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Magnetic Resonance Imaging-Guided Multi-Drug Chemotherapy and Photothermal Synergistic Therapy with pH and NIR-Stimulation Release Ji-Chun Yang,† Yang Chen,‡ Yu-Hao Li,‡ and Xue-Bo Yin*,†,§ †

State Key Laboratory of Medicinal Chemical Biology and Tianjin Key Laboratory of Biosensing and Molecular Recognition, College of Chemistry, Nankai University, Tianjin 300071, China ‡ Tianjin Key Laboratory of Tumor Microenviroment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin 300071, China § Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China S Supporting Information *

ABSTRACT: The combination of multidrug chemotherapy and photothermal therapy (PTT) enhances cancer therapeutic efficacy. Herein, we develop a simple and smart pH/NIR dual-stimulus-responsive degradable mesoporous CoFe2O4@PDA@ZIF-8 sandwich nanocomposite. The mesoporous CoFe2O4 core acts as T2-weighted magnetic resonance (MR) imaging probe, PTT agent, and loading platform of hydrophilic doxorubicin (DOX). A polydopamine (PDA) layer is used to avoid the premature leakage of DOX before arriving at tumor site, enhance PTT efficiency, and facilitate the integration of ZIF-8 (a kind of metal−organic framework). The ZIF-8 shell serves to encapsulate hydrophobic camptothecin (CPT) and as the switch for the pH and NIR stimulation-responsive release of the two drugs. Therefore, T2-weighted MR imaging-guided multidrug chemotherapy and PTT synergistic treatment is achieved. Two kinds of anticancer drugs, hydrophilic DOX and hydrophobic CPT, are successfully loaded in CoFe2O4 and ZIF-8, respectively, so no mutual interference between the two drugs exists. A unique two-stage stepwise release process is exhibited for CPT and DOX with an interval of 12 h to improve the anticancer efficacy under the acidic microenvironment of tumor tissue. NIR irradiation achieves the burst drug-release and PTT after laser stimulation, simultaneously. With this smart design, high drug concentration is achieved at the tumor site by quick release, especially for the therapeutic drugs that show nonlinear pharmacokinetics, and PTT is integrated efficiently. Furthermore, negligible biotoxicity and a remarkable synergic antitumor effect of the hybrid nanocomposites are validated by HepG2 cells and tumor-bearing mice as models. Our multidrug delivery-releasing composite improves tumor therapeutic efficiency significantly compared with a single-drug chemotherapy system. The simple multifunctional composite system can be applied as an effective platform for personal nanomedicine with diagnosis, smart drug delivery, and cancer treatment through its remarkable photothermal property and controllable multidrug release. KEYWORDS: sandwich hybrid nanocomposite, CoFe2O4@PDA@ZIF-8, multidrug chemotherapy, photothermal therapy, T2-weighted magnetic resonance imaging DOX and CPT.5−8 Thus, the development of a multidrug coloading system and programmable release is expected. Some multidrug codelivery systems have been developed, but most of them only load single hydrophilic or hydrophobic mixture drugs,9 and the design of such systems involves a complex preparation procedure owing to their complicated structures. Moreover, the multidrug delivery systems exhibited a relatively low loading efficiency because the loading of one drug inevitably reduced the amount of another drug.10 The

1. INTRODUCTION Chemotherapy is commonly used for cancer therapy, but patients may suffer from drug resistance and side effects.1 Increasing the drug dosage enhances the therapeutic effect, while drug resistance of cancer cells is further intensified with serious biotoxicity and side effects.2 Although there are so many problems, chemotherapy is still imperative for cancer treatment. A multidrug dosing strategy improves the treatment efficiency through its synergistic effect and decreases drug resistance for cancer therapy.3,4 For example, the combined utilization of doxorubicin (DOX) and camptothecin (CPT) enhanced the lethality to resistant cancer cells and inhibited tumor growth significantly, especially with a dosing interval of 12 h between © XXXX American Chemical Society

Received: May 1, 2017 Accepted: June 15, 2017 Published: June 15, 2017 A

DOI: 10.1021/acsami.7b06105 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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Scheme 1. (A) Synthesis of Co/DPZ/C Nanocarrier and (B) Theranostic Strategy of Co/DPZ/C for MR Imaging-Guided Multi-Drug Chemotherapy and Photothermal Synergistic Therapy with pH and NIR-Stimulation Release

cells,28,29 can improve the therapeutic efficacy by a synergistic effect with multidrug chemotherapy. Herein, we design and prepare a simple, controllable, and degradable CoFe2O4@PDA@ZIF-8 nanocarrier (denoted as CoPZ) used for T2-magnetic resonance (MR) imaging-guided multidrug chemotherapy and PTT synergistic treatment as illustrated in Scheme 1. Mesoporous CoFe2O4 core is used to load hydrophilic DOX and acted as a T2-MR imaging probe. The PDA layer avoids the premature leakage of DOX before arriving at tumor site, enhances PTT efficiency, and facilitates the heterogeneous growth of the ZIF-8 shell. Hydrophobic CPT is embedded in the ZIF-8 shell, which is unstable and acts as a pH and NIR dual-response switch. Therefore, a DOX-CPT dual-drug nanocarrier is designed. The two drugs are embedded in different areas independently, so their sequential release becomes possible. Totally different release patterns under pH or NIR stimulation are observed. The acidic microenvironment of the tumor (pH 5.0) achieves a sequential release of CPT and DOX with an interval of approximately 12 h; the interval dosing behavior of CPT and DOX improves therapeutic efficiency by pH stimulation.6 The release of two drugs becomes accelerated when triggered by NIR irradiation because of the enhanced photothermal efficiency of CoFe2O4−PDA. NIR-stimulusrelease promotes drug release at the tumor site and high biosafety toward normal tissues for an improved curative effect by efficient targeted treatment.30 Dual-stimuli and two different controllable drug release modes provide a novel chemotherapy strategy and improve the therapeutic effects significantly. Moreover, NIR irradiation achieves the burst drug-release and PTT, simultaneously, by the enhanced photothermal conversion efficiency of the nanocarrier. Smart multidrug chemotherapy and PTT synergistic treatment remarkably inhibits tumor growth in vivo with our multifunctional nanocarrier. All of the results confirm that the

simultaneous release of drugs also greatly impeded their practical application compared with the programmable release of different drugs.11,12 Thus, treatment efficiency was improved limitedly. In order to probe the transfer and release of the loaded drugs for excellent treatment safety and efficiency, imaging-guided therapy systems for multifunctional smart drug delivery have therefore attracted much attention.13−17 Inorganic mesoporous materials are ideal drug carriers with high loading capacity, but they suffer from an uncontrollable drug release with low release rate.7 An improved strategy is the introduction of stimuli-response controllable switch.18 For example, pH,19,20 light,21 heat,22 and redox23-response release has been developed and the side effect of chemotherapy decrease drastically. As an endogenous stimulus, pH-response is widely used to release drug automatically at the cancer site because of the acidic tumor microenvironment.24 However, pH-response release is still a passive targeting procedure and is governed by drug diffusion and affected by the complicated tumor microenvironment.19,20 Single pH-response drug-release is still difficult to manipulate artificially. Near-infrared (NIR) laser is an external light stimulus with an active targeting capacity that can trigger the spatiotemporal control of drug release.25−27 Improved target selectivity and excellent biosafety are achieved using the high penetration depth of the NIR laser. Moreover, “on-demand” controllable drug delivery is easily achieved by tuning the light parameters, including wavelength, intensity, exposure time, and area remotely.25 If a multidrug treatment is controllable in a combination of endogenous pH and exogenous NIR laser stimuli, then the therapeutic efficiency and safety will be greatly enhanced. In addition, NIR laser photothermal therapy (PTT), as a minimally invasive therapy using the heat generated from photothermal agents after absorbing NIR light to ablate cancer B

DOI: 10.1021/acsami.7b06105 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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ACS Applied Materials & Interfaces

unpolymerized dopamine for further use. Co/DP MNPs were prepared by similar procedure except the addition of 10 mg DOX in Tris buffer and stirring for 12 h before dopamine added. 2.5. Preparation of CoFe2O4@PDA@ZIF-8 (CoPZ) Magnetic Nanoparticles. In a typical synthesis of CoPZ sandwich nanocomposite, the above CoP MNPs were added to 3 mL of 25 mM Zn(NO3)2 methanol solution and mixed for 15 min. Then 3 mL of 50 mM 2-methyl imidazole methanol solution was dripped continuously into the solution and allowed to react at room temperature for 30 min without stirring. After the reaction, the black products were washed with methanol and deionized water for three times to remove the unreacted agents. For the synthesis of CoPZ/C or Co/DPZ/C, the only change was to introduce 3 mg of camptothecin (CPT) into the Zn(NO3)2 methanol solution at the beginning of the synthesis. 2.6. In Vitro Drug Loading and Releasing Studies. To evaluate the drug loading capacity of CoPZ MNPs, the Co/DPZ/C MNPs after loading drugs were collected by centrifugation and washed with deionized water three times to remove the unabsorbed drugs. The concentration of DOX and CPT in the collected supernatants were analyzed by UV−vis absorption measurements. The drugs loaded in CoPZ MNPs were calculated by the difference between the amount of the added drugs and the residual drugs in the supernatants. The drug loading efficiency (LE) was calculated according to eq 1.

system possesses great potential as an excellent therapeutic agent in clinical application and may open a new avenue for controllable drug-release chemotherapy.

2. EXPERIMENTAL SECTION 2.1. Materials and Reagents. FeCl3·6H2O, CoCl2·6H2O, polyethylene glycol (PEG-6000), sodium acetate trihydrate (CH3COONa· 3H2O), ethylene glycol (HOCH2CH2OH), zinc nitrate hexahydrate [Zn(NO3)2], and 2-methyl imidazole (HMeIM) were obtained from Fuchen Chemical Reagent Co., Ltd., Tianjin, China. Dopamine hydrochloride, doxorubicin hydrochloride (DOX) and camptothecin (CPT) were purchased from Sigma-Aldrich Co., Ltd., Shanghai, China. All other chemicals were supplied by Shanghai Aladdin Chemistry Co., Ltd. and of analytic grade without further purification. Milli-Q water was used throughout this study. The mice used in animal experiments were obtained from the Institute of Hematology & Hospital of Blood Disease, Chinese Academy of Medical Sciences & Peking Union Medical College with the license No. SCXK-2014-0013, Tianjin, China. The mice were housed one per cage, and they had free access to water and solid pellet food obtained from HFK, Beijing, China. We confirm that all experimental protocols were approved by the Institutional Animal Care Committee of Nankai University and all methods were carried out in accordance with the relevant guidelines and regulations from the Institutional Animal Care Committee of Nankai University, China. 2.2. Apparatus. Transmission electron microscopy (TEM) images were recorded on a JEM-2010HR microscope (JEOL, Japan) at an operating voltage of 200 kV. Fourier transform infrared spectra (FT− IR) were tested on a Bruker Tensor 27 Fourier transform infrared spectrometer (German). Thermogravimetric analysis (TGA) was performed on a PTC-10ATG-DTA analyzer heated from room temperature to 700 °C at a ramp rate of 10 °C min−1 under air. The saturation magnetization curves were measured at room temperature under a varying magnetic field from −70 k to 70 k Oe on vibrating sample magnetometer (SQUID VSM, U.S.A.). X-ray diffraction (XRD) patterns were recorded on a D/max-2500 diffractometer (Rigaku, Japan) using Cu−Kα radiation (λ = 1.5418 Å). Brunauer− Emmett−Teller (BET) surface area, pore volume, and pore size distribution were studied by N2 adsorption−desorption isotherms on a NOVA 2000e surface area and pore size analyzer (Quantachrome, Florida, FL, U.S.A.) at 77 K. The hydrodynamic sizes and zeta potentials were measured using a Zetasizer Nano ZS, Malvern, England. UV−vis absorption spectrum was recorded by a UV-2450visible spectrophotometer (Shimadzu, Japan). The transverse relaxivity times and T2-weighted MR images were conducted using a spectroscope (1.2 T, Huantong, Shanghai, China). The T2-weighted images were acquired using TR/TE = 120/2.328, 120/6.112, 120/ 9.896, 120/13.68, 120/17.46, and 120/21.24 ms. 2.3. Preparation of CoFe2O4 Magnetic Nanoparticles. Mesoporous CoFe2O4 magnetic nanoparticles (MNPs) were prepared according to a facile one-pot hydrothermal method with a little modification.31 Typically, 74.4 mg CoCl2·6H2O, 168.9 mg FeCl3· 6H2O, 450.0 mg CH3COONa·3H2O, and 250.0 mg PEG-6000 were dissolved in 10.0 mL HOCH2CH2OH at 50 °C for 30 min to form a uniform solution under ultrasonic and vigorous stirring. Then, the mixture was sealed in a Teflon-lined stainless-steel autoclave and heated to 160 °C for 16 h. Then, the black precipitate was magnetically collected and washed with ethanol and deionized water for several times. The obtained mesoporous CoFe2O4 MNPs were dried at 60 °C for 6 h before characterization and utilization. 2.4. Preparation of CoFe2O4@PDA (CoP) Magnetic Nanoparticles. To synthesize CoFe2O4@PDA MNPs (denote as CoP, and the abbreviations of all the products were listed in Table S1 of the Supporting Inormation, SI), 10 mg as-prepared CoFe2O4 MNPs were dispersed in 15 mL Tris buffer (pH 8.5), followed by adding 8 mg of dopamine. After stirring for 24 h at room temperature, CoP MNPs were obtained simply through self-polymerization of dopamine under a weak alkaline environment (pH 8.5).32 Then the product was centrifuged and washed with water for three times to remove the

LE(%) =

weight of loaded drugs × 100% original weight of drugs

(1)

The drug release experiment of the drug-loaded nanocarrier was carried out with a dynamic dialysis method. For pH-responsive release, 6 mg drug-loaded nanocarrier was dispersed in 3 mL of PBS solutions (pH 7.4 or pH 5.0) and sealed in a dialysis bag (MWCO 4000 Da), and then immersing the dialysis bag in 30 mL PBS solutions with pH 7.4 or 5.0 to imitate the pH environment of normal body fluid and tumor tissue. At defined time periods, 100 μL of release media were collected to detect the content of drugs. In the group of laser irradiation, the Co/DPZ/C MNPs were exposed to an 808 nm NIR laser at power densities of 1.3 W cm−2 for 5 min before collecting the solution at pH 7.4. All of the drug-releasing experiments were performed at 37 °C. The release of CPT and DOX from MNPs were measured by UV−vis spectrum, and the release efficiency (RE) is calculated based on eq 2.

RE(%) =

weight of released drugs × 100% weight of loaded drugs

(2)

2.7. In Vitro Cytotoxicity Assay and the Synergic Therapeutic Efficacy. The cell toxicity was assessed by standard 3(4,5-dimethylthialzol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using HepG2 cells as models. Typically, HepG2 cells were seeded in a 96-well plate with a density of 5 × 103 cells/well and cultured in DMEM medium containing 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin at 37 °C under 5% CO2 for 24 h. CoPZ, Co/DPZ, CoPZ/C, and Co/DPZ/C were then added to the cells with different concentrations, respectively. For PTT groups, the HepG2 cells were irradiated with 808 nm NIR laser for 10 min. After incubation for another 24 h, the media were removed, and cells were washed with PBS and treated with 20 μL of MTT for about 4 h. Subsequently, the MTT-formazan generated by live cells was dissolved in dimethyl sulfoxide (DMSO), and a microplate reader (SpectraMaxi3) was used to measure the absorbance centered at 490 nm. The cell viabilities were evaluated by comparing with the untreated control cells. Trypan blue dye exclusion test was performed to confirm the cytotoxicity intuitively. Briefly, HepG2 cells were plated in 6-well plates (5 × 105 cells per well) and exposed to 200 μg mL−1 CoPZ, Co/ DPZ, CoPZ/C, and Co/DPZ/C, respectively. After incubation for 24 h, cell suspensions were washed with sterile PBS twice immediately and stained with 1 mL of 0.4% (wt/vol) trypan blue dye. Both live (unstained) and dead (blue stained) cells were observed by an invert microscope at 100×. The untreated cells were also performed under the same conditions and served as the control. C

DOI: 10.1021/acsami.7b06105 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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Figure 1. (A−C) TEM images and (D−E) DLS size distributions of CoFe2O4 (A, D), CoP (B, E), and CoPZ (C, F).

Figure 2. (A) FTIR spectra, (B) XRD patterns, (C) magnetic hysteresis curves (inset: photo images of well-dispersed CoPZ solution and magnetic accumulation of CoPZ), (D) TGA, (E) N2 adsorption−desorption isotherms, and (F) DFT pore size distribution of (a) CoFe2O4, (b) CoP, and (c) CoPZ. 2.8. In Vitro and In Vivo T2-Weighted Images. MR imaging was performed to verify the capability of Co/DPZ/C MNPs as a T2weighted MR imaging contrast agent. As for the in vitro study, the samples with different Fe concentrations range from 0.1 to 2 mM were prepared with CoFe2O4, CoP, CoPZ, and Co/DPZ/C composites, respectively. The associated relaxivity values (mM−1 s−1) were calculated from the slope of the linear plots of 1/T2 versus Fe concentration. As for the in vivo MR study, 200 μL of 3 mg mL−1 Co/ DPZ/C MNPs dispersion was injected intravenously into a HepG2 tumor-bearing mice via tail vein to “find” tumor through T2-weighted MR imaging. The images of mice before and after injection at different time periods were recorded with conventional spin echo acquisition. 2.9. In Vitro and In Vivo Photothermal Performance. In vitro photothermal performance and PTT efficiency of Co/DPZ/C MNPs were evaluated by measuring the temperature change of different concentrations of Co/DPZ/C suspension (0−400 μg mL−1) under 808 nm NIR laser at the power density of 1.3 W cm−2 for 10 min. CoFe2O4, CoP, and CoPZ suspensions were also tested under the same conditions as a comparison. The change of temperature was

monitored and imaged simultaneously by an infrared thermal imaging camera (FLIR-A300, FLIR Systems Inc., U.S.A.). HepG2 tumor-bearing nude mice were intravenously injected with 200 μL of 3 mg mL−1 Co/DPZ/C suspension to record the in vivo photothermal performance of Co/DPZ/C. After injected for 9 h, the tumor-bearing mice were irradiated with 808 nm NIR laser at the power density of 1.3 W cm−2 for 10 min. The tumor temperature of mice was monitored by an infrared thermal imaging camera. The other HepG2 tumor-bearing mice was injected with saline as the negative control. 2.10. In Vivo Multi-Drug Chemotherapy and PTT Synergic Therapy. In order to assess the multidrug chemotherapy and PTT synergic therapeutic effect of Co/DPZ/C MNPs in vivo. Nude mice (18−20 g) with subcutaneous HepG2 cancer xenografts were selected as model. The tumor-bearing mice were randomly divided into nine groups (n = 3 per group) and treated by intravenous injection of 200 μL of saline, 200 μL of 3 mg mL−1 CoPZ, Co/DPZ, CoPZ/C, Co/ DPZ/C, CoPZ + NIR, Co/DPZ/C + NIR, Co/DPZ/C + NIR + magnet, and Co/DPZ/C + magnet. As one interesting approach, D

DOI: 10.1021/acsami.7b06105 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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ACS Applied Materials & Interfaces magnetic-mediated targeting via an external magnetic field on the tumor site has been proven to be able to direct transportation of magnetic nanoparticles to the tumor sites effectively.33 Thus, a single magnet was placed noninvasively on the surface of tumor site of tumor-bearing mice after tail intravenous injection. The magnet was 30 mm diameter and 10 mm thick. The PTT-related groups were irradiated at the tumor site with 808 nm NIR laser at the power density of 1.3 W cm−2 for 10 min after injection for 9 h. The therapy was repeated every 3 days within 12 days. The body weight and tumor size of tumor-bearing mice were recorded every 2 days after the treatment. The tumor sizes were calculated as volume = (tumor length) × (tumor width)2/2, and relative tumor volumes were determined as V/V0 (V0 was the initial tumor size before treatment). After 12 days, all the mice were sacrificed, and the solid tumors were taken out to be measured and compared. The main organs of mice were also collected after treatment. Hematoxylin and eosin (H&E) stained images were used to investigate the cytotoxicity in vivo. All the animal experiments were performed according to institutional and national guidelines. 2.11. Statistical Analysis. All experiments were repeated at least three times. Data for each experiment were expressed as means ± standard deviation (n = 3). In all tests, statistical significance was set at p < 0.05.

without altering their crystallinity. However, CoP showed a similar XRD pattern to CoFe2O4 because of the amorphous PDA structure. The superparamagnetic properties of different products were investigated (Figure 2C). The saturation magnetization of CoFe2O4 MNPs decreased from 68.5 to 50.3 and 36.4 emu g−1 after wrapping with nonmagnetic PDA and PDA@ZIF-8 layers, respectively. The magnetization value of CoPZ was still as high as 36.4 emu g−1, and the high magnetization revealed not only the great potential of T2-MRI, but also the magnetic targeting capacity of the nanocarrier. The well-dispersed CoPZ solution and magnetic accumulation of CoPZ were confirmed by the images in the inset of Figure 2C. Thermogravimetric analysis (TGA) was used to investigate the composition of different products (Figure 2D). The weight loss before 200 °C was attributed to the removal of the solvents. Both PDA layer and ZIF-8 shell were decomposed at around 300 °C, indicating their high thermal stability. According to the weight loss ratio from TGA, the mass ratios of CoFe2O4 core, PDA layer, and ZIF-8 shell in the nanocarrier were calculated to be 35.0%, 28.4%, and 36.6%, respectively. The drug loading capacity of the nanocarrier was highly dependent on its specific surface area. Thus, the surface area and pore size distribution of different products were tested by N2 adsorption isotherms (Figure 2E,F). CoFe2O4 and CoPZ showed a porous structure and large surface areas with 0.55 cm3 g−1, 0.14 cm3 g−1, and 164 m2 g−1, 349.6 m2 g−1, respectively. The pore volume and surface area of CoP decreased significantly to 0.09 cm3 g−1 and 23.4 m2 g−1 because of the formation of the PDA layer. The pyknotic PDA layer therefore could serve as a cover to prevent the leakage of DOX before arriving at the tumor site. 3.2. In Vitro Drug Loading and Releasing Properties. DOX and CPT were selected as drug models to assess the drug coloading capacity of the CoPZ nanocarrier. Zeta potentials of CoFe2O4, CoP, and CoPZ MNPs were measured to reveal the coloading mechanism of the drugs. The hydrophilic CoFe2O4 core had a large number of carboxyl groups and was negatively charged, while the hydrophobic ZIF-8 shell was positive (Figure S2).37 It is well-known that hydrophilic DOX and hydrophobic CPT are positively and negatively charged, respectively. Thus, DOX was encapsulated easily in mesoporous CoFe2O4 through hydrogen bonding, hydrophilic and electrostatic interaction, while CPT was integrated in the ZIF-8 layer via hydrogen bonding, and hydrophobic and electrostatic interaction. Potential π−π stacking interaction between the aromatic anthracycline also played an important role for the loading of the two drugs.38 The loading efficiency (LE) was calculated to be as high as 98% for DOX and 46% for CPT in Co/DPZ/C, respectively. The ultrahigh loading efficiency of DOX was achieved by the large-pore network of CoFe2O4 and coating effect of the negatively charged PDA layer. It was worth mentioning that we also tried to load DOX in CoFe2O4 MNPs directly without the modification of PDA layer. DOX was actually loaded in hydrophilic CoFe2O4 core after stirring for 12 h, but DOX leaked immediately after washing with water due to the weak interaction between CoFe2O4 and the hydrophilcity of DOX. Thus, the PDA layer is crucial for encapsulating DOX and avoiding the leaking of DOX. The CoFe2O4/DOX@PDA (denoted as Co/DP) was also used to load CPT directly, and the LE was only about 14%, so most hydrophobic CPT was encapsulated in ZIF-8 shell but not PDA layer. The different drugs loaded in different spaces independently offered the

3. RESULTS AND DISCUSSION 3.1. Characterization of CoFe2O4, CoFe2O4@PDA (CoP), and CoFe2O4@PDA@ZIF-8 (CoPZ). The flower-like structure of CoFe2O4, CoP, and CoPZ MNPs with diameters of 70, 100, and 150 nm, respectively, were clearly illustrated in their transmission electron microscopic (TEM) images (Figure 1A−C). CoFe2O4 presents a well-defined mesoporous feature for loading hydrophilic drug. Uniform polydopamine (PDA) and ZIF-8 layers with ca. 15 and 25 nm were wrapped on the surface of CoFe2O4 successfully to form CoP and CoPZ, respectively. A dynamic light scattering study revealed that all the MNPs had relatively narrow size distribution and were well dispersed for real application (Figure 1D−F). The morphology of CoFe2O4@ZIF-8 (denoted as CoZ) without a PDA layer was also recorded with TEM images as a comparison (Figure S1). CoZ MNPs could not form a monodispersed core−shell structure. CoFe2O4 and ZIF-8 disorderly aggregated together by the electrostatic interaction and chelation between the Zn2+ ions and carboxyl groups on the surface of CoFe2O4. Therefore, the modification of PDA was essential to synthesize the sandwich nanocarrier.34 The residual catechol groups in the PDA layer chelated metal ions for convenient heterogeneous integration of the ZIF-8 shell.32 Moreover, the PDA layer also impeded the aggregation of nanoparticles during ZIF-8 growth process by the well dispersibility and colloidal stability of PDA.34 Weak adsorption of the C−N bending vibration was observed at 1506 cm−1 in Fourier transform infrared (FTIR) spectra (Figure 2A) and verified the successful formation of CoP after oxidation−polymerization of dopamine.35 The adsorption between 1535 and 675 cm−1 was the characteristic peak of the organic ligand and confirmed the formation of ZIF8 shell. The powder X-ray diffraction (XRD) patterns were illustrated in Figure 2B. The peaks observed at 18.0°, 30.4°, 35.7°, 43.4°, 53.8°, 57.3°, 62.7°, and 74.7° were assigned to the (111), (220), (311), (400), (422), (511), (440), and (533) planes of cubic spinel phase CoFe2O4 (JCPDS No. 22-1086). The peaks at 7.3°, 12.7°, 18.0°, and 26.7° were correspond to the (011), (112), (222), and (134) planes of crystalline ZIF8.36 The simultaneous existence of the characteristic peaks of CoFe2O4 and ZIF-8 indicated the successful formation of CoPZ E

DOI: 10.1021/acsami.7b06105 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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Figure 3. (A) In vitro drug release profiles of DOX and CPT from Co/DPZ/C in phosphate buffer saline (PBS) at pH 7.4 and 5.0 and (B) drug release profiles at different time points at 808 nm laser irradiation for 5 min.

Figure 4. (A) TEM images of Co/DPZ/C under (A) pH 5.0 at different time periods (from 3 to 24 h) and (B) different NIR irradiation time (from 10 to 40 min) at pH 7.4.

the dialysis bag (MWCO 4000 Da) freely. The deduction was confirmed by an additional experiment (Figure S5). After the drug release experiment, the CoFe2O4 core in the dialysis bag was separated by a magnet, and the contents of drugs in dialysate and CoFe2O4 core were determined by UV−vis measurements. The drugs that did not release into media were retained in the PDA fragments, but not in the CoFe2O4 core. Thus, DOX and CPT did not metabolize along with CoFe2O4, and the chemotherapy efficiency was remarkably enhanced due to the complete drug release in vivo. Under an 808 nm NIR laser irradiation (1.3 W cm−2, 5 min for each pulse), CPT and DOX presented a burst release property, and the two different drugs were released simultaneously. The cumulative release content of CPT and DOX increased from 13.1% and 3.2% to 50.6% and 37.2% at pH 7.4, while it increased from 61.3% and 36.6% to 74.8% and 44.6% at pH 5.0, respectively (Figure 3B). Importantly, the release equilibrium time decreased from 11 h at pH 7.4 to 7 h at pH 5.0. This fast and controllable drug release triggered by NIR laser was beneficial to accumulate the drugs at the tumor site with high concentration to keep them within their therapeutic window for decreasing the side effects of chemotherapy to normal tissue and improving therapeutic effect with high drug concentration in tumor site.30 Moreover, the NIR laser, as an external stimulus, is easily tuned remotely in terms of irradiation time and intensity to obtain the “on-demand” drug-release dosage. Both pH and NIR-stimulus achieves the responsive release of drugs efficiently in two totally different drugs-releasing modes and have their own advantages, so the nanocarrier could improve the treatment efficiency significantly with the multidrug chemotherapy.

possibility of releasing drugs step by step. Furthermore, the presence of characteristic peaks of DOX and CPT in the FTIR spectra of Co/DPZ/C MNPs illustrated the successful loading of the two drugs (Figure S3). Moreover, TEM images of Co/ DP and Co/DPZ/C manifested that the core−shell structure of the nanocarrier was well preserved after loading drugs (Figure S4). The drugs’ release profile of Co/DPZ/C MNPs was tested at different pH conditions as well as with or without an NIR laser. Without NIR irradiation, only 13.1% of CPT and 3.2% of DOX were released at pH 7.4 after 40 h. However, the release content became 61.3% for CPT and 36.6% for DOX at pH 5.0. Therefore, Co/DPZ/C was sensitive to the acidic tumor microenvironment (Figure 3A). The pH-responsive release property of the nanocarrier is beneficial for cancer-targeting therapy since the acidic microenvironment of tumor tissue by the intracellular lysosome and endosome, while biotoxicity becomes low for the normal tissues because of their neutral condition.39 Moreover, a unique two-stage stepwise release process exhibited from Co/DPZ/C MNPs under acidic stimulation (pH 5.0). Hydrophobic CPT was first released and reached a plateau in 12 h. Then, hydrophilic DOX was released because it was embedded in the core of the nanocarrier. The sustainable sequential release characteristics of Co/DPZ/C made the equilibrium release of CPT and DOX with a 12 h interval naturally. Thus, the antitumor efficiency could be enhanced, while the side effect was minimized.6 It was worth mentioning that relatively low cumulative release of drugs was observed possibly because of the strong π−π stacking between drugs and PDA layer.40 Although the PDA layer was peeled off, the chipped PDA layer still could not pass through F

DOI: 10.1021/acsami.7b06105 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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Figure 5. (A) Cell viability and (B) images of HepG2 cells incubated with CoPZ, Co/DPZ, CoPZ/C, Co/DPZ/C, CoPZ + NIR, and Co/DPZ/C + NIR.

Figure 6. (A) Transverse relaxivity (r2) of Co/DPZ/C at different Fe content (Inset: T2-weighted MR images of Co/DPZ/C at varied concentrations). (B) T2-weighted MR images of tumor-bearing mice before and after intravenous injection of Co/DPZ/C at different time points. The liver and tumor regions were marked by red and yellow circles, respectively.

The two drugs were released independently without mutual interference under acidic condition, which was attributed to the separate spaces for storing different drugs, that is, the hydrophilic CoFe2O4 core for DOX and hydrophobic ZIF-8 shell for CPT. However, the mechanism for burst drug release under NIR laser irradiation and interval release under acidic condition is unknown. To investigate the drug release mechanism of the nanocarrier, its TEM images were recorded under acidic condition (pH 5.0) and with NIR laser irradiation at different time periods. As illustrated in Figure 4A, some fragments were observed at the TEM images of Co/DPZ/C under pH 5.0, but the CoFe2O4 core remained stable at different time points. Thus, the ZIF-8 shell was first degraded, followed by the peeling of the PDA layer. Correspondingly, hydrophobic CPT in ZIF-8 was released gradually, and hydrophilic DOX showed fast release after an interval of 12 h with the degradation of ZIF-8 shell under the acidic stimuli. Thus, the stepwise degradation of the ZIF-8 and PDA layer under acidic conditions achieved the pH-responsive sequential release of the two drugs. The ZIF-8 and PDA layers disintegrated rapidly as observed from the TEM images of Co/DPZ/C MNPs under NIR irradiation (pH 7.4, Figure 4B). CoFe2O4 core and PDA layer was possessed of high heat conversion ability, while the ZIF-8 shell showed a low light absorption in NIR region. Thus, CoP and ZIF-8 shell could not be heated simultaneously with the laser irradiation as the uneven distribution of heat in the nanocarrier. The thermal expansion of CoP, acting as hot spot, accelerated the disintegration of the ZIF-8 shell and PDA layer. The Co/DPZ/C nanocarrier was destroyed severely with 10

min NIR irradiation and cracked from the inside. Therefore, the promoted and burst release of CPT and DOX achieved by the local hyperthermia in Co/DPZ/C core induced by the photothermal effect.41 Therefore, the diffusion rate of the drugs increased under NIR-stimulation to achieve their fast and simultaneous burst release. As a conclusion, the different disintegration modes of the core−shell structure of Co/DPZ/C govern the different drug-release behaviors with pH stimulation or NIR laser irradiation. 3.3. In Vitro Cytotoxicity Assay and the Synergic Therapeutic Efficacy. The viability of HepG2 cells was measured with standard MTT [3-(4,5-cimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide] assay to evaluate the cytotoxicity and in vitro synergic therapeutic efficiency of the nanocarrier (Figure 5A). More than 90% of HepG2 cells were viable after being treated with 400 μg mL−1 of CoPZ MNPs, so good biocompatibility was illustrated because of the low toxicity of all the materials used to prepare the nanocomposite. In contrast, the groups treated with CoFe2O4/DOX@PDA@ZIF-8 (denoted as Co/DPZ), CoFe2O4@PDA@ZIF-8/CPT (denoted as CoPZ/C), Co/DPZ/C, CoPZ + NIR, and Co/DPZ/C + NIR exhibited significant cell death in a concentration-dependent manner. The cells incubated with Co/DPZ/C + NIR showed the highest cell mortality rate, which was 97.7% at the same concentration of 400 μg mL−1. Moreover, Co/DPZ/C and Co/ DPZ/C + NIR inhibited the HepG2 cells viability remarkably even compared to the predicted additive effects of two drugs and multidrug chemotherapy combined with PTT treatment (Figure S6A,B). The predicted therapeutic effect of Co/DPZ/C and Co/DPZ/C + NIR was calculated by multiplying the cellG

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ACS Applied Materials & Interfaces viability inhibition ratio of Co/DPZ and CoPZ/C, or Co/ DPZ/C, and CoPZ + NIR, respectively. The sequential release of CPT and DOX enhanced anticancer efficacy of Co/DPZ/C, similar to the results in previous work.6 The excellent cellviability inhibition capacity of Co/DPZ/C+NIR was attributed to the extraordinary synergistic effect of combining the multidrug chemotherapy with PTT. Trypan blue experiment was further performed to confirm the cytotoxicity and the synergistic therapeutic efficiency of the nanocarrier. As shown in Figure 5B, the dead cells were stained with trypan blue and about 5, 55, 50, 80, 40, and 90% of the cells died after incubation with 200 μg mL−1 of CoPZ, Co/ DPZ, CoPZ/C, Co/DPZ/C, CoPZ + NIR and Co/DPZ/C + NIR, respectively. The results were consistent with those observed from the MTT assay. The efficient photothermal capacity of Co/DPZ/C under NIR irradiation improved the performance of multidrug chemotherapy through the accelerated drug release, the increased permeability of the cell membrane, and the multiple treatment pathways with low risk of recurrence.38 3.4. In Vitro and In Vivo T2-Weighted MR Imaging. T2weighted MR imaging was tested to evaluate the feasibility of Co/DPZ/C as an MR contrast agent for diagnostics and imaging-guided dual-therapy. Figure 6A showed that the relaxation rate of Co/DPZ/C varied linearly with increased Fe concentration and the longitudinal relaxivity value (r2) was 34.6 mM−1 s−1. The composite presented an apparent Fe concentration-dependent darkening effect and thus confirmed their T2-weighted MR efficiency in vitro (inset of Figure 6A). The relaxation properties of CoFe2O4, CoP, and CoPZ were also studied under the same conditions as comparisons. Their r2 values were 53.3, 32.9, and 38.3 mM−1 s−1, respectively (Figure S7A−C). CoFe2O4 exhibited the highest r2 value, indicating the good T2-weighted imaging capacity of CoFe2O4 core. The r2 value of CoP, CoPZ, and Co/DPZ/C decreased because of the tightly wrapped layer of nonmagnetic PDA, which inhibited the exchange of water in the CoFe2O4 core. However, the added PDA layer also improved the hydrophilia of the nanocarrier, so the decreased r2 values were still fine for T2-weight MR imaging. The similar r2 values of CoP, CoPZ, and Co/DPZ/C were observed and ascribed to the porous structure of ZIF-8 to permit the water to pass freely. In order to investigate in vivo MR imaging potential, 200 μL of 3 mg mL−1 Co/DPZ/C MNPs solution was intravenously injected into HepG2 tumor-bearing mice. As depicted in Figure 6B, a dramatic dark signal was observed in the liver region after 1 h postinjection, and the highest darkening signal at the tumor area was observed at 9 h after injection as the enhanced permeability and retention (EPR) effect of tumors, demonstrating the ability of Co/DPZ/C to enhance in vivo T2weighted MR imaging. The enlarged images of the tumor region at different times were illustrated in Figure S8 after intravenous injection of Co/DPZ/C MNPs to further confirm their imaging efficiency. 3.5. In Vitro and In Vivo Photothermal Performance. Figure 7A shows the UV−vis−NIR spectra of 100 μg mL−1 of CoFe2O4, CoP, CoPZ, and Co/DPZ/C to reveal their light absorption capacity. PDA, as an excellent absorbing material, remarkably enhances the NIR absorption ability of the CoFe2O4 MNPs. Thus, CoP presented the strongest NIR absorption at 808 nm, while the NIR absorption of CoPZ and Co/DPZ/C decreased because of the decreased CoP content. UV−vis−NIR spectra of Co/DPZ/C were measured at the

Figure 7. (A) The UV−vis−NIR absorption spectra of 100 μg mL−1 of CoFe2O4, CoP, CoPZ, and Co/DPZ/C. (B) The UV−vis−NIR absorption spectra of Co/DPZ/C at different concentrations. (C) Temperature variation curves of 400 μg mL−1 CoFe2O4, CoP, CoPZ, and Co/DPZ/C under 808 nm irradiation with a power density of 1.3 W cm−2. (D) Temperature variation curves of Co/DPZ/C at different concentrations under same irradiation condition. (E, F) In vitro and in vivo infrared thermal photographs of PBS and Co/DPZ/C exposed to 808 nm laser recorded at different time intervals.

concentration ranging from 50 to 400 μg mL−1 and confirmed the high NIR absorption capacity of the nanocarrier (Figure 7B). Moreover, the characteristic peaks of CPT and DOX were obviously observed at 365 and 485 nm in the UV−vis−NIR spectra and also confirmed that the two kinds of drugs were successful integrated. The in vitro photothermal effect of the nanocarrier was confirmed by irradiating with an 808 nm laser from 0 to 10 min at 1.3 W cm−2. As shown in Figure 7C,D, the temperature of the solutions increased with the increasing concentration of the composite and irradiation time. CoP exhibited the highest photothermal efficiency, which was consisted with the UV− vis−NIR spectra. An infrared thermal imaging camera was used to record the photothermal capacity intuitively (Figure 7E). 400 μg mL−1 Co/DPZ/C solution was rapidly heated to higher than 65 °C after laser exposure for 10 min, but no obvious H

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ACS Applied Materials & Interfaces temperature raising was observed in the phosphate buffer saline (PBS) as control. According to the highest MR imaging darkening signal at the tumor site, the in vivo photothermal performance was studied at 9 h after intravenous injection with the irradiation of 808 nm laser (Figure 7F). In the case of the Co/DPZ/C injection, the temperature of the tumor surface increased from 32 to 50 °C rapidly within 10 min. The fast heating and suitable temperature were perfect for tumor ablation and avoiding the damage of surrounding healthy tissues. Whereas a negligible temperature raising was observed in tumor-bearing mice injected with PBS. The results demonstrated that Co/DPZ/C MNPs had a high NIR light−heat conversion efficiency in vivo for PTT. Furthermore, the excellent photothermal ability of Co/DPZ/C also validated the fast and burst drugs release process under the NIR stimulation. 3.6. In Vivo Multi-Drug Chemotherapy and PTT Synergic Therapy. The antitumor effect of Co/DPZ/C MNPs was investigated using HepG2 tumor-bearing mice as a model, and the treatment of all groups was repeated every 3 days within 12 days, including intravenous injection and laser irradiation. Tumor growths were remarkably inhibited in Co/ DPZ, CoPZ/C, Co/DPZ/C, and CoPZ + NIR groups compared with the control group. Notably, the groups treated by combined multidrug chemotherapy and PTT exhibited higher therapeutic efficacy with the synergistic effect (Figure 8A,B). The group of Co/DPZ/C + magnet was also recorded to validate the effectiveness of magnetic targeting therapy. The results confirmed that the therapeutic effect was further enhanced in the presence of a strong magnet by the accumulation of the nanocarrier (Figure S9). The relative tumor sizes and histologic coagulative tumor necroses of different groups were illustrated in Table 1 to demonstrate the cancer treatment efficiency clearly. It was noteworthy that the tumor volumes of Co/DPZ and CoPZ/C groups slightly increased at the later stage of treatment, possibly due to the drug resistance of the tumors.42 Therefore, our multidrug nanoplatform could overcome drug resistance problem caused by single-drug chemotherapy effectively. The tumor inhibition efficiencies in vivo were consistent with the results of the in vitro MTT study. Thus, our nanocarrier achieved a combinational antitumor capacity with multidrug chemotherapy and PTT. In addition, the body weights of all groups did not decrease with the long treatment time, so high biocompatibility and safety was observed from our theranostic agent (Figures 8C and S9). Tumor sizes were not the only evaluation index of cancer therapeutic efficiency; coagulation necrosis level could illustrate precisely the content of dead cells, which do not show biological activity and are usually generated during the process of cancer therapy.43,44 Moreover, the coagulation necrosis cells are difficult to ablate and/or absorb by the circulatory system timely after treatment.43,44 All of the tumors in different groups were therefore collected and stained for hematoxylin-eosin (H&E) histologic analysis after 12 d treatment (Figure 8D). The tumor cells grew densely in PBS and CoPZ groups. In contrast, apoptotic and necrotic tumor cells were observed in other treatment groups to some extents, and more than 97% apoptotic and necrotic tumor cells were found in the Co/DPZ/ C + NIR + magnet group. The ultrahigh cell apoptosis rate was attributed to the accumulation and fast drug release, as well as the synergistic effect between multidrug chemotherapy and PTT. The results of the H&E staining analysis were consistent

Figure 8. (A) Representative photographs of tumor-bearing mice (1− 8 represented PBS, CoPZ, Co/DPZ, CoPZ/C, Co/DPZ/C, CoPZ + NIR, Co/DPZ/C + NIR, and Co/DPZ/C + NIR + magnet groups). (B) Relative tumor sizes and (C) body weights of mice after various treatments as indicated. (D) H&E stained images of tumor slices from different groups after 12 days treatment.

with the tumor inhibition capacities of different groups. No appreciable damages or inflammatory lesions were observed on normal tissues for the mice after treatment, as revealed by the results of histologic analysis (Figure S10). It further evidenced that our nanocarrier is safe for in vivo application.

4. CONCLUSIONS In summary, we have developed a facile, novel, and controllable CoPZ sandwich nanocarrier used for T2-MR imaging-guided multidrug chemotherapy and photothermal synergistic treatment of cancer. Two kinds of completely different release behaviors were exhibited with pH or NIR stimulation for hydrophilic DOX and hydrophobic CPT. The drugs presented a unique step by step sequential release with a 12 h interval under the acidic condition (pH 5), while burst release of the two drugs was observed under the stimulation of NIR laser. The different release behaviors make CoPZ MNPs not only provided multitherapeutic modes of multidrug chemotherapy to enhance therapeutic efficacy, but also minimize the side effects of traditional chemotherapy. Importantly, the NIR irradiation achieved the laser-stimulation drug-release and photothermal therapy (PTT), simultaneously. Thus, a T2-MR imaging-guided burst drug-release chemotherapy and PTT synergistic ability was observed different to the single-drug chemotherapy or photothermal therapy alone. All of the results demonstrated that the synthesized CoPZ composites with low I

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ACS Applied Materials & Interfaces Table 1. Relative Tumor Volumes and Histologic Coagulative Tumor Necrosis of Different Groupsa groups

relative tumor volume (V/V0)

histologic coagulative tumor necrosis (%)

± ± ± ± ± ± ± ± ±

3 5 35 40 75 50 90 97 80

PBS CoPZ Co/DPZ CoPZ/C Co/DPZ/C CoPZ + NIR Co/DPZ/C + NIR Co/DPZ/C + NIR + magnet Co/DPZ/C + magnet

5.5 4.9 3.2 2.4 1.2 1.9 0.6 0.3 0.9

1.2 0.9 0.6 0.6 0.6 0.4 0.2 0.1 0.4

a CoPZ, CoFe2O4@PDA@ZIF-8; Co/DPZ, CoFe2O4/DOX@PDA@ZIF-8; CoPZ/C, CoFe2O4@PDA@ZIF-8/CPT; Co/DPZ/C, CoFe2O4/ DOX@PDA@ZIF-8/CPT; CoPZ + NIR, CoFe2O4@PDA@ZIF-8 + NIR; Co/DPZ/C + NIR, CoFe2O4/DOX@PDA@ZIF-8/CPT + NIR; Co/ DPZ/C + NIR + magnet, CoFe2O4/DOX@PDA@ZIF-8/CPT + NIR + magnet; Co/DPZ/C + magnet, CoFe2O4/DOX@PDA@ZIF-8/CPT + magnet.

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biotoxicity and good biocompatibility have great promise in tumor diagnosis and treatment.

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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.7b06105. Abbreviation names of the products in main text; TEM image of CoZ; zeta potentials of CoFe2O4, CoP and CoPZ; FTIR spectra of DOX, CPT, CoPZ, Co/DPZ, and Co/DPZ/C; TEM images of Co/DP and Co/DPZ/ C; UV−vis−NIR spectra of CoFe2O4 core and dialysate after drugs release experiment; the predicated and actual effects of cell viability of HepG2 cells incubated with Co/ DPZ/C and Co/DPZ/C + NIR; the transverse relaxivity curves of CoFe2O4, CoP and CoPZ at different Fe concentrations; the enlarged images of tumor region of T2-weighted images; images of tumor-bearing mice, relative tumor sizes and body weights, H&E stained images of Co/DPZ/C + magnet group; and H&E stained images of major organ slices of mice from different groups after treatment (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Fax: +86-22-23503034. E-mail: [email protected] (X.B.Y.). ORCID

Xue-Bo Yin: 0000-0002-7954-163X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by Natural Science Foundation of China (Nos. 21435001, 21675090, and 81671179), the National Basic Research Program of China (973 Program, No. 2015CB932001), and Tianjin Natural Science Foundation (15ZCZDSF00060).

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