mg/mL) and 140 μL of an aqueous solution of DOX (DOX concentration is 10 mg/mL) were added to a 100 mL round flask. The solution pH was adjusted by a tris(hydroxymethyl)aminomethane− hydrochloric acid (Tris−HCl) buffer solution (50 mM, pH 8.5) to 8− 8.5, and the solution was stirred for 24 h at room temperature. Second, 700 μL of an aqueous solution of DA (DA concentration is 1 mg/mL) was added into this 100 mL round flask dropwise and the solution pH was kept at 8−8.5. An aqueous solution of HCl (0.1 M) was used to adjust the solution pH to 7 when the Mn-SS/DOX@PDA nanoparticle size was about 100 nm. Then, 7 mg of C18PMH-PEG was put into this reactor and stirred overnight at room temperature. The C18PMH-PEG polymer was synthesized according to a previous report.53 Finally, the mixed solution was concentrated by ultrafiltration and washed with distilled (deionized) water repeatedly to obtain the purified Mn-SS/DOX@PDA-PEG nanoparticles. Characterization. TEM images were taken by a Philips CM300 TEM. A GENESYS 10S UV−vis spectrophotometer was used to record absorbance spectra. DLS measurements of the nanoparticles were performed by a Zetasizer Nano-ZS (Malvern Instruments, U.K.). BET measurements were performed by an ASAP2050 system. TGA measurements were performed using a Setaram TGA 92 instrument from 25 to 800 °C. In Vitro Drug Release Experiment. Mn-SS/DOX@PDA-PEG (1 mL, DOX concentration is 1 mg/mL) was added to a dialysis bag with the molecular weight cutoff of 14800 Da. The release of DOX from Mn-SS/DOX@PDA-PEG was measured in 5 mL PBS (pH 7.4 and 5.5) at room temperature in the presence or absence of 10 mM GSH. At desired time intervals (1/12, 0.25, 0.5, 1, 2, 3, 4, 6, 10, 12, 24 h), 1 mL of the medium was taken out. The amount of released DOX was determined by DOX absorbance.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (Z.G.). *E-mail: [email protected] (Z.L.). ORCID

Zhuang Liu: 0000-0002-1629-1039 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was partially supported by the Ministry of Science and Technology (MOST) of China (2016YFA0201200), the National Natural Science Foundation of China (51525203, 81671028), China National Textile and Apparel Council (J201405), Collaborative Innovation Center of Suzhou Nano Science and Technology, and a Project Funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.

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Redox-Sensitive Nanoscale Coordination Polymers for Drug Delivery

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