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Cite This: ACS Appl. Mater. Interfaces 2019, 11, 23065−23071
Mild Hyperthermia-Enhanced Enzyme-Mediated Tumor Cell Chemodynamic Therapy Xinhe Liu,† Ying Liu,† Junning Wang,† Tianxiang Wei,*,†,‡ and Zhihui Dai*,†,§ †
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Jiangsu Collaborative Innovation Centre of Biomedical Functional Materials and Jiangsu Key Laboratory of Biofunctional Materials, School of Chemistry and Materials Science, ‡School of Environment, and §Center for Analysis and Testing, Nanjing Normal University, Nanjing 210023, People’s Republic of China ABSTRACT: The heterogeneity and diversity of tumors seriously attenuate the curative outcome of single treatment modes. Combined therapy has been demonstrated to be a promising candidate to enhance therapeutic efficacy compared with monotherapy. As an emerging therapeutic strategy, chemodynamic therapy (CDT) has drawn extensive attention in recent years. However, the therapeutic efficiency of CDT is still unsatisfying because the level of intracellular hydrogen peroxide (H2O2) restricts the production of hydroxyl radicals (•OH). In this study, a novel curative strategy which combines glucose oxidase (GOx)-mediated Fe3O4-based Fenton reaction and multiwalled carbon nanotube (MWNT)-produced mild hyperthermia enhancer is proposed, achieving a mild hyperthermia-enhanced enzyme-mediated tumor cell CDT. GOx can catalyze the conversion of glucose into gluconic acid and H2O2, which can elevate acidity in the tumor microenvironment and boost Fe3O4-based Fenton reaction, producing a myriad of •OH to induce tumor cell death. Furthermore, by using the theory that a temperature rise expedites the kinetics of a chemical reaction, producing a higher reaction rate and more resultants per unit time, we integrate MWNTs in this therapy system, which generate mild hyperthermia so as to accelerate the Fenton reaction for increasing the productivity of •OH. Therefore, an amplified CDT can be realized. The therapy platform, mild hyperthermia-enhanced GOx-mediated CDT, provides an effective treatment for cancer and takes CDT a step further. KEYWORDS: chemodynamic therapy, mild hyperthermia, hydroxyl radicals, combined therapy, glucose oxidase
1. INTRODUCTION Recently, cancer is a primary cause of mortality worldwide.1,2 Despite enormous efforts in the fight against cancer, the clinical treatment options are far from satisfactory owing to the tumorous heterogeneity and diversity.3 Scientists have joined forces to develop efficient ways to cure cancer, including radiotherapy,4 chemotherapy,5,6 photodynamic therapy,7,8 immunotherapy,9 photothermal therapy (PTT),10,11 and chemodynamic therapy (CDT).12 Although great progress has been obtained, these treatments still have their respective limitations. Thus, combined therapy, which adopts the integration of two or more forms of monotherapy, is an alternative approach to surmount the limitations of individual treatment modes and achieve a better curative outcome utilizing synergetic effect.13−16 CDT, as an emerging strategy, has demonstrated superior potency against cancer cells with minimized harmful adverse effects.17 CDT is defined as the decomposition of hydrogen peroxide (H2O2) via an intracellular Fenton reaction to generate highly toxic hydroxyl radicals (•OH), which could induce cancer cell death through destroying cellular biomolecule substances such as lipids, nucleic acids, and proteins.18,19 Unfortunately, the treatment effect of CDT is © 2019 American Chemical Society
restricted by the discontented Fenton reaction effectiveness in the tumor microenvironment because the intracellular H2O2 level (50−100 μM) is too low to generate a desirable amount of •OH, inhibiting its practical application.20,21 Moreover, the cellular acidity also hampers the Fenton reaction efficiency to some extent.22 Therefore, the limitations mentioned above inspired us to develop a method which can not only increase the level of H2O2 but also decrease the pH value of the system. Recognized as a feasible way, the introduction of glucose oxidase (GOx) could enable the conversion of glucose into H2O2 and gluconic acid.23 Therefore, the produced H2O2 and gluconic acid were able to improve the intracellular H2O2 concentration and elevate the cellular microenvironment acidity, respectively, which are beneficial for the Fenton reaction to enhance the generation efficacy of •OH.24 Besides, there is another efficient treatment way, PTT. It is a phototherapy paradigm that utilizes photothermal conversion agents to engender heat under laser light irradiation for the treatment of cancer.25,26 Laser light is noninvasive, adjustable, Received: May 12, 2019 Accepted: June 7, 2019 Published: June 7, 2019 23065
DOI: 10.1021/acsami.9b08257 ACS Appl. Mater. Interfaces 2019, 11, 23065−23071
Research Article
ACS Applied Materials & Interfaces
Fenton reaction catalyzed by Fe3O4 nanoparticles to produce OH. Besides, MWNTs could generate mild hyperthermia by the near-infrared (NIR) laser irradiation, which further accelerates the catalytic Fenton reaction activity for an increased •OH yield. This new strategy can harvest a synergetic effect on fighting cancer and may offer theory guidance for CDT development.
allows for multiple pulsed regimens, and can generate heat energy resulting in cancer cell destruction.27 Nevertheless, to attain effective tumor tissue ablation, a high temperature of over 50 °C is necessary, which may confer collateral harm to adjacent healthy cells because of the inevitable heat diffusion.28,29 Recently, the developed mild PTT strategy, which manages the temperature at a relatively low level in the tumor site, has emerged as a novel candidate.30 Unfortunately, the potency of mild PTT as a single treatment modality is relatively low because of the insufficient heat. Therefore, it is significant and imperative to combine mild PTT with other cure methods, forming a multimodal synergistic therapy to increase the therapeutic performance. It is well recognized that a temperature rise expedites the kinetics of a chemical reaction, resulting in a higher reaction rate and more resultants per unit time. By synthetically considering CDT and mild PTT, we anticipate mild PTT can be applied to the Fenton reaction-based CDT to generate a good synergy. Lately, some researchers have set foot in amplified Fenton reaction via combining PTT with CDT and obtaining a high therapeutic effect.31,32 However, hightemperature PTT may confer collateral harm to adjacent cells. Accordingly, we utilize the combination of mild hyperthermia with GOx-mediated CDT for cancer treatment to produce a more efficient CDT and reduce harm resulting from hyperthermia. The combination of mild PTT and CDT not only utilizes mild hyperthermia to promote the Fenton process but also circumvents the deficiency of mild PTT. Taking advantage of the combined therapeutic approach, the generated heat in mild PTT accelerates the kinetics of the chemical reaction of the Fenton reaction, which leads to produce more •OH per unit time, potentiating the efficacy of CDT. In this work, we combine mild PTT with CDT to develop a new mild hyperthermia-enhanced enzyme-mediated CDT (Scheme 1). In this strategy, we used polyethylenimine (PEI)-coated Fe3O4 that reacted with PEGylated multiwalled carbon nanotubes (MWNTs) to form polyethylene glycol (PEG)−MWNT−Fe 3O 4 (PMF) and further covalently combined GOx via amide bond formation to prepare the final composite, PMF−GOx (PMFG). GOx is competent to convert glucose into abundant H2O2 for the subsequent
•
2. EXPERIMENTAL SECTION 2.1. Materials. MWNTs were purchased from Shenzhen Nanotech Port Co., Ltd. (Shenzhen, China). Iron(III) acetylacetonate [Fe(acac)3], 1-ethyl-3-[(3-dimethylamino)-propyl]carbodiimide (EDC), N-hydroxysuccinimide (NHS), PEI (branched), 5,5-dimethyl-1-pyrroline N-oxide (DMPO), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(PEG)-2000] (DSPE−PEG 2000 − COOH), and 2′,7′-dichlorofluorescein diacetate (DCFH-DA) were obtained from Sigma-Aldrich. Oleylamine and methylene blue (MB) were received from Aladdin Chemistry Co., Ltd. (Shanghai, China). GOx, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and the annexin V-fluorescein isothiocyanate (FITC)/ propidium iodide (PI) cell apoptosis kit were purchased from Sangon Biological Engineering Technology & Company Ltd. (Shanghai, China). All other chemicals and solvents used were of analytical grades. 2.2. Apparatus. Transmission electron microscopy (TEM) was conducted by using FEI Tecnai G2 F20. The elemental composition of the synthesized samples was characterized by energy-dispersive Xray spectrometry. The X-ray diffraction (XRD) patterns were recorded on a model D/max-RC X-ray diffractometer. Ultraviolet− visible (UV−vis) absorption spectroscopy was carried out on a Cary 60 spectrophotometer (Agilent, USA). The electron spin resonance (ESR) signal was obtained on a Bruker A300 (X-band) spectrometer (Bruker, Germany). Photothermal experiments were conducted using Fotric 225 (IR thermal camera). MTT assay was measured at 490 nm by using a microplate reader (Thermo Scientific Multiskan GO, USA). The confocal laser scanning microscopy (CLSM) images were recorded on a Nikon A1 confocal microscope (Nikon, Japan). Flow cytometry was performed on FACSVerse (Becton Dickinson, USA). 2.3. Synthesis of Fe3O4@PEI. The oleylamine-stabilized Fe3O4 nanoparticles (Fe3O4-om) were synthesized by thermopyrolysis of Fe(acac)3 in oleylamine according to the previous studies.33,34 Thereafter, 2.0 mL of Fe3O4-om (50 mg mL−1) in chloroform was added to a beaker, and next the black chloroform solution was mixed with 20 mL of aqueous solution including 1.0 g PEI. The beaker was put in an ultrasonic cleaner. After the entire evaporation of chloroform with the ultrasonic bath (about 1.5 h), the resultants were shifted to ultrapure water.35 The resulting substance was denoted Fe3O4@PEI. 2.4. Preparation of PEG−MWNTs. The MWNTs were purified by acid treatment according to the previous literature.36 PEG− MWNTs were prepared by the MWNTs noncovalently functionalized with DSPE−PEG2000−COOH.37,38 In brief, 20 mg of MWNTs and 10 mg of DSPE−PEG2000−COOH were added in a small beaker and dispersed in 5.0 mL of water before sonication was performed in an ultrasonic bath for 2 h at room temperature. The resulting PEG− MWNTs were rinsed with methanol repeatedly to remove the excess polymer. Finally, the PEG−MWNTs were obtained with centrifugation. 2.5. Preparation of PMF. Briefly, EDC (7.0 mg), NHS (2.0 mg), and PEG−MWNTs (15 mg) were dispersed into ultrapure water (5.0 mL). The reaction mixture was kept for 50 min to activate the carboxylic groups at room temperature and then was added into a solution of 10 mg Fe3O4@PEI in water, and the reaction proceeded for 12 h (stirring). Subsequently, it was washed and separated to obtain PMF. 2.6. Preparation of PMFG. The loading of GOx onto PMF was obtained through an amide reaction. The preparation involved the following steps: GOx was dissolved in 5.0 mL of phosphate-buffered saline (PBS, 7) in a beaker, to which 10 mg PMF, which was activated
Scheme 1. Schematic Illustration of PMFG for Mild Hyperthermia-Enhanced Enzyme-Mediated Tumor Cell CDT
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DOI: 10.1021/acsami.9b08257 ACS Appl. Mater. Interfaces 2019, 11, 23065−23071
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Figure 1. TEM images of (A) Fe3O4 and (B) PMFG. (C) XRD patterns of (a) MWNTs−Fe3O4 and (b) Fe3O4. (D) UV−vis absorption spectra of PMF and PMFG. experiment, MCF-7 cells were plated onto 20 mm glass-bottom cell culture dishes at a density of 3 × 104 cells per dish and allowed to adhere overnight. Then, the culture media were replaced with DMEM (pH 6.5) as the following groups: PBS (control), PMF (50 μg mL−1), PMFG (50 μg mL−1), and PMFG (50 μg mL−1) + NIR (0.8 W cm−2, 5 min). After incubation for 24 h, the DCFH-DA solution (10 μM) was added to the cells for another 30 min. The cells were washed with PBS several times, and the intracellular ROS was evaluated with CLSM. 2.12. Flow Cytometry Characterization of Cell Apoptosis. Flow cytometry was applied to analyze the cell apoptosis. MCF-7 cells were planted in six-well plates and permitted to adhere overnight. After this, the culture medium was replaced with a fresh medium containing PBS (control), PMF (50 μg mL−1), PMFG (50 μg mL−1), and PMFG (50 μg mL−1) + NIR (0.8 W cm−2, 5 min). After incubating for 24 h, the cells were digested and collected by centrifugation at 1500 rpm. Then, the annexin V-FITC/PI apoptosis detection kit was utilized to stain the cells according to the instructions before the flow cytometry analysis.
in advance by 7.0 mg EDC and 2.0 mg NHS in 5.0 mL of water, was added under stirring. This reaction mixture was stirred for 5 h, and the as-synthesized sample was separated and washed with water (PMFG). 2.7. Photothermal Properties of PMFG. To assess the photothermal generation performance, different concentrations (0, 15, 25, 50, and 80 μg mL−1) of PMFG aqueous solutions were exposed to an 808 nm laser at a power density of 0.8 W cm−2 for 5 min. The temperature changes were monitored by an infrared thermal camera (Fotric 225). 2.8. Investigation of •OH Generation. The generation of •OH was detected by a UV−vis spectrophotometer with MB that served as a sensor.39 Briefly, 12 μg mL−1 MB and 100 μg mL−1 PMFG were mixed in a solution containing 0.8 mg mL−1 glucose at pH = 6.5. After 3 h, the •OH-induced MB solution depigmentation was monitored by the absorbance change at 665 nm. Besides, enhancing the temperature to 45 °C simulates mild hyperthermia during PTT, to assess the enhancement. The absorbance was normalized to the control. ESR spectroscopy was then implemented to further validate the production of •OH and the capacity of mild hyperthermia-enhanced •OH generation using DMPO as a spin-trapping agent for •OH. PMFG was placed in a solution containing glucose with or without mild hyperthermia. After 3 h, 20 μL of the DMPO buffer solution (100 mM) was added into the solution and detected immediately. 2.9. Cell Culture. MCF-7 breast cancer cells were obtained from Jiangsu Keygen Biotech Corp., Ltd. The cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) plus 10% fetal bovine serum and incubated at 37 °C under 5% CO2 in a cell incubator. 2.10. Cytotoxicity Assay. To survey the cell toxicity of PMFG combined with an NIR treatment to MCF-7 cells, the cells were inoculated into a 96-well plate with a density of 7000 cells per well and maintained for 24 h to allow the attachment of cells. Subsequently, the original culture medium was removed and added with new ones containing PMF and PMFG with different concentrations of 0, 8.9, 17.6, 32.4, 50.6, 100.3, and 146.7 μg mL−1. The pH value of the medium was adjusted to 6.5 by the addition of dilute HCl. The samples were further incubated for 24 h. After this, the PMFG (0, 8.9, 32.4, and 50.6 μg mL−1) group was irradiated using an 808 nm laser with a power density of 0.8 W cm−2 for 5 min. After adding PBS to wash the cells thrice, MTT (15 μL, 5 mg mL−1) was added into each well. After 4 h of further incubation, the MTT solution was removed, and 150 μL of dimethyl sulfoxide was added into every well to dissolve the formazan crystals. Finally, the plates were shaken gently for 10 min, and the absorbance at 490 nm was measured using a microplate reader. 2.11. Intracellular Reactive Oxygen Species Detection. The intracellular generation of reactive oxygen species (ROS) was measured by a fluorogenic substrate DCFH-DA.40 To perform the
3. RESULTS AND DISCUSSION 3.1. Characterization. To verify the synthesis of PMFG composites, various characterization methods were performed, including TEM, XRD, and UV−vis spectroscopy. TEM was performed to observe the microstructure of the composites. A spherical morphology and good dispersity of Fe3O4 nanoparticles were observed in Figure 1A. The average size of these nanoparticles was about 12−20 nm. Figure 1B displays the TEM image of PMFG, and it is clearly seen that Fe3O4 nanoparticles were modified on the surface of MWNTs. The structural information of Fe3O4 nanoparticles were obtained from XRD. Figure 1C shows the XRD patterns of MWNTs− Fe3O4 and Fe3O4. As shown, the diffraction peak at 2θ of 26.28° was attributed to the graphite crystalline phase (MWNTs). The peaks at 30.03°, 35.57°, 43.14°, 53.61°, 56.99°, and 62.56° can be assigned to (220), (311), (400), (422), (511), and (440) diffractions, respectively. These results coincided with the earlier report.41 The UV−vis absorption spectra of PMF and PMFG are shown in Figure 1D. As shown, compared to PMF, PMFG displayed two absorption peaks at 382 and 452 nm which are attributed to the flavin groups in the structure of GOx.42 The result confirmed the existence of GOx in the composites. Building on 23067
DOI: 10.1021/acsami.9b08257 ACS Appl. Mater. Interfaces 2019, 11, 23065−23071
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Figure 2. (A) Temperature increase curves of PMFG with different concentrations under an 808 nm laser irradiation (0.8 W cm−2). (B) Infrared thermal images of water and 50 μg mL−1 PMFG under an 808 nm laser irradiation (0.8 W cm−2).
Figure 3. (A) Colorimetric analysis of the Fenton reaction for MB decolorization of different groups (a, control; b, MB + glucose; c, MB + glucose + GOx; d, MB + glucose + PMFG; and e, MB + glucose + PMFG + 45 °C). (B) ESR spectra of different reaction systems with DMPO as the spin trap in the presence of glucose.
Figure 4. Relative cell viability of MCF-7 cells with (A) PMF and (B) PMFG at different concentrations (0, 8.9, 17.6, 32.4, 50.6, 100.3, and 146.7 μg mL−1) after incubation for 24 h. (C) Relative cell viability of MCF-7 cells incubated with PMFG at different concentrations (0, 8.9, 32.4 and 50.6 μg mL−1) with an 808 nm laser irradiation (0.8 W cm−2).
observed when MB was incubated with glucose and PMFG (d), whereas no apparent change was observed in the a, b, and c groups. This result indicated that glucose and PMFG are able to yield •OH eliciting the decoloration of MB. In other words, H2O2 produced in GOx-catalyzed glucose decomposition could participate in the Fenton reaction. Moreover, a more significant decline in absorbance at 45 °C indicated the generation of more abundant •OH radicals (e), meaning the thermal-enhanced effect on promoting the Fenton reaction for the generation of •OH. We further detected the •OH generation. Here, ESR was utilized to monitor the •OH signals by using DMPO as a spintrapping agent. As illustrated in Figure 3B, quartet signals with a relative intensity of 1:2:2:1 were obtained in the ESR spectrum, demonstrating that •OH were formed.43 Noteworthily, the assessment at 45 °C exhibited a higher intensity of ESR, which demonstrated that mild hyperthermia can facilitate •OH generation. The result was consistent with the MB degradation experiment. Combined with the previous experimental results, the constructed PMFG could induce the generation of •OH. Moreover, the heat from the photothermal conversion would further strengthen the Fenton reaction, resulting in more •OH generation.
these observations, PMFG composites have been successfully prepared. 3.2. Photothermal Performance. We investigated the photothermal effect of the composites. A series of PMFG solutions with various concentrations of 0, 15, 25, 50, and 80 μg mL−1 were irradiated by an 808 nm laser (0.8 W cm−2) for 5 min. We then used a thermal imaging camera to record the temperature variation as the irradiation time (Figure 2). According to the temperature curves (Figure 2A), it was found that the degree of temperature rise upon NIR irradiation was positively related with the concentration of PMFG. As shown in Figure 2B, the temperature eventually rises to 45 °C after 5 min of irradiation when the concentration was 50 μg mL−1, which was sufficient to enhance CDT. As a control, the temperature of water was slightly increased under identical laser conditions. Therefore, the concentration of 50 μg mL−1 PMFG was selected for the following experiment to strengthen the combinatory therapy effect of PTT and CDT. 3.3. Hydroxyl Radical Detection. The potential of PMFG to act as a trigger for the generation of •OH was investigated. First, MB, a dye that can be bleached by •OH, was employed to detect the production of •OH. As shown in Figure 3A, an obvious reduction in maximum absorbance was 23068
DOI: 10.1021/acsami.9b08257 ACS Appl. Mater. Interfaces 2019, 11, 23065−23071
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Figure 5. Confocal fluorescence imaging of DCFH-DA-stained MCF-7 cells treated with (A) PBS (control), (B) PMF, (C) PMFG, and (D) PMFG + NIR. Scale bar: 50 μm.
Figure 6. Flow cytometric apoptosis analysis of annexin V-FITC/PI-stained MCF-7 cells after different treatments: (A) PBS (control), (B) PMF, (C) PMFG, and (D) PMFG + NIR.
3.4. Cell Viability Evaluation. MTT assays were employed to assess the cytotoxicity of the composites in MCF-7 cells because cytotoxicity is crucial for biological applications. As indicated in Figure 4A, the cell viability has no obvious differences with the varied concentrations of PMF, indicating that the synthesized PMF is featured with low cytotoxicity and good biocompatibility. Subsequently, the anticancer effect of PMFG was evaluated on MCF-7 cancer cells. It has been found that the cell viabilities are dependent on the dosage of PMFG (Figure 4B,C). Notably, the survival rate of the cells irradiated with laser was apparently lower than that of those without laser irradiation, indicating laser irradiation improved anticancer activity, which was consistent with the aforementioned production of •OH radicals by PMFG. These results suggested that mild hyperthermia induced by the 808 nm laser irradiation could promote the CDT effect of PMFG. 3.5. Intracellular ROS Study. To assess the •OH generation in cells, an indicator, DCFH-DA, was applied to identify ROS generation, which could be oxidized to 2′,7′dichlorofluorescein with green fluorescence in the presence of ROS (Figure 5). The fluorescence was detected by laser confocal microscopy. Compared to the control group, PMF and PMFG, PMFG + NIR-treated MCF-7 cells show a significant fluorescence enhancement, which implied much more generation of •OH. This was attributed to the photothermal effects generated by PMFG under an 808 nm laser irradiation, reinforcing the production effectiveness of • OH. Furthermore, gluconic acid produced from the reaction of GOx and glucose also enhances the Fenton reaction. 3.6. Flow Cytometric Apoptosis Assay. Furthermore, the intracellular catalytic therapeutic mechanism of the PMFG nanoplatform was studied by the typical flow cytometry apoptosis analysis after staining with annexin V-FITC and PI.44 According to the fluorescence intensity, cell populations are divided into four quadrants, including living, early apoptotic, late apoptotic, and necrotic cells (Figure 6). MCF-7 cells were incubated in various conditions including PBS (control), PMF,
PMFG, and PMFG + NIR. Compared to the control group, the cells treated with PMF and the PMFG group display pronounced apoptosis owing to the cytotoxicity of •OH. The cells incubated with PMFG exhibit an observably boosted apoptosis, which demonstrates that more •OH has been produced in the presence of GOx. More importantly, cells in the group of PMFG + NIR show the most enhanced cell apoptosis, indicating massive •OH production under the laser irradiation condition (Figure 6D). The above results suggested that the localized heat generated by the photothermal treatment promoted the Fenton process to achieve mild PTT/CDT synergistic therapy.
4. CONCLUSIONS In summary, based on the theory that a temperature rise promotes the kinetics of a chemical reaction, we have developed a novel cancer therapy platform, mild hyperthermia-enhanced GOx-mediated CDT. The nanocomposites, PMFG, can elevate the concentration of intracellular H2O2 and acidity in the tumor microenvironment by the catalysis of GOx, thus accelerating the Fenton reaction to engender a myriad of •OH, which leads to the increase of the cancer cell apoptosis. Moreover, the Fenton reaction can be further strengthened under an 808 nm laser irradiation through the mild hyperthermia generated from MWNTs, which obviously accelerates the kinetics of the Fenton reaction and enhances the CDT effect. Therefore, the work provides an alternative path, which integrated the Fenton reaction and moderate hyperthermia cancer treatment together, to achieve a better therapeutic outcome.
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*E-mail:
[email protected]. Phone/Fax: +86-2585891051 (Z.D.). *E-mail:
[email protected] (T.W.). 23069
DOI: 10.1021/acsami.9b08257 ACS Appl. Mater. Interfaces 2019, 11, 23065−23071
Research Article
ACS Applied Materials & Interfaces ORCID
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Zhihui Dai: 0000-0001-7049-7217 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 (21625502, 21475062, and 21705079) and the Natural Science Foundation of Jiangsu Province (BK20171033). We appreciate the financial support from the Priority Academic Program Development of Jiangsu Higher Education Institutions and the Program for Jiangsu Collaborative Innovation Center of Biomedical Functional Materials.
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