Artemisinin-loaded Mesoporous Nanoplatform for ... - ACS Publications

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Cite This: ACS Appl. Mater. Interfaces 2018, 10, 6155−6167

Artemisinin-Loaded Mesoporous Nanoplatform for pH-Responsive Radical Generation Synergistic Tumor Theranostics Lidong Liu,† Yuxin Liu,† Liyi Ma, Fang Mao, Anqi Jiang, Dongdong Liu, Lu Wang, Qi Jia, and Jing Zhou* Department of Chemistry, Capital Normal University, Beijing 100048, PR China S Supporting Information *

ABSTRACT: The development of novel and effective cancer treatments will greatly contribute to prolonging and improving patient lives. In this study, a multifunctional nanoplatform was designed and developed based on mesoporous NiO (mNiO) nanoparticles and terbium complexes as an artemisinin (ART) vehicle, a T2-weighted contrast agent, and a luminescence imaging probe. mNiO is a novel pH-responsive material that can degrade and release nickel ions (Ni2+) in an acidic tumor microenvironment. The endoperoxide bridge bond in the structure of ART tends to react with Ni2+ to produce radicals that can kill tumor cells. On the basis of its excellent near-infrared absorbance, mNiO can also be considered as a novel photothermal conversion agent for cancer photothermal therapy (PTT). Compared with free ART or PTT only, this novel agent showed remarkably enhanced antitumor activity in cultured cells and in tumor mice models, owing to the hypoxic tumor microenvironment impelling synergistic therapeutic action. These results provide a novel way of using a promising natural drug-based nanoplatform for synergistic therapy of tumors. KEYWORDS: mesoporous, artemisinin, photothermal therapy, synergistic therapeutic, hypoxic

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antitumor effects in vivo,30−35 which are accompanied by fewer side effects compared with conventional treatments.36−38 Therefore, the combination of these two treatment modalities could complement each other to realize a relatively better therapeutic effect on tumor with fewer side effects to normal cells.39−42 The pH value of the tumor microenvironment is generally lower than that of blood or normal tissues.43 Thus, there is an opportunity to develop effective pH-sensitive drug carriers.44−46 Hypoxia is another common feature of all solid tumors; as tumors grow, the interior of the tumor gets removed from the blood supply, leading to hypoxic conditions.47−52 The hypoxia microenvironment of the tumor will inevitably lead to some problems, mainly increasing hypoxic resistance to traditional tumor treatment including chemotherapy.53−56 Therefore, it is necessary to develop therapeutic agents that are less dependent upon oxygen concentration. This idea came into being when the pH-response behavior of mNiO, assisted by the free radical process of ART to overcome the hypoxic or make it independent of the hypoxia state of tumor, could ultimately solve a series of problems mentioned above and achieve a better therapeutic effect. In this work, a multifunctional nanoplatform was designed and developed based on ART-loaded mesoporous NiO (mNiO)

INTRODUCTION Cancer is a life-threatening disease, and great effort has been made to treat the various forms of this serious malady over the last several decades.1−3 However, among the various therapies,4−8 chemotherapy is still most used clinically. Although many varieties of antitumor drugs have been developed and applied as chemotherapy, most causes side effects in patients, including physical and mental pain, and many have low therapeutic efficacy.9−11 Unlike artificial drugs, natural drugs extracted from herbs exhibit less side effects. As a plant-derived sesquiterpene lactone, artemisinin (ART) has been considered as a traditional Chinese medicine for centuries.12−14 ART has been widely used to treat a variety of malignancies, and although it is famous for malaria treatment, there are reports where ART was used to inhibit malignant tumors as well.15,16 Unlike traditional antitumor drugs, the main mechanism of the antitumor activity of ART is that the endoperoxide bridge of this compound can be cleaved in a process mediated by the Fenton-like effects of ions (such as Fe2+, Mn2+, and Ni2+), generating free radicals that kill cancer cells.17 Thus, the antitumor activities of ART-based drugs have a close relationship with Fenton ions. As a radical-induced therapeutic drug, ART has certain shortcomings. It is difficult to achieve local treatment, and it relies on the speed cancer cell proliferation far more than traditional drugs as well. Photothermal therapy (PTT) is an emerging therapeutic modality that has attracted recent attention because of its effective and selective treatment properties.18−29 PTT has been reported to show excellent © 2018 American Chemical Society

Received: December 2, 2017 Accepted: January 30, 2018 Published: January 30, 2018 6155

DOI: 10.1021/acsami.7b18320 ACS Appl. Mater. Interfaces 2018, 10, 6155−6167

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ACS Applied Materials & Interfaces

Scheme 1. Schematic Illustration of the Synthesis of a mNiO−Tb−ART Nanoplatform for the Tumor MicroenvironmentResponsive Enhanced Synergistic Tumor Theranostics

In Vitro and in Vivo Luminescence Imaging and Magnetic Resonance Imaging (MRI). Tb-based complexes have been used as luminescence probes for many years.57,58 To equip mNiO with luminescence imaging properties, typical Tb− diethylene triamine pentacetate acid (Tb−DTPA) complex was synthesized and adsorbed into mNiO (mNiO−Tb). Fourier transform infrared spectroscopy (FTIR) indicated the vibrational band around 1634 and 1398 cm−1, attributing to carbonyl and alkyl groups of DTPA. The peaks in the mNiO−Tb spectrum showed a partial shift to the low wavenumber region, which could be attributed to the coordination between DTPA and Tb (Figure S4). The FTIR results confirmed that Tb−DTPA was successfully absorbed into the nanoparticles. Given that Tb− DTPA was absorbed into mNiO, the hydrodynamic diameters and zeta potential of the acquired nanoparticles were also measured (Figure S5). The zeta potential decreased from 3.61 mV of mNiO to −1.34 mV of mNiO−Tb, which also confirmed that mNiO−Tb was obtained. The hydrodynamic diameters of mNiO and mNiO−Tb were 277 and 310 nm, respectively. These results indicated that this method of generating mNiO−Tb was effective. The luminescence properties of mNiO−Tb were then tested. Upon 350 nm laser irradiation, both free Tb−DTPA and mNiO−Tb emitted luminescence centered at 485, 542, 584, and 621 nm, corresponding to the transition between 5D4 → 7F6, 5D4 → 7F6, 5D4 → 7F4, and 5D4 → 7F3, respectively (Figure S6). Compared with mNiO, mNiO−Tb exhibited characteristic absorption peaks of the Tb complex (Figure 1I). These results indicated that the Tb complex was successfully absorbed into mNiO and would provide favorable luminescence imaging potential. Bluish-green luminescence was observed by the naked eye under a UV lamp, which confirmed strong luminescence intensity in the 480−570 nm range.62−64 Owing to the strong green luminescence emission, mNiO−Tb appeared green, which was further converted to the Commission Internationale de l’Eclairage chromaticity coordinates (Figure S7). As an important parameter, the relaxivity of the T2-weighted MRI contrast agent was calculated for evaluating the capacity of MRI.59 With increase of the mNiO−Tb concentration, the transversal relaxation time (T2) of water protons was significantly and accordingly shortened from 1240.4 to 159.5 ms. The

nanoparticles. mNiO is a new pH-responsive material that is stable at physiological pH 7.4 but can degrade and release Ni2+ in acidic tumor microenvironments. The release of Ni2+ can cause the endoperoxide bridge of ART to break down and produce free radicals. Even under hypoxic conditions, this radical-induced therapy is independent of oxygen, which will benefit the treatment of hypoxic tumors. Meanwhile, mNiO is also a photothermal conversion agent based on its near-infrared (NIR) absorbance properties. Moreover, mNiO is a T2-weighted contrast agent and a luminescence imaging probe when loaded with terbium (Tb) complexes, allowing multifunctional imaging. In this study, we explored the synergistic effects of these radical and photothermal therapeutic properties on tumor cells (Scheme 1).

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RESULTS AND DISCUSSION Synthesis and Characterization. mNiO nanoparticles were obtained by calcining the precursor Ni(OH)2 nanoparticles. The related characterizations of the precursor are shown in the Supporting Information (Figures S1 and S2). The morphology and size of mNiO were characterized by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) analysis (Figure 1A,B), which showed that they are almost circular plates, with a size of approximately 150 nm. The crystalline structure of mNiO was deduced using high-resolution TEM (HRTEM), selective area electronic diffraction (SAED) (Figure 1C,D), and powder X-ray diffraction (XRD). The XRD pattern showed that mNiO has cubic NiO phase corresponding to the standard files 47-1049 (Figure 1E). X-ray photoelectron spectroscopy (XPS) of mNiO indicated characteristic peaks for nickel 2p, 853.7 eV (NiO) (Figure 1F). Energy-dispersive X-ray analysis (EDXA) revealed compositions of Ni and O, respectively (Figure S3). The Brunauer−Emmett−Teller (BET) surface area of mNiO was measured to be 98.4141 m2 g−1, and the pore volume was approximately 0.3035 cm3 g−1 (Figure 1G). The average pore size was calculated to be around 3.33 nm, which showed a rough surface with pores inside. These data confirmed that mNiO has been prepared. The UV−vis− NIR spectra of mNiO solution exhibited broad absorbance in the 400−900 nm region (Figure 1H). 6156


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Figure 1. Characterization of mNiO. (A) SEM image of mNiO (scale bar: 100 nm). (B) TEM image of a single nanoparticle (inset, scale bar: 50 nm). (C) HRTEM image of mNiO (scale bar: 5 nm). (D) SAED images of mNiO (scale bar: 5 nm−1). (E) XRD pattern of pure mNiO for the cubic phase and the standard data of NiO (JCPDS card no. 47-1049). (F) XPS of mNiO indicated characteristic peaks for nickel 2p, 853.7 eV (NiO). (G) N2 adsorption−desorption isotherms and the pore size distribution of mNiO (inset graph). (H) Normalized UV−vis−NIR absorption spectra of mNiO at different concentrations. Inset: standard curve of absorbance at 785 nm. (I) Luminescence spectra of Tb (Tb−DTPA), mNiO, and mNiO−Tb, excited by 370 nm at RT. (J) Relaxation rate (1/T2) vs different concentrations of mNiO−Tb; color-mapped phantom MR images of mNiO−Tb (inset).

transverse relaxivity (r2) and T2-weighted MR images were also measured as a function of mass concentration under 0.5 T magnetic fields. The r2 value for mNiO−Tb was 6.30 (mg mL−1)−1 s−1, which was calculated from Figure 1J. With increase of the mass concentration of the mNiO−Tb solution, the T2weighted MRI signal intensity increased, resulting in darker images (Figure 1J, inset). These results, especially the high r2 value, suggested that mNiO−Tb was a promising T2-weighted MRI contrast agent. Photothermal Properties. Furthermore, the photothermal properties of the mNiO−Tb solution (2 mg mL−1) were detected by exposing to NIR laser irradiation (785 nm, 2.0 W cm−2), and the temperature changes were detected by an infrared thermal imaging camera. The photothermal images indicated

that the temperature of the solution increased from 21.2 to 58.9 °C within 15 min (Figure 2A), which could be applied to cause tumor cells with irreversible damage. Besides, the color of the mNiO−Tb solution became darker as the concentration increased (Figure S8). The photothermal conversion effects of different concentrations of the mNiO−Tb solution (0−1.0 mg mL−1) were detected upon the same laser irradiation. It is notable that the temperature increased by 10.8−28.5 °C with the increase of the concentration but no obvious increase for water (Figure 2B). Herein, these results indicated that the mNiO−Tb nanomaterials can convert the 785 nm laser energy into the thermal energy, followed by the absorbance, high heating rate, and the photothermal conversion efficiency (η) value (48.88%) (Figure 2C,D and eq S1). Given this ability to convert NIR to 6157


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Figure 2. Assessment of photothermal effect and photostability of mNiO−Tb. (A) Digital image of materials and the photothermal images for the mNiO−Tb solution (2 mg mL−1) irradiated by a 785 nm NIR laser (2.0 W cm−2, 0−15 min). (B) Temperature changes of mNiO−Tb (0−1.0 mg mL−1) upon 785 nm laser irradiation (2.0 W cm−2). (C) Temperature change of the mNiO−Tb solution. (D) Cooling time of mNiO−Tb vs −ln θ obtained from the cooling period of (C). (E) Temperature change of the mNiO−Tb solution (2 mg mL−1) for laser on and off switches. (F) Photostability of the mNiO−Tb solution (2 mg mL−1) and digital images before and after 785 nm irradiation. (G) Photostability of the mNiO−Tb solution after being allowed to stand for 1, 7, 15, 30, and 60 days.

ART Delivery and Radical Release. ART, a traditional Chinese natural drug, showed potent antitumor activities after metal ion-mediated cleavage of its endoperoxide bridge.17 ART can be absorbed into mNiO−Tb because of the mesoporous structure of the nanoparticle. mNiO−Tb−ART was synthesized by simply stirring, and FTIR of mNiO−Tb−ART revealed peaks at 1737 and 1116 cm−1. The corresponding peak (1737 cm−1) could be attributed to the stretching vibrations of the γCO bond and inner ester (Figure S4). Also, the stretching vibrations of the γC−O bond of ART were indicated by the peak at 1116 cm−1. These results confirmed that ART was loaded into the mNiO−Tb nanoparticles.

heat energy, mNiO−Tb has the potential to be a photothermal agent for clinical applications. The repeatability of the photothermal conversion of mNiO− Tb was then explored. The photothermal cycles of mNiO−Tb (2 mg mL−1) were measured by laser on/off switch within 30 min (Figure 2E). Moreover, the absorbance curves of mNiO−Tb remained the same before/after laser irradiation (Figure 2F) and stranded for 60 days (Figure 2G), which demonstrated excellent reproducibility and photostability of mNiO−Tb. Thus, mNiO− Tb was investigated to be a promising photothermal agent according to the data above. 6158


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Figure 3. ART delivery and radical release experiments. (A) Loading rate of ART in mNiO−Tb−ART. (B) ART released from mNiO−Tb−ART in pH 7.4 and 6.4. (C) Investigation on the degradation process of mNiO under different pH conditions and time. Relative luminescence (D) and MR (E) signal change of mNiO−Tb−ART with time under pH 6.4. Relative intensity (F) and images (G) of intracellular fluorescence from the radical production by DCFH-DA were shown in these groups: (a) blank, (b) mNiO, (c) mNiO (pH 6.4), (d) Ni2+, (e) mNiO−Tb−ART, (f) ART, (g) mNiO− Tb−ART (pH 6.4), and (h) Rosup.

loading rate changed from 0 to 59.7% (eq S2 and Figure S9). Compared with some other silica, carbon, and metal−organic framework-based nanocarriers57−61 with pore structures, the loading capacity of mNiO is proper (59.7%), which is probably

To obtain the ART-loading capacity, we measured the absorbance of ART in the supernatant, and the loading capacity (ART/NiO−Tb [w/w] = 1:1) was quantified as 43.3% (Figure 3A). Moreover, by changing the ART quantity (0−11 mg), the 6159


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Figure 4. Imaging and synergistic effect of mNiO−Tb. (A) Luminescence images of HeLa cells after 4 h incubation using a luminescence microscope. (B) In vivo T2-weighted MRI of preinjection and 2 h postinjection with mNiO−Tb (10 mg kg−1 injection). (D) Relative MR signal in tumor, liver, kidney, and spleen with mNiO−Tb (10 mg kg−1) postinjection (0, 30, 60, 90, and 120 min). Photothermal images (C) and temperature difference diagram (E) in vivo after intravenous injection of mNiO−Tb−ART (10 mg kg−1), exposed to the irradiation from a 785 nm laser (2.0 W cm−2, 4 min). (F) Synergistic tumor therapy in vitro (the ART solution (80 μg mL−1) was used in the ART-only group and the laser power was 2.0 W cm−2). (G) In vivo tumor volume changes on different groups (blank, ART, laser, mNiO−Tb−ART, mNiO−Tb + laser, and mNiO−Tb−ART + laser) after different treatments. Results are expressed as mean ± SD (n = 3). Error bars are standard error of the mean. *p < 0.05, **p < 0.01.

partly because of the mesoporous properties with high specific surface areas and the approximate pore volume. As shown in Figure 3B, ART release from mNiO−Tb−ART was time- and pH-dependent. It was clear that the release rate at pH 6.4 was higher than that at pH 7.4, probably because of the partial degradation of the oxide under acidic conditions based on a neutralization reaction. To test our hypothesis, a degradation experiment was performed. To this end, nickel oxide degradation was detected in buffer solutions (pH 4.4, 5.4, 6.4, and 7.4) by UV−vis−NIR absorption (Figure 3C). The maximum degrada-

tion was at pH 4.4, whereas neutral conditions showed little degradation. In contrast, there was a certain degree of decomposition at pH 6.4. There was no obvious degradation under neutral conditions (pH 7.4), and the pH value of the tumor is generally 6.4,56 so it can be speculated that our materials can degrade well in the tumor area. In addition, the release process of Ni2+ was measured by inductively coupled plasma mass spectroscopy (ICP-MS) directly in buffer solutions with different pH values (Figure S10), which is also investigated from the UV−vis−NIR measurements. In conclusion, the degree of 6160


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source (excitation at 370 nm). Intense cell luminescence was observed after incubation with mNiO−Tb−ART for 24 h at 37 °C (Figure 4A). The cell luminescence images demonstrated that mNiO−Tb−ART can be uptaken by cells under acidic conditions, and the results indicated that mNiO−Tb−ART could play a role in the field of cell imaging. Luminescence imaging possesses unique properties, such as real-time and accurate tracking when applied at the cellular level.35 However, its penetration ability is not high enough, as optical signals are easily absorbed by surrounding tissues, whereas MRI is well-known for its properties of high resolution and three-dimensional details,70−75 and the combination of these two technologies can make the imaging information more comprehensive and accurate.76 To determine its utility for in vivo tumor MRI, the mNiO−Tb solution (10 mg kg−1) was intravenously injected into the HeLa tumor mice models. The relative MRI signals in the organs (Figure 4B) were then measured, in which the mNiO−Tb uptake and retention were obviously demonstrated in tumor and liver sites within 2 h (n = 3). As shown in Figure 4D, T2-weighted MR signals were increased by 17.24 and 27.34% in liver and tumor sites, respectively. This suggested that mNiO−Tb may passively target tumors because of the nanomaterial’s enhanced permeability and retention effect, confirming that mNiO−Tb acts as a T2-weighted MR contrast agent for in vivo MRI. In conclusion, this material can be used as a diagnostic probe in dual-mode imaging during treatment. Synergistic Therapy. Prior to in vivo studies, we conducted preliminary in vitro experiments to test the application of the nanomaterial as a treatment modality. HeLa cancer cells were treated in six groups (blank, laser, ART, mNiO−ART, mNiO + laser, and mNiO−Tb−ART + laser). As shown in Figure 4F, the mNiO−Tb−ART + laser group exerted the highest therapeutic effect on HeLa cells when evaluated with the 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The lower cell viability (33.85%) of all HeLa cells survived in this group is compared with the relatively high survival rate in other groups. Additionally, the mNiO−Tb + laser group also showed low cell viability, demonstrating the photothermal property of mNiO. The therapeutic effect of the mNiO−Tb− ART group indicated that mNiO degradation promoted the production of free radicals by ART in cancer cells, which increased intracellular lipid hydroperoxides and induced apoptosis. The relative cell viability experiments (Figure S13) of the last three groups (mNiO−Tb−ART, mNiO + laser, and mNiO−Tb−ART + laser) with a set of different concentrations of ART and nanocomposites and with disparate pH values (7.4 and 6.4) for 24 h also indicated the better therapy effect under acidic conditions. As shown in Figure S14, calcein-acetoxymethyl (AM)/propidium iodide (PI) cell staining in four groups (blank, mNiO, mNiO−ART, and mNiO−ART + NIR) also demonstrated the significant synergistic effect in vitro. These results demonstrated synergistic effects in the mNiO−Tb−ART + laser group from combined photothermal and radical-induced therapy. These synergistic antitumor effects were further investigated in HeLa tumor-bearing nude mice. Mice were separated into six experimental groups (once the tumor volume reached 700 mm3): the laser (785 nm, 2.0 W cm−2, 4 min), ART only (80 μg mL−1), mNiO−Tb−ART, mNiO−Tb + laser, mNiO−Tb−ART + laser, and phosphate-buffered solution (PBS) blank. The nanomaterials were mainly distributed within tumors after 24 h with the 10 mg kg−1 dosage for each injection, and the

nickel oxide degradation increased as the buffer solution acidity increased, the degradation rate was the highest under acidic conditions compared with the neutral conditions (pH 7.4), and the photothermal effect indeed could promote the process of drug release to a certain extent (Figure S11). To test the luminescence properties of the nanomaterial during the degradation process, the luminescence changes of mNiO−Tb−ART under acidic conditions (pH 6.4) were monitored. Intriguingly, we found that the luminescence intensity increased over time and inferred that this was due to the degeneration of Förster resonance energy transfer (FRET) (Figure 3D). The specific process that allows this is as follows: as the Tb complex is wrapped into the mNiO surface, the luminescence energy can be transferred from the Tb complex to mNiO when excited by UV irradiation, which resulted in highefficient luminescence quenching. However, when NiO was decomposed under acidic conditions, the Tb complex was released from mNiO, which decreased the FRET efficiency and hence enhanced luminescence. Additionally, changes in the MRI signal were also monitored under same acidic conditions. As shown in Figure 3E, the signal decreased slightly over time, which can be illustrated by the enhancement of spin-canting effect. When mNiO−Tb−ART was degraded to Ni2+, the T2-weighted imaging effect will be partially weakened, gradually enhancing the brightness of the inset image in the corresponding graph (Figure S12). In conclusion, the above phenomena suggest that mNiO− Tb−ART is degraded under acidic conditions, which result in the change of imaging effects. It has been reported that Fenton metal ions can interact with ART and increase its antitumor efficacy by producing free radicals.17,65−67 We hypothesized that Ni2+ could possess the similar influence as these Fenton ions and enhance the antitumor efficacy of ART in vitro by the pH-responsive Ni2+ release of the drug delivery system. To test our hypothesis, following radical detection experiments were performed. The free radicals were evaluated by detecting the luminescence signal from 2,7dichlorodi-hydrofluorescein diacetate (DCFH-DA), which reacts with free radicals to exhibit stronger luminescence (Figure 3F,G). Among the blank group (Figure 3G(a)) and control groups (Figure 3G(b−f)), the mNiO−Tb−ART (pH 6.4) group (Figure 3G(g)) exhibited the highest luminescence signals, which were similar to that of the positive control group (Rosup group, Figure 3G(h)). This phenomenon can be attributed to the free radicals generated by the released Ni2+ and ART. It is notable that the mNiO (pH 6.4) group (Figure 3G(c)) showed stronger fluorescence than the blank group (Figure 3G(a)) probably because of the partial generation of hydroxyl radicals by endogenous H2O2 reacted with Ni2+ according to some previous work.68,69 Meanwhile, the ART group (Figure 3G(f)) also showed strong luminescence, which may contribute to the endoperoxide bridge, further illustrating that the ART was the essential part for radical generation when compared with the mNiO (pH = 6.4) group (Figure 3G(c)). Brighter luminescence of the mNiO−Tb−ART (pH 6.4) group (Figure 3G(g)) than that of the mNiO (pH 7.4) group (Figure 3G(b)) and the mNiO (pH 6.4) group (Figure 3G(c)) was clearly displayed, directly showing the Ni2+-induced ART radical in the nanosystem, which also indicated that the radicals playing a role in the treatment come from ART in the nanosystem. Cell Luminescence Imaging and in Vivo MRI. The potential application of mNiO−Tb−ART for luminescence imaging was first investigated in cells, evaluated by a luminescence microscope using a mercury lamp as the excitation 6161


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Figure 5. Evaluation of biosafety in vitro and in vivo. (A) In vitro MTT assays of HeLa cells, cell viability vs incubated mNiO−Tb concentration for 24 and 48 h, normalized by the cell samples without mNiO−Tb incubation (blank). Serum study results obtained from the mice injected with mNiO−Tb (10 mg kg−1) in different times (1, 7, and 30 days) postinjection and mice receiving no injection (blank). (B) ALT (alanine aminotransferase) and AST (aspartate aminotransferase); (C) TBIL (total bilirubin); (D) TP (total protein); (E) ALB (albumin); and (F) CREA (creatinine). (G) H&E-stained heart, kidney, liver, lung, and spleen sections from mice PBS injection (blank) and 1, 7, and 30 days postinjection with mNiO−Tb (20 mg kg−1).

temperature of the tumor reached up to 47.2 °C upon NIR irradiation (Figure 4C,E). These results suggest that this technique has photothermal therapeutic potential. Although tumors in the laser and blank groups showed similar growth rates, the relative tumor volume (V/V0) reached 2.1 within 11 days (Figure 4G, inset). However, most tumors in the mNiO−Tb− ART + laser group nearly disappeared by day 14, with a V/V0 of approximately 0.3, confirming the strong antitumor effects (Figure 4G). Although tumors in the ART group, mNiO−Tb− ART group, and mNiO−Tb + laser group display a slight volume decrease, the variation of the tumor volume in the mNiO−Tb− ART + laser group showed apparently tumor growth suppression compared with the others. Thus, this obvious effect was ascribed to the combined radical-induced and photothermal effects, which together improved therapeutic efficacy. The photos of mice/ tumor after different treatments were obtained by a digital

camera (Figure S15), and it is also worth noting that the body weight of the mice barely changed during the treatment process (Figure S16), suggesting the stable condition of mice during the treatment and verifying the PTT therapeutic efficacy. These results suggested that synergetic therapy was achieved. Cytotoxicity. To further ensure the safety before application, the cytotoxicity of nanomaterials was studied in vitro. The MTT assay, as a vital data, indicated the presence of mNiO−Tb in HeLa cells with low toxicity. Most of all HeLa cells survived (85%), even at a high mNiO−Tb concentration (10 mg mL−1) after 48 h incubation (Figure 5A). Collectively, our results showed that mNiO−Tb itself was not noticeably toxic to cells. As Ni2+ showed no apparent release under neutral conditions, such as in normal tissues, ion release could only be observed after the degradation in acidic microenvironments, such as tumors. 6162


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ACS Applied Materials & Interfaces The toxicity of mNiO−Tb (20 mg kg−1) and its potential utility were also evaluated by in vivo experiments. No death or obvious abnormal behaviors (retarded movement or lethargy) were observed, even after receiving high-dose mNiO−Tb. The serum biochemical assays were investigated in the mNiO−Tbinjected mice on days 1, 7, and 30, as well as complete blood tests were taken. Liver and kidney function indices were all normal (Figure 5B−F), suggesting that no biodysfunction occurred. Furthermore, hematoxylin−eosin (H&E)-stained images demonstrated that the tissues were normal as same as the PBS injection (blank) group (Figure 5G). These results corresponded to the in vitro results and demonstrated low toxicity of mNiO− Tb. These findings further indicated that mNiO−Tb could be a tool for antitumor therapy with reduced toxicity and good biocompatibility.

emission gun operating at 20 kV. Samples were dispersed in cyclohexane, and water was dropped on the surface of a silicon pellet. The XRD pattern was obtained on a Rigaku DMAX 2500 power diffractometer with ultra 18 kW Cu radiation. XPS was performed on Thermo ESCALAB 250Xi. The specific surface areas were measured by a nitrogen adsorption−desorption instrument (3H-2000PS1, BeiShiDe company) by the BET method, and the pore volume and pore size were calculated from the adsorption branch of the isotherm based on the Barrett−Joyner−Halenda model. UV−vis−NIR spectroscopy light absorption analysis was performed using a UV-3600 UV−vis−NIR spectrophotometer from Shimadzu Company. FTIR spectra were recorded on a Bruker TENSOR 27 FT-IR spectrometer. Dynamic light scattering (DLS) and zeta potential experiments were carried out on an ALV-5000 spectrometer. The concentration of the nickel ion was measured by ICP-MS (Agilent 7500ce ICP-MS). ART Delivery Experiment and Releasing Experiment. To obtain mNiO−Tb−ART, 5 mg of NiO−Tb nanoparticles was stirred in ART ethanol solution (1 mg mL−1, 5 mL) for 24 h at RT. The resulting nanoparticles were then collected by centrifugation and washed with distilled water several times to remove free ART. For acquiring the ARTloading rate, the supernatants in a whole process were collected together, and the drug-loading content was measured by the UV−vis− NIR spectrophotometer. The mNiO−Tb−ART nanosuspension was added into about 10-fold ethanol and sonicated for minutes to ensure that the ART loaded was completely dissolved, and then the nanosuspension was centrifuged at 12 000 rpm for 5 min to separate ART and mNiO−Tb to test the amount of ART attached on mNiO−Tb. Subsequently, the obtained solution was hydrolyzed by a fivefold sodium hydroxide solution (0.2%) for half an hour in a water bath (50 °C). The efficiency of ART loading and the quantity of mNiO were further measured at 291 and 785 nm by a UV test, respectively. All washing solutions were collected, and the loading rate was approximately 45.46% (w/w) when the mass ratio is 1:1 (ART/mNiO) based on the UV−vis−NIR absorption technique. This result confirmed that the incorporation of ART into mNiO was successful. Then, we transferred the supernatant containing ART into sodium hydroxide aqueous solution in a water bath (50 °C, 30 min). After the hydrolytic process of ART, a UV-absorbing compound appeared and the absorption peak was detected to be 291 nm.

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CONCLUSIONS In conclusion, ART and Tb-complex-loaded novel mNiO were successfully developed as a multifunctional nanoplatform for cancer theranostics. With outstanding performance in both T2weighted MRI (r2 = 6.30 (mg mL−1)−1 s−1) and luminescence imaging, this nanoplatform can serve as an efficient dual modality probe for monitoring ART delivery and PTT. It is noteworthy that the obtained mNiO can degrade in an acidic tumor microenvironment and release free Ni2+, which benefits the controlled release of ART. More importantly, the released Ni2+ played an essential role in the generation of free radicals by clearing the endoperoxide bridge in the ART molecule, killing tumor cells more efficiently with the assistance of PTT. Both the in vitro and in vivo experiments strongly confirmed this valuable finding. This work further highlighted the potential application of ART in cancer therapy and encouraged the development of multifunctional pH-responsive drug delivery nanovehicles.

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EXPERIMENTAL SECTION

Materials. ART, nickel nitrate hexahydrate (Ni(NO3)2·6H2O), and oleylamine (OM) were purchased from Shanghai Energy Chemical Co., Ltd. Sodium hydroxide (NaOH), ethanol, and cyclohexane were purchased from Sinopharm Chemical Reagent Co., Ltd. DTPA and terbium nitrate hexahydrate (Tb(NO3)3·6H2O) were purchased from Shanghai Macklin Biochemical Co., Ltd. Synthesis of mNiO. The mNiO nanoparticles were obtained by calcining Ni(OH)2 nanoplates, which were synthesized by a hydrothermal reaction according to the reported hydrothermal method.77 In a typical experiment, 1 mL of aqueous solution containing 0.5 g Ni(NO3)2·6H2O was added into 9 mL of OM with gentle magnetic stirring for 10 min at room temperature (RT). The reaction was then treated at 160 °C for 18 h after transferring into a Teflon-lined stainless steel autoclave and was allowed to cool to RT naturally. The resulting precipitate was collected by centrifugation at high speed (12 000 rpm) for 2 min and washed with ethanol and cyclohexane several times. The Ni(OH)2 nanoplate precursors were finally dried in vacuum at 70 °C and then carefully calcined at 400 °C in a quartz tube furnace for 5 h. Finally, mNiO was obtained. Preparation of mNiO−Tb. To load mNiO with the Tb complex (mNiO−Tb), 100 mg of Tb(NO3)3·6H2O and 100 mg of DTPA were added into 5 mL ethanol (50%) in a flask; afterward, the pH value of the reaction system was adjusted to 7.4 by carefully adding 1 M NaOH aqueous solution and stirred at RT for 12 h. The mixture was then stored at 4 °C for the next step use. The acquired solution was added dropwise into a mortar containing 50 mg mNiO. In this process, continuous grinding is necessary until the obtained materials become dry powder. Characterization. TEM and HRTEM images were taken on a Tecnai G2F30 transmission electron microscope with a field emission gun operating at 300 kV. SEM images and EDXA spectra were obtained on a Hitachi SU8010 scanning electron microscope, with a field

Loading content = (weight of ART in mNiO−Tb−ART) /(weight of mNiO−Tb + ART) The releasing assay was performed at 37.0 °C. The as-prepared material was then dispersed in 5 mL aqueous buffer solutions (pH 7.4 and 6.4 citric Na2HPO4−C6H8O7 buffer) at RT. The 500 μL of suspension was imbibed at predetermined time. Then diluting the solution to 3 mL and the delivery of ART from the nanocomposites to the buffer solution was monitored via the absorbance band of ART at 291 nm. In the same way, we further tested the NIR-sensitive drug-release behavior of mNiO−Tb−ART in four groups (pH 7.4, pH 7.4 + NIR, pH 6.4, and pH 6.4 + NIR) at RT. Relaxation Rate in Vitro and in Vivo. The T2-weighted MR images in vitro and in vivo were performed using a 3 T Siemens MAGNETOM Trio running on Siemens’ Syngo software version B15. For the in vitro experiment, we used several 2.0 mL centrifuge tubes containing different concentrations of mNiO−Tb solution (5, 10, 20, 40, and 80 μg mL−1) for testing. Mice models bearing HeLa tumor were intravenously injected with mNiO−Tb−ART (10 mg kg−1). Luminescence Properties. The photoluminescence spectrum was recorded using a spectrometer (F-7000, Hitachi) with the Xe lamp as the excitation source. In a typical experiment, the quartz cuvette containing 3 mL of mNiO−Tb suspension liquid was set at the sample holder, with the excitation wavelength 370 nm, and the slice 5 nm, in which the spectrum was collected in the range of 400−700 nm. Cell Culture Experiments. HeLa cells were provided by the Institute of Basic Medical Sciences Chinese Academy of Medical Sciences. During the experimental process, 1 × 105 cells well−1 were seeded in glass coverslips for 24 h attachment. For use in the 6163


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Statistical Analysis. Data are presented as mean ± SD, and the statistical significance was performed using analysis of variance (p < 0.05).

experiments, a certain amount of HeLa cells were seeded in a 10 mm plastic culture dish. HeLa cells were cultured in Dulbecco’s modified Eagle’s high-glucose medium containing 10% fetal bovine serum at 37 °C in 5% CO2 atmosphere. In Vitro Luminescence Imaging. HeLa cells were incubated with mNiO−Tb solution (0.5 mg mL−1) for 4 h, and the luminescence imaging was obtained by optical microscopy, in which the bright photo was taken with a halogen lamp and the luminescence imaging was recorded with the mercury lamp as the excitation source. The images were captured using a luminescence microscope with an excitation laser (370 nm), showing green luminescence in the 520−550 nm region. Photothermal Imaging in Vitro. To evaluate the photothermal property, the acquired mNiO solution (2 mg mL−1, 2 mL) in bottles was exposed to a 785 nm laser (2.0 W cm−2) irradiation for 900 s. Meanwhile, an IR thermographic camera (FLIR E40) was used to record the photothermal data during the experiment. Degradation Studies and Radical Detection. mNiO−Tb−ART (0.125 mg mL−1) was dispersed in 10 mL buffer solution with different pH values (4.4, 5.4, 6.4, and 7.4), and the UV−vis−NIR spectra were then taken at different time points. The degradation process of mNiO− Tb−ART was reflected by the UV−vis−NIR spectra. Besides, the pHsensitive behavior of the released Ni2+ was measured directly by ICP-MS within 40 min in the same way. The DCFH-DA method was carried out to detect the intracellular radical level. To investigate the pH-sensitive behavior of the radical, cells were incubated with mNiO, Ni2+, mNiO (pH 6.4), mNiO−Tb−ART, ART, and mNiO−Tb−ART (pH 6.4) as the experiment group, the blank group, and Rosup group were set as control groups. We used the luminescence microscope with an excitation laser (488 nm) during this process. PTT. A similar set of HeLa cell samples were exposed to the 785 nm laser (2.0 W cm−2) for 4 min. For the cell uptake studies, the cells were grown on a 96-well cell culture plate, treated with different nanoparticles in six groups (blank, laser, ART, mNiO−Tb−ART, mNiO + laser, and mNiO−Tb−ART + laser). The ART (80 μg mL−1) solution was prepared and used for the ART-only group. Also, the cell viability of samples was measured after 4 and 24 h by following the method described in the MTT assay. Furthermore, the cell viability was also measured in mNiO−Tb− ART, mNiO + laser, and mNiO−Tb−ART + laser with a set of concentrations (0, 0.2, 0.4, 0.6, 0.8, and 1.0 mg mL−1) of the nanocomposite under the pH values 7.4 and 6.4 for 24 h. Four groups of HeLa cells (PBS (blank), mNiO, mNiO−ART, and mNiO−ART + NIR) were cultured in a medium to evaluate the synergistic therapy effect. The HeLa cells were then stained with calceinAM (excited at 490 nm) and PI (excited at 535 nm). We finally used a microscope to observe the cell-staining images. An in vivo experiment with animals obeyed the protocol as approved by IACUC. HeLa tumor mice models were divided into six groups for treatments when the tumor volume reached to 700 mm3 (PBS blank, ART only, laser only, mNiO−Tb−ART, mNiO−Tb + laser, and mNiO−Tb−ART + laser groups). The mice were gas-anesthetized and injected with mNiO−Tb−ART (10 mg kg−1) through caudal vein. After 1 h, the tumor section was exposed to the irradiation of 785 nm laser (2.0 W cm−2) for 4 min. The treatment was given every 2 or 3 days, and the tumor volume (length/2 × width2) was recorded during the experiment. MTT Assay. HeLa cells were seeded into a 96-well cell culture plate (90 μL well−1, 105 mL−1) and incubated for 12 h. After that, PBS solution containing different concentrations of mNiO−Tb (0, 2, 4, 6, 8, 10 mg mL−1, and 10 μL well−1) was added into left and right half part of the 96-well plate for 24 and 48 h, and the 10 μL MTT solution (5 mg mL−1) was then added to each well and incubated for another 4 h. The 96-well plate was then made to stand for 30 min after the addition of dimethylsulfoxide (100 μL well−1). Then the absorption value of each well was measured at 690 nm, and we calculated the viability of cell growth by the below formula.

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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.7b18320. Details on calculation of the photothermal conversion efficiency, hematotoxicity, and histopathological evaluation; related characterizations, EDXA spectrum and XRD pattern of Ni(OH)2; EDXA spectra of mNiO (A) and mNiO−Tb; FTIR spectra of ART, DTPA, mNiO−Tb, and mNiO−Tb−ART; DLS and zeta potential of mNiO and mNiO-Tb; excitation and emission spectra of the Tb− DTPA complex; chromaticity coordinates of multicolor emissions from Tb (Tb−DTPA) and mNiO−Tb shown in luminescence spectra; digital images of different concentrations of mNiO−Tb solution; ICP−MS data; ART released from mNiO−Tb−ART after various treatments; MR images and relative MR signals; therapy effect in vitro; luminescence images of HeLa cells; and body weight of different groups of HeLa tumor-bearing mice (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jing Zhou: 0000-0002-5348-1966 Author Contributions †

L.L. and Y.L. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Zhigao Lu from the Institute of Chemistry, Chinese Academy of Sciences (ICCAS), for his help in the in vivo experiments; Luoyuan Li from Renmin University of China for her help in FTIR measurements; Jiahuan Ren and Peng Gao from the Department of Chemistry, Capital Normal University, for their help in laser light path adjustment and N2 adsorption− desorption measurements, respectively. The authors thank the funding of the National Natural Science Foundation of China (21301121), Youth Innovative Research Team of Capital Normal University, and Beijing Talent Foundation Outstanding Young Individual Project (2015000026833ZK02), Project of Construction of Scientific Research Base by the Beijing Municipal Education Commission, Yanjing Young Scholar Development Program of Capital Normal University, Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan (IDHT20180517), Project of Construction of Scientific Research Base by the Beijing Municipal Education Commission, and Opening Project of Shanghai Key Laboratory of Magnetic Resonance.

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⎛ mean Abs value of treatment group ⎞ Cell viability (%) = ⎜ ⎟ × 100% ⎝ mean Abs value of control group ⎠ 6164


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