Communication Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
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DNA-Functionalized Metal−Organic Framework: Cell Imaging, Targeting Drug Delivery and Photodynamic Therapy Yuanchao Zhang,†,‡ Qingli Wang,‡ Guang Chen,*,† and Pengfei Shi*,‡ †
School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, Shandong, P. R. China Shandong Provincial Key Laboratory of Detection Technology for Tumor Markers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276000, Shandong, P. R. China
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‡
S Supporting Information *
bonds ensure that MOFs are biodegradable.1 According to the literature, MIL-100, ZIF-8, UiO-66, and many classical MOFs were selected for drug loading and delivery.17−19 Because of tunable inorganic building blocks and organic linkers, MOFs not only possess large pore sizes and high surface areas for drug encapsulation but also integrate PSs into periodic arrays, such as porphyrinic NMOFs.20−22 Porphyrinic NMOFs have presented promising perspectives for cancer therapy because of their definite advantages over the traditional PDT systems, such as high PS loading and inevitable self-quenching behavior.23 In 2014, Lin’s group first reported a hafnium porphyrin NMOF that exhibited highly effective PDT of resistant head and neck cancer.24 In the last 5 years, MOFs as carriers for drug delivery and PSs have been increasingly reported. For example, Damirin’s group developed folic acid modified Fe-MIL-53NH2 for magnetic resonance/optical imaging and targeted drug delivery.17 Zhou’s group reported targeting PCN-224 through postsynthetic modification with folic acid for targeted PDT.25 However, the combination of chemotherapy with PDT based on NMOFs is rare.26 It is noteworthy that NMOFs are able to be surface modified.27−29 Therefore, postmodification NMOFs with targeting ligands is feasible, which would improve their cancer-targeting ability.30 Herein, we demonstrate that DNA-functionalized NMOFs can trace tumor cells targeted by drug delivery and PDT. As is well-known, the morphology and size of the NMOFs affect the drug loading and whether they can be engulfed by cells. Therefore, the size-controlled synthesis of NMOFs is important. As shown in Scheme 1, nanoscale PCN-224 was built with 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP), benzoic acid, N,N-dimethylformamide, and biocompatible Zr4+ ions by a stirring method and served as the carrier for doxorubicin (DOX). The structure of DOX is shown in Figure S1. DOX was always used as a model for antitumor drugs to investigate the loading capacity and pH-responsive release behavior.1 After DOX loading, the system was functionalized with the aptamer (DNA) of A549 lung cancer cells. The aptamer of A549 cells has a good affinity and a high specificity to A549 cells.31 Meanwhile, the aptamer was modified with carboxyl and fluorescein at the two terminals. The carboxyl was linked with Zr6+ ions by a coordination bond, realizing DNA-functionalized PCN-224. Fluorescein could trace the A549 cells by targeting of PCN-224DNA into the cells. When touching a tumor cell, DNA-
ABSTRACT: Here, DNA-functionalized nanoscale PCN224 is established with the aptamer of A549 lung cancer cells. The aptamer was modified with carboxyl and fluorescein at the two terminals. When touching the A549 cells, DOX@PCN-224-DNA can trace tumor cells and present good targeting therapy by the combination of chemotherapy and photodynamic therapy. This facile aptamer functionalization of PCN-224 offers an opportunity to develop metal−organic framework-based targetdirected therapy and biosensors.
C
ancer, caused by uncontrolled cell growth, is facing a global outbreak. The usual cancer treatment methods include radiotherapy, chemotherapy, photodynamic therapy (PDT), and surgical resection at present.1−3 Although these methods have been studied and reported, conventional treatments such as chemotherapy and radiotherapy are not satisfactory for aggressive tumor treatment because of their high recurrence rate and strong side effects.4 Compared with traditional methods, PDT has been employed to treat cancer in recent years, which can generate reactive oxygen species (ROS) with photosensitizers (PSs) and oxygen by light irradiation, particularly singlet oxygen (1O2), resulting in cell apoptosis and necrosis.5 Although PDT can selectively kill tumor cells and minimize collateral damage to normal tissues by localizing the PSs and light exposure to tumor regions, accurate targeting of the tumor cells cannot be completed.6 Thus, targeted therapy is worthy of attention and research7 because it is an effective treatment to accurately trace tumor cells, greatly reduce the impact on normal cells, and improve the curative effect.8 Targeted therapy is the use of targeting ligands, such as aptamer, antibody, and some overpress molecules, in tumor cells.9 Much research indicates that targeting ligands have a good affinity and a high specificity to specific tumors, presenting great potential in drug-delivery systems and molecular probes.10 Nanoparticles have been explored as an alternative to deliver drugs and PSs to tumors for therapy.11,12 The new emerging class of porous materials in 21st nano metal−organic frameworks (NMOFs) has received attention for its wide applications in biosensing, drug delivery, and other applications.13−15 In the last decade, drug loading and delivery based on MOFs have drawn great attention because of their structural advantages, which make it capable of controlling drug interactions with biological systems and release.16 Meanwhile, weak coordination © XXXX American Chemical Society
Received: March 13, 2019
A
DOI: 10.1021/acs.inorgchem.9b00734 Inorg. Chem. XXXX, XXX, XXX−XXX
Communication
Inorganic Chemistry
confirmed by UV−vis absorbance of DNA measurements before and after modification with PCN-224 (Figure S3). Additionally, similar powder X-ray diffraction patterns of PCN-224, DOX@ PCN-224, and DOX@PCN-224-DNA (Figure S4) were observed, verifying the stability of PCN-224. The simulation of DOX loading based on PCN-224 is shown in Figure S5. According to UV absorption of DOX, the loading efficiency was 50 μg/mg (Figure S6), which may be ascribed to the combined efficiency of hydrophobic interactions and π−πstacking effects. The pH-response release properties of DOX provided smart drug delivery for tumor-targeting treatment. In normal biological environments (pH 7.4), DOX in PCN-224DNA was released slightly (5% after 48 h, as shown in Figure S7), which ensured a high biocompatibility and a low side effect to normal tissues. As was expected and proven in some reported Articles,33 in acidic conditions (pH 5.0), also in cancerous conditions, DOX was released relatively fast (30% after 12 h and 45% after 48 h), indicating that DOX@PCN-224-DNA displays a capacity for therapeutic effects, as shown in Figures 2A and S8. Thus, drug delivery based on PCN-224-DNA could be applied in tumor-targeting treatment with pH-response release of DOX.
Scheme 1. Schematic Representation of DNA-Functionalized PCN-224 for Tumor Cell Imaging, Targeting Drug Delivery and PDT
functionalized PCN-224 can recognize the tumor cell by specificity with the surface protein tumor cell. The low pH in the tumor microenvironment leads to the release of DOX from PCN-224, which induces apoptosis of the A549 cells. Moreover, TCPP is a highly effective PS for PDT, which further increases the tumor cell mortality. The results indicate that DOX@PCN-224-DNA can trace and target A549 cells with drug delivery and PDT. The nanoscale PCN-224 was synthesized according to the previous literature.25,32 The morphology of the obtained PCN224 was observed by transmission electron microscopy (TEM). As illustrated in Figure 1A,B, PCN-224 presents a good
Figure 2. (A) pH-triggered DOX release performance of DOX@PCN224 in pH 5.0 and 7.4 PBS. (B) Dependence of the fluorescence intensity of ABDA based on PCN-224 and TCPP on the irradiation time at 437 nm. (C) Viability of the A549, LO2, and MCF-7 cells after incubation with PCN-224 for different concentrations. (D) Viability of the A549 and MCF-7 cells after incubation with different conditions: (a) incubation with PCN-224; (b) irradiation by a 650 nm laser; (c) incubation with PCN-224 and irradiation by a 650 nm laser; (d) incubation with DOX@PCN-224; (e) incubation with DOX@PCN224 and irradiation by a 650 nm laser; (f) incubation with DOX@PCN224-DNA; (g) incubation with DOX@PCN-224-DNA and irradiation by a 650 nm laser.
Figure 1. TEM image (A), size distribution (B), and DLS (C) of PCN224. (D) ζ potentials of PCN-224 (1), DOX@PCN-224 (2), and DOX@PCN-224-DNA (3).
TCPP is a highly effective PS for PDT. Therefore, the photophysical properties of PCN-224 were studied in detail (Figures S9−S12). Compared with TCPP, the UV−vis absorption of PCN-224 presented a red shift, which was attributed to the enlarged conjugate area of porphyrin after coordination between Zr4+ and TCPP. Moreover, PCN-224 displayed a good photostability. As was verified in documents, TCPP can generate ROS 1O2 by light irradiation, resulting in cell apoptosis and necrosis. Thus, the PDT ability of PCN-224 was investigated. For comparison, the PDT efficiency of TCPP was also determined as the indicator. 9,10-Anthracenediylbis(methylene)dimalonic acid (ABDA) was chosen to evaluate
monodispersed size distribution at around 198 nm. Upon immersion in phosphate-buffered saline (PBS) and DOX loading, the morphology of PCN-224 remains almost constant and stable, as shown in Figure S2. In accordance with TEM observations, a narrow hydrodynamic size distribution of PCN224 was also observed at around 230 nm (Figure 1C). Moreover, the ζ potential of PCN-224 was changed from −26 to −20 mV after DOX loading because of the positive amount of DOX. After DNA functionalization, the ζ potential of DOX@PCN-224DNA was −47 mV (Figure 1D), indicating that DOX@PCN224 was successfully modified with DNA, which was also B
DOI: 10.1021/acs.inorgchem.9b00734 Inorg. Chem. XXXX, XXX, XXX−XXX
Communication
Inorganic Chemistry the 1O2 generation efficiencies of TCPP and PCN-224. ABDA was oxidized by 1O2, leading to degenerative fluorescence, which could be quantified with a fluorimeter. As shown in Figures 2B and S13 and S14, ABDA displays strong fluorescence at 406, 437, and 458 nm in the absence of light irradiation. After light irradiation for 1 min, the fluorescence intensity of ABDA decreases. The decreasing fluorescence represented the capacity of 1O2. With increasing light irradiation time, the fluorescence of ABDA wore off until quenching, also corresponding with the increasing generation of 1O2. The cytotoxicity of PCN-224 was measured to evaluate their biocompatibility using a standard Cell Counting Kit-8 (CCK-8) assay. The cell viabilities of cancer cells A549 (a human lung cell line) and MCF-7 (a human breast cell line) and normal cell LO2 were recorded with the treatment of PCN-224 at diverse concentrations for 12 h. As shown in Figure 2C, for all dosages, the cell viability is over 90%, demonstrating a lower cytotoxicity effect in vitro. Meanwhile, significance analysis was conducted on the cytotoxicity data,34 as shown in the Supporting Information. Additionally, the blood routine reports of mice after the injection of PCN-224 were also studied (Table S1). All results indicate that the dosage of PCN-224 in this Article is safe. To investigate the chemotherapy and PDT effects of DOX@ PCN-224-DNA on the cancer cells A549, the cell viabilities of the A549 and MCF-7 cells with related groups (PCN-224, DOX@PCN-224, DOX@PCN-224-DNA, and DOX) were studied under a 650 nm laser for 15 min (100 mW/cm2). As shown in Figure 2D, PCN-224 exhibits nearly negligible cytotoxicity to both cell lines. With a single laser, the viabilities of the A549 and MCF-7 cells were 88% and 87%. The viabilities of the A549 and MCF-7 cells were 78% and 82% with a single PCN-224 in a laser. After incubation of DOX@PCN-224, the viabilities of the A549 and MCF-7 cells were 62% and 60%, respectively, with a single chemotherapy treatment. As expected, the viabilities of the A549 and MCF-7 cells with chemotherapy and PDT treatment were 55% and 58%, which confirmed the synergistic effect of chemotherapy and PDT. These results also demonstrate that DOX@PCN-224 can well-induce cancer cell death for A549 and MCF-7. To further evaluate the targeted chemotherapy and PDT effects, the aptamer of A549 was used to modify DOX@PCN-224 and DOX@PCN-224-DNA. The viability of the A549 and MCF-7 cells with chemotherapy and/ or PDT treatment was conducted after incubation with DOX@ PCN-224-DNA. The viability was 50% for A549, whereas it was 62% for MCF-7 with single chemotherapy. Upon simultaneous treatment with chemotherapy and PDT, the viability was 30% for A549, whereas it was 45% for MCF-7, indicating that DOX@ PCN-224-DNA presents impressive targeting PDT and chemotherapy effects to A549 cells. To further investigate the tracing behavior of DOX@PCN224-DNA to cancer cells, fluorescence tracking imaging was performed on the A549 and MCF-7 cells using confocal laser scanning microscopy (CLSM). DOX@PCN-224-DNA was incubated with A549 cells for 3 and 6 h, respectively, and CLSM imaging is shown in Figures 3A and S15. Blue fluorescence in the cell nuclei was attributed to 4′,6diamidino-2-phenylindole (DAPI). Green fluorescence was attributed to FAM, which was modified on DNA, whereas the red emission was attributed to DOX. The fluorescence imaging gets clearer with extension of the incubation time. After 6 h of incubation, the fluorescence of FAM and DOX during cell imaging is obvious for the A549 cells. However, the fluorescence of FAM and DOX is weak on the MCF-7 cells (Figure 3B). This
Figure 3. CLSM images of the A549 (A) and MCF-7 (B) cells incubated with DOX@PCN-224-DNA for 6 h and (C) the A549 cells incubated with DOX@PCN-224-DNA (single base mismatch) for 6 h. The images from left to right represent the DOX fluorescence, FAM fluorescence, DAPI, and merged fields.
result demonstrates that DOX@PCN-224-DNA is present prior to entering into the A549 cells. Moreover, DNA with single base mismatch was also modified with DOX@PCN-224. As is shown in Figure 3C, the fluorescence imaging is slightly weak, further confirming the targeting effect of DOX@PCN-224-DNA. In summary, nanoscale PCN-224 was modified with the aptamer of A549 lung cancer cells, constructing a DNAfunctionalized MOF. Because the aptamer is a targeting ligand on the surface of PCN-224, DNA-functionalized PCN-224 can recognize the A549 cells and present a good targeting therapy by the combination of chemotherapy and PDT. Therefore, targetinduced imaging and therapy were achieved using PCN-224. This facile aptamer functionalization of PCN-224 offers an opportunity to develop MOF-based target-directed therapy and biosensors.
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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.inorgchem.9b00734. Materials and reagents, instrumentation, detailed experimental section, and some figures and a table (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Guang Chen: 0000-0002-0454-1686 Pengfei Shi: 0000-0001-6121-270X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the NSFC (Grants 21775062 and 21505064), the China Postdoctoral Science Foundation (Grants 2018M642606 and 2017M622254), the Project of Shandong Province Higher Educational Science and TechnolC
DOI: 10.1021/acs.inorgchem.9b00734 Inorg. Chem. XXXX, XXX, XXX−XXX
Communication
Inorganic Chemistry
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ogy Program (J16LC11), and the Natural Science Foundation of Shandong Province (Grant ZR201709240033).
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DOI: 10.1021/acs.inorgchem.9b00734 Inorg. Chem. XXXX, XXX, XXX−XXX
