Phosphorescent Coordination Polymer Nanoparticles as a Three-in

Dec 9, 2014 - Phosphorescent Coordination Polymer Nanoparticles as a Three-in-One Platform for Optical Imaging, T1-Weighted Magnetic Resonance Imaging...
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Phosphorescent Coordination Polymer Nanoparticles as a Three-inOne Platform for Optical Imaging, T1‑Weighted Magnetic Resonance Imaging, and Photodynamic Therapy Yang Lu, Fengfeng Xue, Hong Yang,* Min Shi, Yuping Yan, Lijie Qin, Zhiguo Zhou, and Shiping Yang* The Key Laboratory of Resource Chemistry of Ministry of Education, Shanghai Key Laboratory of Rare Earth Functional Materials, and Shanghai Municipal Education Committee Key Laboratory of Molecular Imaging Probes and Sensors, Shanghai Normal University, Shanghai 200234, China S Supporting Information *

ABSTRACT: Water-soluble coordination polymer nanoparticles (Ir−Gd CPPs) were conveniently synthesized in high yields in the presence of polyvinylpyrrolidone (PVP), adopting magnetic Gd(III) ions, and phosphorescent iridium complexes with carboxyl groups as building blocks. The Ir−Gd CPPs showed good stability in simulated biological media and low cytotoxicity toward a model line of HeLa cancer cells. The Ir−Gd CPPs exhibited absorption in the visible region, red phosphorescence centered at 560 nm, and higher longitudinal relaxivity (r1) of ∼29.5 mM−1 s−1 in a 3 T MRI system. Furthermore, the effective uptake of Ir−Gd CPPs by HeLa cells was confirmed by confocal laser scanning microscopy and flow cytometry, suggesting they may be useful as an optical probe for living cells. The generation of 1O2 upon irradiation with a visible light prompted an investigation into the possibility of using Ir−Gd CPPs in photodynamic therapy. After incubation with 200 μg mL−1 of Ir−Gd CPPs for 6 h, the viability of HeLa cells was only ∼16.6% after irradiation with a visible light (λ > 400 nm, 300 mW cm−2).

1. INTRODUCTION The research and development of novel nanoparticulate theranostic agents, which combine both diagnostic and therapeutic functions, has attracted much attention by scientists working across diverse interdisciplinary fields of materials and medicine.1−5 Generally, theranostic agents are constructed via one of two methods. One is to load the diagnostic and therapeutic components onto dendrimers, polymeric micelles, or inorganic materials;6−13 the other is to combine the diagnostic and therapeutic units by physical interactions or chemical bonds.14−17 The traditional approach to obtain nanoparticulate theranostic agents requires the complicated synthetic procedure to prevent the unpredictable risks in vivo. To address the problem, we recently developed a single component nanomaterial exhibiting both imaging and therapeutic functionalities for theranostic application.18,19 Nanoscale coordination polymer particles (CPPs) have been paid much attention by the scientists in the field of materials and chemistry owing to their highly flexible properties, which can be applied for heterogeneous catalysis,20,21 gas storage,22,23 imaging, biosensing, and drug delivery.24−27 Our group previously developed magnetophosphorescent CPPs for optical imaging and magnetic resonance (MR) imaging in vitro.28 To further improve the diagnostic accuracy of the CPPs, we have also reported Gd-based CPPs for targeted T1- and T2-weighted MR imaging in vivo.29 The tuning of the structure and function of CPPs with the various ligands and metal ions provides great scope for application in the field of theranostics. © XXXX American Chemical Society

Iridium complexes exhibit simultaneously strong phosphorescence and can sensitize singlet oxygen formation (1O2) due to the heavy atom effect of iridium.30−34 Gd(III) ions with long electronic relaxation times and high magnetic moments confer excellent suitability for contrast enhancement of magnetic resonance signals.35 In the present paper, we have developed a method to prepare Ir−Gd CPPs by coordination assembly of carboxy-functionalized Ir(III) complexes ([(pq)2Ir(Hdcbpy)] (pq, 2-phenylquinoline; Hdcbpy, 3-carboxy-2,2′-bipyridyl-3′carboxylate)) (Scheme 1) providing theranostic properties with magnetic Gd(III) ions for MR imaging in the presence of polyvinylpyrrolidone (PVP). The CPPs showed excellent phosphorescence, longitudinal relaxivity (r1), and the ability to generate 1O2. The luminescence and T1-weighted magnetic resonance (MR) imaging in living cells has been recorded. The photodynamic therapy (PDT) in vitro has also been investigated in detail.

2. EXPERIMENTAL SECTION 2.1. Materials. IrCl3·H2O, 2-ethoxyethanol, and 2-phenylquionline (pq) were purchased from Shanghai Jiuyue Chemical Co., Ltd., Acros Corporation, and Shanghai Ruiyi Medical Tech. Co., Ltd., respectively. Other reagents were bought from Received: September 1, 2014 Revised: November 12, 2014

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Scheme 1. Schematic Synthesis and Theranostic Applications of Ir−Gd CPPs

Figure 1. Typical SEM (a) and TEM (b) images of the Ir−Gd CPPs. (c) Curves of hydrodynamic diameter of Ir−Gd CPPs dispersed in water (■), PBS with 10% FBS (●), and RPMI-1640 with 10% FBS (▲) as a function of time. (d) Zeta potential of the Ir−Gd CPPs in aqueous solution.

6.76 (t, J = 7.2 Hz, 2H), 6.17 (d, J = 7.6 Hz, 2H). HRMS (TOF): Calcd for IrC42H27N4O4 (M + H+) 844.1740, found 845.1748. 2.4. Synthesis of Ir−Gd CPPs. (pq)2Ir(Hdcppy) (4.3 mg (0.005 mmol)) and 50 mg of PVP K-30 (Mw = 45000−55000) were dissolved in 5 mL of DMSO, and 2.0 mg (0.005 mmol) of Gd(Ac)3·4H2O were dissolved in 2 mL of DMSO by sonication, respectively. Then, the above two solutions were mixed each other. The mixture was reacted at 110 °C for 12 h, and then dialyzed (MWCO, 14000) against deionized water for 2 days. 2.5. Relaxivity Measurements in Solution. T1-weighted MR images were obtained in a 3.0 T system using a traditional spin−echo sequence with the parameters as follows: TR/TE = 1500/7.9 ms, 128 × 320 matrices, 64.00 × 160.00 mm field of view, 313 Hz/Px of bandwidth, and a slice thickness of 3.0 mm. 2.6. Singlet Oxygen Detection in Solution. Singlet oxygen generation of Ir−Gd CPPs was observed by detecting the decrease of fluorescence intensity of 9,10-dimethylanthracene (DMA) on a fluorescence spectrophotometer. In a typical experiment, 50 μL of DMA (10.0 mM) in ethanol was mixed with an ethanol/water (4:1) solution of Ir−Gd CPPs (4 mL, 200 μg mL−1). The DMA solution, Ir−Gd CPPs containing DMA (50 μL), and saturated NaN3 were used as the control experiments. Each sample solution was irradiated with a visible

Sinopharm Chemical Reagent Co., Ltd. All solvents were dried by a standard procedure before use. [(pq)2Ir(μ-Cl)2(pq)2] was synthesized according to the literature.36 2.2. General Instruments. Transmission (TEM) and scanning electron microscopy (SEM) images were recorded at 200 kV with a JEOL JEM-2100 transmission electron microscope and a Hitachi S-4800 scanning electron microscope, respectively. Phosphorescence spectra were recorded on a Varian Cary Eclipse fluorescence spectrophotometer. Luminescence lifetimes were performed on an Edinburgh FL 920 system excited by a 375 nm laser. UV−visible spectra were measured on a Beckman Coulter DU 730 spectrometer. Flow cytometry (Beckman Coulter, USA) was used to carry out related experiments. 2.3. Synthesis of (pq)2Ir(Hdcbpy). [(pq)2Ir(μ-Cl)2(pq)2] (0.318 g, 0.25 mmol) and 2,2′-bipyridine-3,3′-dicarboxylic acid (0.146 g, 0.60 mmol) were added to the CH2Cl2/MeOH solution (24 mL, 1:1, v/v) under a nitrogen atmosphere. The mixed solution was stirred under reflux for 6 h and formed a red solution. After the solution was cooled, the solvent was removed under the reduced pressure. The solid was purified by SiO2 column using CH2Cl2/MeOH (10:1, v/v) to obtain the red product in a yield of 90%. 1H NMR (400 MHz, DMSO) δ (ppm): 8.51 (dd, J = 14.4 Hz, 4H), 8.19 (d, J = 7.6 Hz, 2H), 7.92 (d, J = 8.0 Hz, 8H), 7.45 (t, J = 6.8 Hz, 2H), 7.32 (t, J = 6.8 Hz, 2H), 7.22 (t, J = 8.0 Hz, 2H), 7.07 (t, J = 8.0 Hz, 2H), B

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light (λ > 400 nm, 300 mW cm−2) for an interval of 1 min. The fluorescence spectra of DMA (λex = 360 nm) was measured. 2.7. T1-Weighted MR Imaging in HeLa Cells. HeLa cells were incubated with a suspension of Ir−Gd CPPs in RPMI1640 for 24 h. T1-weighted MR images were acquired using a traditional spin−echo sequence with the parameters as follows: TR/TE = 500/12 ms, 90.78 × 140.00 mm field of view, 256 × 166 matrices, 120 Hz/Px of bandwidth, and a slice thickness of 2 mm. 2.8. Optical Imaging. HeLa cells were plated in 20 mm cells culture dish for 24 h. After incubation with Ir−Gd CPPs (200 μg mL−1) for 6 h, the cells were washed with phosphate buffer saline (PBS) twice. Luminescence images were obtained using a Leica TCS SP5-II microscopy excited by a 405 nm laser equipped with a 63× oil objective lens. 2.9. Flow Cytometry. HeLa cells were incubated with different concentrations (0, 10, 20, 50, 100, and 200 μg mL−1, respectively) of Ir−Gd CPPs in serum-free medium for 24 h. After rinsing the cells with PBS three times, the cells were harvested by trypsinization. The cells were resuspended in PBS, then determined by flow cytometry. The data were analyzed using FlowJo 7.6.1 software. 2.10. Trypan Blue Staining. HeLa cells were incubated with Ir−Gd CPPs (200 μg mL−1) in serum-free medium for 24 h. Afterward, the medium was replaced with fresh RPMI-1640, and the cells were irradiated with a visible light (λ > 400 nm, 300 mW cm−2) for 10 min. The cells were further incubated for 1 h. One milliliter of 4% trypan blue in PBS solution was added into every well, followed by rinsing with PBS three times.

Figure 2. (a) UV−vis absorption and emission spectra (λex = 345 nm) of the Ir−Gd CPPs in PBS (red) and DMSO (black) solution. Inset: Photographs of color and phosphorescence in water excited by a UV lamp (the central wavelength is ∼365 nm). (b) T1-weighted MR images (b) and T1 relaxivity plot (c) of Ir−Gd CPPs in water in a 3.0 T MR system.

3. RESULTS AND DISCUSSION The water-soluble Ir−Gd CPPs were synthesized via coordination assembly according to our previous report.28 To achieve the good dispersity, water solubility, and biocompatibility of Ir−Gd CPPs, PVP was added during the synthesis process. The morphology and size of the Ir−Gd CPPs were characterized. As resulted from TEM and SEM, the Ir−Gd CPPs have an average diameter of ∼150 nm (Figure 1). Dynamic light scattering (DLS) in water revealed an average diameter of ∼268.8 ± 3.4 nm, suggesting a little aggregation in aqueous solution. To assess the stability of the Ir−Gd CPPs, they were dispersed in water, PBS with 10% FBS, and RPMI1640 medium with 10% FBS for one month, respectively. As presented in Figure 1c, no obvious changes of the diameter of Ir−Gd CPPs were observed, indicating excellent colloidal stability in these simulated biological media. This high stability is owing to the presence of PVP on the particle surface and the large zeta potential of −12.8 ± 0.8 mV (Figure 1d). The optical properties of the Ir−Gd CPPs in PBS and DMSO solution were studied. As shown in Figure 2a, the absorption region from 270 to 350 nm is attributed to the ligand-centered transitions 1LC (1π → π*) localized on the C− N (Hdcbpy) and N−N ligands (pq). The absorption between 350 and 450 nm was resulted from the singlet-to-singlet metalto-ligand charge-transfer transition 1MLCT.37 The absorption greater than 450 nm could be assigned to 3LC transition accompanied by the 3MLCT transition character.38 The Ir−Gd CPPs exhibited the strong red phosphorescence located at 560 nm in PBS and DMSO solution at room temperature excited by a 345 nm light. While the luminescence lifetime of Ir−Gd CPPs in PBS was measured to be ∼0.51 and 0.61 μs with and without O2, respectively, the luminescence lifetime of Ir−Gd CPPs in DMSO was measured to be ∼0.50 and 0.80 μs with and

Figure 3. (a) Mechanism of DMA to detect 1O2. (b) Changes of fluorescence spectra of DMA (λex = 360 nm) measured after an interval of 1 min in an ethanol/water (4:1, v/v) solution for 15 min. (c) Changes of the fluorescence intensity of DMA centered at 426 nm without (■) or with (●) the saturated NaN3 solution in the presence of Ir−Gd CPPs (200 μg mL−1) and the DMA solution (▲) in an ethanol/water (4:1, v/v) solution irradiated by a visible light (λ > 400 nm, 300 mW cm−2) for 15 min.

without O2, respectively. The fact indicated the phosphorescent nature of the emission of Ir−Gd CPPs.39 The luminescence quantum yield of Ir−Gd CPPs in deoxidized PBS and DMSO solution was also determined to be 0.0133 and 0.2215 using a [Ru(bpy)3]Cl2 solution (φ = 0.042) as the reference, respectively. Considering the existence of Gd(III) ions in the Ir−Gd CPPs, we investigated a possibility for magnetic resonance (MR) imaging of Ir−Gd CPPs. Generally, nanoparticulate GdC

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Figure 4. (a) Cell viability of HeLa cells and Chang liver cells incubated with different concentrations of Ir−Gd CPPs (10−200 μg mL−1) for 12 and 24 h, respectively. (b) Cellular uptake of Ir−Gd CPPs measured by flow cytometry. HeLa cells were incubated with 0 (control), 10, 20, 50, 100, and 200 μg mL−1 of Ir−Gd CPPs for 6 h, respectively. (c) The confocal optical image (c1), bright field image (c2), and the overlay of c1 and c2 (c3) of HeLa cells incubated with 200 μg mL−1 Ir−Gd CPPs for 6 h (λex = 405 nm, λem = 560 ± 20 nm). (d) The magnified confocal optical image as shown in panel c1. (e) The profile of the optical intensity across the line shown in panel d: 1, the cytoplasm; 2, the nucleus.

CPPs was observed. Furthermore, the fluorescence intensity of DMA solution irradiated by a visible light remained stable. These control experiments confirmed that the decrease in the fluorescence intensity of DMA should be due to the generation of 1O2. The generation of 1O2 is ascribed to intersystem crossing (ISC) from the Ir complex singlet and the triplet excited states promoted by the strong spin−orbit coupling induced by the iridium atom.41 The cytotoxicity of the Ir−Gd CPPs was determined with HeLa cells and Chang liver cells using a standard MTT assay. After the cells were incubated with different concentrations of Ir−Gd CPPs, no significant cytotoxicity was detected (Figure 4a). Even with a maximum concentration of the Ir−Gd CPPs under our experimental condition (200 μg mL−1), above 82% cells remained alive for both HeLa cells and Chang liver cells. The low cytotoxicity of the Ir−Gd CPPs confirms their potential suitability for further biological applications. Cellular uptake was quantitatively determined by flow cytometry. As presented in Figure 4b, with the incubation of the Ir−Gd CPPs below 20 μg mL−1, weak fluorescence of HeLa cells was observed indicating the low uptaken amount of the Ir−Gd

based MR imaging contrast agents exhibit the large relaxivity. As presented in Figure 2b, the signal intensity resulted from the T1-weighted MR images of the Ir−Gd CPPs in aqueous solution displayed an obvious enhancement with the increase in Gd concentration. According to the quantitative analysis of T1weighted MR images, the longitudinal relaxivity (r1) value was calculated to be ∼29.5 mM−1 s−1 in a 3.0 T MR system (Figure 2c). This value is much higher than that of the clinical MR contrast of Gd-DTPA (r1 = 4.8 mM−1 s−1),40 indicating that the Ir−Gd CPPs exhibit a much brighter T1-positive contrast effect. To explore the potential application of the Ir−Gd CPPs for PDT, the generation of 1O2 was evaluated by measuring the change of the fluorescence intensity of 9,10-dimethylanthracene (DMA) upon irradiation with a visible light. As shown in Figure 3, the fluorescence intensity of DMA in an ethanol/water (4:1) solution of Ir−Gd CPPs reduced by ∼61% after irradiation with a visible light for 10 min (λ > 400 nm, 300 mW cm−2). To further confirm the generation of 1O2, inhibition experiments were performed. In the presence of NaN3, which is a wellknown 1O2 scavenger, no significant change in the fluorescence intensity of DMA in an ethanol/water (4:1) solution of Ir−Gd D

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Figure 5. (a) T1-weighted MR images of the Ir−Gd CPPs in HeLa cells after incubation with different concentrations for 6 h in a 3.0 T MR system. (b) Intensity analysis of T1-weighted signal in HeLa cells.

CPPs. As HeLa cells were incubated with the concentration from 50 to 100 μg mL−1, the luminescence intensity increased rapidly from 26.5% to 79.5%. With the incubation of 200 μg mL−1, the luminescence intensity of HeLa cells reached a maximum. Thus, the concentration of 200 μg mL−1 was selected for further studies. The uptake of the Ir−Gd CPPs by living cells was also investigated by confocal laser scanning microscopy. Strong luminescence was observed after incubated with 200 μg mL−1 of Ir−Gd CPPs in RPMI-1640 for 6 h (Figure 4c). The luminescence spectrum (Figure S3b, Supporting Information) recorded by confocal laser scanning microscopy was consistent with that observed in the solution of Ir−Gd CPPs (Figure 2a), suggesting that the intracellular luminescence can be attributed to the uptake of Ir−Gd CPPs. The overlay of the bright field image (Figure 4c1) and confocal luminescence image (Figure 4c2) after incubation demonstrated that the Ir−Gd CPPs stained the cytoplasm (Figure 4c3). The profile of the phosphorescence intensity42 across the line revealed an extremely high signal ratio of the average luminescence intensity between the cytoplasm (1) and nucleus (2), which further suggested selective staining for the cytoplasm (Figure 4e). Additionally, Z series imaging was performed to construct three-dimensional representations,43 further indicating that Ir−Gd CPPs should be localized in the cytoplasm (Figures S2 and S3a, Supporting Information). Trypan blue staining of the HeLa cells under the same conditions as the optical imaging supported the survival of the HeLa cells (Figure S4, Supporting Information). To evaluate the potential application of the Ir−Gd CPPs as a probe for MR imaging in vitro, T1-weighted MR images were collected incubated with the concentration from 10 to 50 μg mL−1 of the Ir−Gd CPPs for 6 h. As shown in Figure 5a, it is obvious that the HeLa cells showed a distinct MR signal enhancement with an increase in the incubation concentration of the Ir−Gd CPPs (Figure 5a). The MR signal intensity of HeLa cells was also analyzed quantitatively after incubation

Figure 6. Trypan blue staining (a) and cell viability (b) of HeLa cells (control), HeLa cells irradiated by a visible light for 10 min (visible light), HeLa cells incubated with Ir−Gd CPPs (Ir−Gd CPPs), and HeLa cells incubated with Ir−Gd CPPs irradiated with a visible light for 10 min (Ir−Gd CPPs + visible light). The incubating concentration of Ir−Gd CPPs was 200 μg mL−1.

with the Ir−Gd CPPs for 6 h (Figure 5b). The intensity of the T1 signal of HeLa cells incubated with Ir−Gd CPPs (10 and 20 μg mL−1, respectively) for 6 h was 1.7 and 2.3 times more than that of control HeLa cells, respectively. After incubation at a concentration of 50 μg mL−1 for 6 h, the signal intensity of the HeLa cells was 2.5 times more than that of control HeLa cells. Our results suggest that Ir−Gd CPPs have the excellent potential application for positive contrast agents for MR imaging. Because of the generation of 1O2 by Ir−Gd CPPs in solution, the PDT efficacy in HeLa cells as a model cancer cell line was investigated. The HeLa cells were incubated with Ir−Gd CPPs (200 μg mL−1) for 6 h, and the photodynamic effect was evaluated by trypan blue staining and a standard MTT (methyl thiazolyl tetrazolium) assay after the visible light irradiation (λ > 400 nm, 300 mW cm−2) for 10 min. As shown in Figure 6, most of cells were stained by trypan blue after irradiation. The viability of the HeLa cells was determined quantitatively to be just ∼16.6% by MTT assay. For the control experiments, several HeLa cells were stained blue and either irradiated in the absence of Ir−Gd CPPs or only incubated with Ir−Gd CPPs (no irradiation). The cell viabilities of the above control HeLa E

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cells were above 85%. Therefore, our Ir−Gd CPPs can be used as an effective visible light driven PDT agent.

4. CONCLUSIONS In conclusion, we have developed a coordination assembly method in the presence of PVP to prepare a novel, multifunctional theranostic agent based on luminescent Ir and magnetic Gd complex architectures (Ir−Gd CPPs). The Ir−Gd CPPs were readily uptaken by HeLa cells and exhibited low cytotoxicity. Because of the phosphorescent properties of the iridium complex and the magnetic properties of the metallic Gd(III) ions, the Ir−Gd CPPs could be simultaneously used as an optical probe and MR contrast agent. Furthermore, 1O2 is generated effectively upon irradiation with a visible light, which can be used for the photodynamic therapy of cancer cells. We believe that this simple strategy highlights the potential of coordination polymer nanoparticles as a platform for multimode imaging guided theranostics.

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ASSOCIATED CONTENT

S Supporting Information *

Z-scan images of HeLa cells incubated with 200 μg mL−1 of Ir− Gd CPPs for 6 h (λex = 405 nm), and HeLa cells stained by trypan blue before and after the optical imaging. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was partially supported by National Natural Science Foundation of China (Nos. 21271130 and 21371122), Program for Changjiang Scholars and Innovative Research Team in University (No. IRT1269), Shanghai Science and Technology Development Fund (Nos. 12ZR1421800 and 13520502800), Shanghai Pujiang Program (13PJ1406600), Shanghai Municipal Education Commission (No. 13ZZ110), Shanghai Normal University (DYL201305), and Internation Joint Laboratory on Resource Chemistry (IJLRC).

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REFERENCES

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The Journal of Physical Chemistry C

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dx.doi.org/10.1021/jp508837e | J. Phys. Chem. C XXXX, XXX, XXX−XXX