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MnO2‑Functionalized Co−P Nanocomposite: A New Theranostic Agent for pH-Triggered T1/T2 Dual-Modality Magnetic Resonance Imaging-Guided Chemo-photothermal Synergistic Therapy Longhai Jin,† Jianhua Liu,† Ying Tang,§ Lanqing Cao,∥ Tianqi Zhang,† Qinghai Yuan,*,† Yinghui Wang,‡ and Hongjie Zhang‡ †
Department of Radiology and ∥Department of Pathology, The Second Hospital of Jilin University, Changchun, 130041 P.R. China ‡ State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry (CIAC), Chinese Academy of Sciences (CAS), Changchun, 130022 P.R. China § Department of Gastroenterology, The First Hospital of Jilin University, Changchun, 130021 P.R. China S Supporting Information *
ABSTRACT: Construction of stimuli-responsive theranostic nanoagents that can increase the accuracy of imaging diagnosis and boost the therapeutic efficacy has been demonstrated for a promising approach for diagnosis and treatment of cancer. Herein, we constructed a novel theranostic agent with Co−P nanocomposites as core, mesoporous silica as shell, and manganese dioxide (MnO2) nanosheets as gatekeeper, which have been employed for pH-activatable T1/T2 dual-modality magnetic resonance imaging (MRI)-guided chemotherapeutical and photothermal combination anticancer therapy in vitro and in vivo. Co− P core-enabled theranostic platform could be applied for both photothermal therapy and T2-weighted MRI in the normal circulation owing to its strong near-infrared absorbance and intrinsic magnetic properties. In the acidic environment of tumors, MnO2 cap could be dissolved into Mn2+ ions to not only realize pH-responsive on-demand drug release but also activate T1weighted MRI contrast enhancement. Such T1/T2 dual-mode MR imaging provides further comprehensive details and accurate information for tumor diagnosis, and the on-demand chemo-photothermal synergetic therapy greatly improved the therapeutic effectiveness and effectively mitigated side effects. These findings demonstrate that Co−P@mSiO2@DOX−MnO2 are promising as pH-responsive theranostic agents for tumor diagnosis and treatment, and stimulate interest in exploration of novel stimuliresponsive theranostic nanoagents which posssess good potential for clinical application in the future. KEYWORDS: theranostic agent, pH-responsive, T1/T2 dual-mode MRI, chemotherapy, photothermal therapy, synergetic effect
1. INTRODUCTION
combine PTT with other therapeutic approaches for synergetic therapy. Chemotherapy, as a routine therapeutic method for cancer, is generally subjected to restrictions of limited therapeutic efficacy, drug loss during delivery, and severe side effects in patients.27 The development of a controllable drug release system that can transport the therapeutical payload with an intelligent stimuli-responsive manner to targeted tumor tissues has therefore been regarded as a promising strategy for settling these matters.28−30 Among numerous stimuli, pH has received the most investigation and has the greatest practical meaning for therapy of cancer in clinical since tumor exhibits different pH than normal tissues.31−33 Therefore, the combination of PTT and pH-triggered chemotherapy may be an optional method to conquer certain limitations in cancer therapy.34,35
Cancer, as one of the major diseases, has become the leading killer of human health.1−3 Recent advances in nanomedicine significantly accelerate the development of theranostic nanoagents for concurrent cancer diagnostic and therapeutic interventions.4−8 Photothermal therapy (PTT), based on nanomaterials with the ability to transform near-infrared (NIR) light into heat, has drawn increased attention recently thanks to its several significant advantages, such as minimal invasiveness, improving treatment accuracy, and decreasing damage to normal tissues.9−12 Currently, various kinds of nanomaterials have been employed as photothermal agents, for instance, various gold nanostructures,13−16 copper sulfide nanoparticles,17,18 carbon nanomaterials,11,19,20 palladium nanosheets,21,22 and organic polymers.23 However, the inhomogeneous heat distribution within tumor tissue makes PTT alone to hardly achieve the desired curative effect for cancer therapy.24−26 In view of this inadequacy, there is an urgent need to design multifunctional nanocomposites which can © 2017 American Chemical Society
Received: July 19, 2017 Accepted: November 8, 2017 Published: November 8, 2017 41648
DOI: 10.1021/acsami.7b10608 ACS Appl. Mater. Interfaces 2017, 9, 41648−41658
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Scheme 1. Schematic Illustration of (a) Synthetic Process of Co−P@mSiO2@DOX−MnO2 and (b) Mechanism of Cellular Uptake Process and pH-Triggered T1/T2 Dual-mode MRI and Chemo-photothermal Synergetic Therapy
Recently, MnO2 nanosheets have been employed successfully as pH-responsive activated T1-weighted MRI CAs owing to the generation of paramagnetic Mn2+ ions in acidic environment of tumors by MnO2 nanosheets disintegration. Along this line, if MnO2 nanosheets, which can serve as not only T1 MRI but also the “gatekeeper” to realize pH-response on-demand drug release in the acidic microenvironment of tumors,50,51 are combined with Co−P nanocomposites, the scaffolds will not only serve as pH-triggered T1/T2 dual-modal CAs for MRI but also improve the therapeutic effect. Building from these ideas, we have successfully developed novel nanotheranostic agents (Co−P@mSiO2−MnO2) for the first time through functionalizing mesoporous silica-coated Co−P nanocomposites with MnO2 nanosheets, applying to T1/ T2 dual-modality MRI-guided chemo-photothermal combination anticancer therapy in vitro and in vivo (Scheme 1). When the strong NIR absorbance of Co−P@mSiO2−MnO2 is employed, effective PTT could be realized. MnO2 as the gatekeeper can prevent the early drug leak until it is disintegrated into Mn2+ ions in the acidic microenvironment of tumors to achieve pH-triggered drug release, which effectively mitigates side effects. Complete eradication of tumor demonstrated the synergetic therapy effect of combined PTT and chemotherapy. MnO2 acts not only as a gatekeeper to control drug release but also as a pH switch to activate T1/T2 dual-mode MRI. The generated paramagnetic Mn2+ ions and intrinsic magnetism of Co−P nanocomposites enable Co−P@ mSiO2−MnO2 to act as pH-responsive T1/T2 dual-mode MRI CAs in a tumor environment, providing more comprehensive diagnostic information for tumors with high target-to-background ratios. Such findings validated our belief that our
Imaging probes are the important part of theranostic agents, which could report the existence of a tumor and its status, monitor physiological responses to therapy, and evaluate the therapeutic efficacy.36−38 MRI, as a widely applied clinical imaging technology for early cancer diagnosis, has the ability to afford anatomical and functional images of soft tissues and organs with excellent spatial resolution.39 Some exogenous magnetic materials have been generally employed as T1- or T2weighted MRI contrast agents (CAs) for improving image contrast and sensitivity, that is, iron oxide, manganese oxide, and gadolinium complexes. Despite every MRI mode having its own advantage (for example, T1-weighted MRI has excellent resolution in displaying normal soft-tissue anatomy, and T2weighted MRI is more outstanding in softer tissue imaging with high sensitivity to detect lesions such as tumors and inflammation39,40), single MRI mode cannot meet the high diagnostic requirements owing to their inherent defects.41,42 Importantly, most MRI CAs always exert the function of enhancing MR contrast regardless of their accumulation in tumor or other tissues, leading to poor target-to-background ratios. Consequentially, stimuli-activated T1 and T2 dual-mode MRI CAs are highly desirable for achieving comprehensive diagnostic information, which is able to complement the insufficiency of each other.9,43 However, to the best of our knowledge, few studies have focused on exploring stimuliactivated T1/T2 dual-mode CAs so far,44−46 to say nothing of incorporation of PTT and pH-responsive chemotherapy to construct theranostic agent. Cobalt phosphides are an important class of non-noble-metal nanomaterials.47−49 Encouragingly, previous study showed that Co−P nanocomposites possess intrinsic magnetic behavior, which is feasible to act as contrast agent for T2-weighted MRI. 41649
DOI: 10.1021/acsami.7b10608 ACS Appl. Mater. Interfaces 2017, 9, 41648−41658
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Figure 1. TEM images of (a) Co−P, (b) Co−P@mSiO2, and (c) Co−P@mSiO2−MnO2, (d) HADDF-STEM image of Co−P@mSiO2−MnO2, and (e−g) EDS mapping of Co, Si, and Mn element based on the image in Figure 1d. 6.0) and stirred for 2 h. Then 0.5 mL of KMnO4 (10 mM) was sequentially instilled into the above solution. The reactant was sonicated for 30 min. Finally, after centrifugation, obtained Co−P@ mSiO2−MnO2 was washed with water three times to remove the free manganese ions and superfluous potassium and then redispersed in 5 mL of deionized water. Drug Loading and Releasing. Doxorubicin (DOX) loading onto Co−P@mSiO2 was achieved by blending 10 mL of DOX (1 mg/mL) with 12 mg of Co−P@mSiO2 in phosphate buffer solution (PBS). The solution was then stirred for 24 h at 37 °C in the dark. After centrifugation, Co−P@mSiO2@DOX was gently washed with PBS three times. All of the washing supernatant liquid was saved for measuring the DOX loading content via UV−vis measurement. For blocking the pores of the Co−P@mSiO2 loaded with DOX, MnO2 was capped on the surface of Co−P@mSiO2@DOX. For investigating the pH-triggered drug release, 2 mL of various buffer solutions (pH 7.4, 6.5, 6.0, 5.4, and 5.0) were used to disperse Co−P@mSiO2@DOX− MnO2, and then enclosed in dialysis bags (molecular weight cutoff = 8000). The dialysis bags were immersed in the buffer solution (20 mL) at different pH values with shaking for 24 h at 37 °C. The released DOX was detected by collection dialysis buffer at predetermined time intervals. Chemotherapy and PTT Treatments In Vitro and In Vivo. The chemo-photothermal cytotoxicity assays of the samples were carried out using 4T1 murine breast cancer cells. The cells were incubated in 96-well plates (5 × 104 cells per well) for 24 h, and then diverse concentrations of Co−P@mSiO2−MnO2, Co−P@mSiO2@ DOX−MnO2, and free DOX were added for another 4 h. Subsequently, the cells incubated with Co−P@mSiO2−MnO2 and Co−P@mSiO2@DOX−MnO2 were washed with PBS two times; after the irradiation of 808 nm NIR laser (1.5 W cm−2) for 5 min, these cells were cultured for another 24 h. Thereafter, MTT assay was used to evaluate the cell viability. Balb/c mice with average weight of 20 g were purchased from the Center for Experimental Animals, Jilin University (Changchun, China), and all mouse experiments were operated in compliance with institutional and national guidelines. The xenograft models were built by hypodermic injection with 4T1 cells in the back of each female mice. When the tumors grew to reach the size of around 6−8 mm, the xenograft model mice were randomly divided into five groups (n = 5 group−1) and were injected intratumorally with PBS (as control), PBS + NIR irradiation, Co−P@mSiO2@DOX−MnO2, Co−P@mSiO2− MnO2 + NIR irradiation, and Co−P@mSiO2@DOX−MnO2 + NIR
nanotheranostic agents are promising for pH-triggered T1/T2 dual-mode MRI guidance combined cancer treatments.
2. MATERIALS AND METHODS Materials. Oleylamine (OM, 80−90%), cobalt(II) acetate tetrahydrate (Co(ac)2·4H2O, AR), triphenylphosphine (TPP, AR), tetraethyl orthosilicate (TEOS), triethanolamine (TEA), sodium chloride (NaCl), 2-(N-morpholino)ethanesulfonic acid (MES), methanol (AR), cyclohexane (AR), acetone (AR), and ethanol (AR) were purchased from Aladdin. Cetyltrimethylammonium chloride (CTAC) and potassium permanganate (KMnO4) were purchased from Sinopharm Chemical Reagent Co., Ltd. Synthesis of Co−P Nanocomposites. Co−P nanocomposites were fabricated following the previous literature with slight modifications.49 In detail, 1.2 mmol of Co(ac)2 was mixed with 2.4 mmol of TPP and 21 mL of OM in a 100 mL three-necked flask. The mixture was heated to 110 °C for 30 min under an argon flow to exclude the water as well as oxygen, and then heated up to 290 °C for 3 h. Co−P nanocomposites were obtained after centrifugation of the black solution while it was cooled down to room temperature. Then Co−P nanocomposites were washed with a mixed solution of cyclohexane, acetone, and ethanol several times and dispersed in 30 mL of cyclohexane. Synthesis of Co−P@mSiO2. Co−P@mSiO2 were prepared according to previous literature.52 Five milliliters of cyclohexane and Co−P nanocomposites was added into 10 mL of deionized water, followed by injecting 40 μL of HCl (37 wt %). After the solution was stirred for 2 h, almost all Co−P nanoparticles were transferred from cyclohexane to water. Then the ligand-free Co−P nanoparticles were centrifuged, washed with water three times, and finally dispersed in 15 mL of deionized water. Two grams of CTAC and 18 μL of TEA were mixed in a flask with 20 mL of deionized water and then continuously stirred intensely for 1 h. Then 15 mL of ligand-free Co−P nanocomposites solution was added and sonication maintained for 1.5 h. Afterward, 100 μL of TEOS was dropwise added under stirring and then the mixture was heated to 80 °C for 1 h. After the mixture was washed with ethanol several times, Co−P@mSiO2 products were extracted with the mixture of 0.3 g of NaCl and 30 mL of methanol for 3 h. To remove the template CTAC, the extraction process was performed several times, and the obtained Co−P@mSiO2 products were finally dispersed in 10 mL of deionized water for future use. Synthesis of MnO2-Modified Co−P@mSiO2(Co−P@mSiO2− MnO2). Co−P@mSiO2 was dispersed in 5 mL of MES (100 mM, pH 41650
DOI: 10.1021/acsami.7b10608 ACS Appl. Mater. Interfaces 2017, 9, 41648−41658
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Figure 2. XPS spectra of Co−P nanocomposites (a) and Co−P@mSiO2−MnO2 (b).
Figure 3. (a) DOX release from Co−P@mSiO2@DOX−MnO2 at pH 5.0, 5.4, 6.0, 6.5, and 7.4 at 37 °C, (b) plots of temperature change (ΔT) with 300 s versus the concentration of Co−P@mSiO2@DOX−MnO2, and (c) infrared thermal images of Co−P@mSiO2@DOX−MnO2 at timed intervals in vitro. The tumor-bearing mice were anesthetized by injecting 10% chloral hydrate intraperitoneally. The anesthetized mice were scanned before and after injection with Co−P@mSiO2@DOX−MnO2 intratumorally. For intravenous injection, the anesthetized mice were treated by tail vein injection with Co−P@mSiO2@DOX−MnO2; MRI images were acquired at timed intervals. T1-weighted imaging parameters are as follows: Repetition time (TR) = 569 ms, echo time (TE) = 20.7 ms, field of view (FOV) = 200 × 200 mm, and slice thickness = 2.0 mm. T2-weighted imaging parameters are as follows: TR = 3000 ms, TE = 104.6 ms, FOV = 200 × 200 mm, and slice thickness = 2.0 mm. In Vivo Long-Term Toxicity Evaluation. The histological analysis was performed for evaluation of the toxicity in vivo. After intravenous injection with Co−P@mSiO2−MnO2 for 30 days, the tissues on the major organs of heart, spleen, liver, kidney, and lung were isolated for hematoxylin and eosin (H&E) staining. Statistical Analysis. Two-tailed Student’s t test was used for statistical analysis, and the results of *P < 0.05 and **P < 0.01 were considererd statistically significant and extremely significant.
irradiation, respectively. Every 2 days, the mice body weights and tumor sizes were recorded after therapy. Biodistribution of Co−P@mSiO2@DOX−MnO2 In Vivo. The mice bearing tumors (n = 3) were administrated by intravenous injection with Co−P@mSiO2@DOX−MnO2, and euthanized after 24 h. The tumors and the major organs (heart, spleen, liver, kidney, and lung) were isolated to be weighed. Concentrated nitric acid and H2O2 (v/v = 1:2) were applied to dissolve tumors and organs and then the mixtures were heated to 70 °C until the solutions became clear. The concentrations of Co ions in each solution were determined by inductively coupled plasma mass spectrometry (ICP-MS); afterward, the concentrations of Co−P@mSiO2@DOX−MnO2 in each tumor and organ at different time intervals were calculated. In Vitro and In Vivo MR Imaging. The in vitro and in vivo MR images were acquired using a clinical MRI instrument (GE Discovery MR750 3.0T). Co−P@mSiO2@DOX−MnO2 was dispersed in buffer solutions at differernt pH (7.4 or 5.0) at various Co and Mn concentrations (by ICP-MS measurement). T2 and T1 relaxation times and the corresponding R2 and R1 maps were subsequently obtained from a Bruker Avance III (9.4 T, 400 MHz) nuclear magnetic resonance spectrometer. The r2 and r1 relaxivity values were calculated through the curve fitting of 1/T2 and 1/T1 relaxation times (s−1) versus the Co and Mn concentrations (mM), respectively.
3. RESULTS AND DISCUSSION Co−P nanocomposites were prepared following previous literature.49 The as-prepared Co−P nanocomposites show urchin-like morphology and uniform size (Figure 1a, and 41651
DOI: 10.1021/acsami.7b10608 ACS Appl. Mater. Interfaces 2017, 9, 41648−41658
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Figure 4. MR imaging contrast effects of Co−P@mSiO2−MnO2. (a) Possible mechanism of pH activation MRI. (b) In vitro T2-weighted image of Co−P@mSiO2−MnO2. (c) In vitro T1-weighted image of Co−P@mSiO2−MnO2 after pH activation. (d, e) Relaxivity plot of r2 and r1 versus Co and Mn contents. (f, g) T2 and T1-weighted MR images of a 4T1-bearing mouse: before and after the administration of Co−P@mSiO2−MnO2 in situ.
drug release from the mesopores. The morphology of Co−P@ mSiO2 and Co−P@mSiO2−MnO2 still stayed uniform as revealed in the transmission electron microscope (TEM) images (Figure 1b,c). X-ray energy-dispersive spectroscopy (EDS) illustrates the coexistence of the Co, P, Si, and Mn elements (Figure S4), which certifies the success of the synthetic process. HAADF-STEM and elemental mapping analysis indicate that Co elements are distrubuted in the core, and Si and Mn elements present homogeneous distribution
Figure S1 in the Supporting Information). The X-ray diffraction (XRD) pattern demostrates that Co−P nanocomposites are composed of hexagonal close-packed Co and orthorhombic Co2P orthorhombic phase (Figure S2). The mesoporous silica shell was coated on the surface of Co−P nanocomposites for loading drug, and the surface areas of 446 m2/g according to BET measurements from the nitrogen adsorption−desorption isotherm (Figure S3). Subsequently, the obtained Co−P@ mSiO2 was capped with MnO2 layer as the gatekeeper to block 41652
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buffer solution compared to that at pH 7.4; the r2′ value was determined to be 253. 44 mM−1 s−1 (Figure S10). Such greatly enhanced MR relaxivities may be attributed to the following facts: (i) The greater number of paramagnetic Mn2+ ions for water ligation generated from dissolution of MnO2 shells in the acidic condition, leading to significantly enhanced T1-weighted MRI performance;50,51,53 (ii) after removal of the MnO2 shells, more water molecules could access the Co−P core faster and more easily, thereby improving T2-weighted MRI performance; and (iii) the reduced proton relaxation interference further improves both T1 and T2 performance simultaneously.44 Such results manifest that pH can not only trigger the drug release but also activate T1/T2 dual-mode MRI with high r1 and r2 values, which make Co−P@mSiO2−MnO2 have the capacity to be applied as pH-responsive T1/T2 dual-mode MRI CAs in vivo. To evaluate the feasibility of Co−P@mSiO2−MnO2 as T1/ T2 dual-mode MRI CAs for in vivo applications, a Balb/c mouse 4T1 cancer xenograft model was established, and the images were recorded by 3.0 T clinical human MRI scanner. First, a xenograft model mouse was intratumorally injected with Co−P@mSiO2−MnO2; an obvious negative signal appeared at the tumor site in T2-weighted images after injection compared to that before injection (Figure 4f). At the same time, tumor signals from T1-weighted images also became brighter in the injection area (Figure 4g). Subsequently, Co−P@mSiO2− MnO2 was intravenously injected into tumor-bearing mice for assessing their tumor detection potential. T1- and T2-weighted MR images of these mice were acquired before and after tail vein injection with Co−P@mSiO2−MnO2 at different time intervals (Figure 5). It is noteworthy that Co−P@mSiO2− MnO2 provides both T1- and T2-weighted contrast enhancement in MR imaging within 24 h postinjection. In comparison with the before injection images, T1-weighted image signals of tumor gradually enhanced during time intervals after injection (Figure 5a,b), while the signals of tumor in T2-weighted images became darker (Figure 5c,d). Such a significant signal enhancement in tumor tissues was attributed to the highefficiency ability of cellular uptake and high tumor accumulation of Co−P@mSiO2−MnO2 owing to the extravasation via seepy tumor vasculature with high penetrability and accumulation in tumor tissues by enhanced permeability and retention (EPR) effect after administration into the blood circulation.54,55 The biodistribution of Co−P@mSiO2−MnO2 in major organs and tumor 24 h postinjection was detected by ICP-MS analysis (Figure S11). The result further demonstrated Co−P@ mSiO2−MnO2 could accumulate at tumor tissues 24 h postinjection. These results demostrate that Co−P@mSiO2− MnO2 could simultaneously provide distinct positive T1 and negative T2 MR images of tumor, and had great potential to be applied to tumor theranostic applications. The outstanding photothermal performace and pH-reponsive drug release capacity of Co−P@mSiO2−MnO2 encouraged us to further investigate their potential as photothermal agents and drug delivery systems for synergistic PTT and chemotherapy of tumor in vitro and in vivo. Murine breast cancer 4T1 cells were treated with control, 808 nm NIR laser irradiation, Co−P@ mSiO2@DOX−MnO2, Co−P@mSiO2−MnO2 + NIR irradiation, and Co−P@mSiO2@DOX−MnO2 + NIR irradiation, and then costained with the nucleic acid specific dyes acridine orange (AO)/ethidium bromide (EB) (AO can stain the nuclei of live cells and give green fluorescence and EB can stain the nuclei of dead cells and give red fluorescence). As shown in
throughout the surface of Co−P nanocomposites, which clearly demonstrates their core−shell structure (Figure 1d−g). The average hydrodynamic diameter of Co−P@mSiO2−MnO2 became larger than that of Co−P@mSiO2, further proving the successful coating of MnO2 (Figure S5). Obvious characteristic peaks of Co 2p3/2 at 778.2 eV and P 2p at 129.1 eV are observed in the X-ray photoelectron spectroscopy (XPS) spectrum, which is in accordance with the literature (Figure 2a).49 The appearance of the peak of Si 2p and Mn 2p further confirm successful coating of the mesoporous silica and MnO2 shells on Co−P nanocomposites (Figure 2b). As depicted in Scheme 1, after endocytosis of Co−P@ mSiO2@DOX−MnO2, MnO2 nanosheets desintegrated into Mn2+ ions in the acidic microenvironment of tumor, realizing both pH-responsive drug release and MRI enhancement. To test this idea, DOX was chosen as a model anticancer drug and loaded into mesopores of Co−P@mSiO2, and MnO2 nanosheets subsquently blocked the mesopores. The controlled drug release performances of Co−P@mSiO2@DOX−MnO2 were studied under buffer solution with different pH values (pH 7.4, 6.5, 6.0, 5.4, and 5.0), respectively. The drug-loading content was calculated to be 404.98 mg g−1. Such pH values were selected to mimic the normal physiological microenvironment (pH 7.4) and tumor acidic microenvironment (pH 5.0−6.5). Figure 3a shows that Co−P@mSiO2@DOX−MnO2 exhibits low release rate in a normal physiological microenvironment, while the release rate enhances as the pH decreases, especially in pH 5.0 and 5.4. Such results clearly demonstrate the pHtriggered release properties of Co−P@mSiO2@DOX−MnO2. Furthermore, the content of Mn2+ releasing in different pH certified that Co−P@mSiO2@DOX−MnO2 could act as a controlled drug release system for chemotherapy (Table S1). The Co−P@mSiO2−MnO2 shows good dispersion stability in a physiological environment, such as PBS and serum (Figure S6). For sake of investigating the photothermal properties of Co−P@mSiO2@DOX−MnO2, the temperature variations of different concentrations of Co−P@mSiO2@DOX−MnO2 irradiated with 808 nm NIR laser were detected by a thermal imaging camera. Figure S7 revealed a distinct concentration/ time-dependent photothermal transformation. The temperature of Co−P@mSiO2@DOX−MnO2 solutions were increased by 30.2 °C at a concentration of 2 mM (Figure 3b,c) in contrast to water. Such outstanding photothermal effect enables Co−P@ mSiO2@DOX−MnO2 to be an excellent photothermal agent for PTT. The different structural and physicochemical properties of Co−P@mSiO2−MnO2 under the different pH conditions were expected to influence the proton relaxation in a magnetic field (Figure 4a). In normal blood circulation, Co−P@mSiO2− MnO2 can serve just as T2-weighted CAs owing to the intrinsic magnetic properties of Co−P core (Figure S8). Figure 4b displays that the darker MR images of Co−P@mSiO2−MnO2 with the increasing of Co concentration, and the transverse relaxivity value was determined to be r2 = 169.93 mM−1 s−1 (Figure 4d). In this case, few paramagnetic Mn2+ ions generate, resulting in weak T1-weighted MRI, as shown in Figure S9. To activate T1-weighted MRI, Co−P@mSiO2−MnO2 was dispersed in pH 5.0 buffer solution (imitate acidic microenvironment of tumor) for different concentrations. As shown in Figure 4c, the T1 positive signals became significantly lighter with increasing Mn2+ concentration, The r1 value was determined to be 9.05 mM−1 s−1 (Figure 4e). Interestingly, we found that T2 signals also enhanced obviously in pH 5.0 41653
DOI: 10.1021/acsami.7b10608 ACS Appl. Mater. Interfaces 2017, 9, 41648−41658
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Figure 6, cells treated with laser alone exhibited negligible cell death. In contrast, Co−P@mSiO2@DOX−MnO2 with the irradiation of NIR laser for 5 min exhibits the highest cell mortality in comparison with simplex treatment of Co−P@ mSiO2@DOX−MnO2 (chemotherapy) or Co−P@mSiO2− MnO2 with NIR laser irradiation (photothermal therapy). The quantitative treatment effect of aforementioned treatments were evaluated by the MTT assay (Figure S12). However, without light irradiation the Co−P@mSiO2@DOX−MnO2 treatment alone shows comparable or better anticancer effect than free DOX due to the improved cellular uptake of DOX released from Co−P@mSiO2@DOX−MnO2. For cell-killing effect comparison, Co−P@mSiO2@DOX−MnO2 with NIR irradiation shows the highest efficiency at all the investigated concentrations in contrast to the chemotherapy and PTT alone. These results further confirm that combinatorial chemotherapy and photothermal therapy could significantly improve therapic effect, thereby reducing drug dose and mitigating the side effect. Motivated by the remarkable synergistic chemo-photothermal therapic effect in vitro, the synergetic antitumor efficacy in vivo was further studied using Balb/c mice 4T1 cancer xenograft model. First, the temperature changes of the tumor area after administration of Co−P@mSiO2@DOX− MnO2 were detected by the IR thermal camera to vertify the photothermal performance in vivo. As shown in Figure 7, the temperature of the tumor promptly increased to ≈55.4 °C after irradiating with 808 nm NIR laser (1.5 W cm−2) for 5 min, which was high enough to kill cancer cells and restrict their malignant proliferation. In contrast, tumors injected with PBS showed little temperature rise at the same irradiation conditions. Such good photothermal performances in vivo enable Co−P@mSiO2@DOX−MnO2 to act as photothermal agent to locally enhance the tumor temperature for ablating tumor. Subsequently, the tumor-bearing mice were randomly divided into five groups and treated with PBS as control (group I), PBS + 808 nm NIR irradiation (group II), Co−P@
Figure 5. (a, b) T1-weighted and (c, d) T2-weighted MR images of a tumor-bearing mouse before and after intravenous injection of Co− P@mSiO2−MnO2 at timed intervals.
Figure 6. Confocal images of 4T1 cells treated with PBS (control), NIR, Co−P@mSiO2@DOX−MnO2, Co−P@mSiO2−MnO2 + NIR, and Co− P@mSiO2@DOX−MnO2 + NIR. Viable cells were stained with AO (green), and dead cells were stained with EB (red). 41654
DOI: 10.1021/acsami.7b10608 ACS Appl. Mater. Interfaces 2017, 9, 41648−41658
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Figure 7. Infrared thermal images of 4T1 tumor-bearing mice after injection with PBS or Co−P@mSiO2@DOX−MnO2 (2 mM, 100 μL) and exposed to under 808 nm NIR irradiation (1.5 W cm−2).
Figure 8. (a) Curves of body weight and (b) relative tumor volume of mice after various treatments. (c) Photographs of excised tumors from representative euthanized mice after various treatments. (d) Tumor weights and (e) representative H&E-stained tumors histological images of different groups after various treatments (I, PBS solution as control; II, NIR; III, Co−P@mSiO2@DOX−MnO2; IV, Co−P@mSiO2−MnO2 + NIR; V, Co−P@mSiO2@DOX−MnO2 + NIR; *p < 0.05 and **p < 0.01 by the student’s two-tailed t-test).
mSiO2@DOX−MnO2 (group III), Co−P@mSiO2−MnO2 + NIR (group IV), and Co−P@mSiO2@DOX−MnO2 + NIR (group V), respectively. The tumor dimensions and the body weights of mice were tracked every 2 days after respective treatments (Figure 8a,b). After treatments, tumors were excised and weighed, respectively (Figure 8c,d). As expected, laser irradiation only (group II) showed nearly no influence on the tumor growth. In the meantime, although the single chemotherapy or PTT (group III and IV) exhibited notably enhanced
tumor growth inhibition, individually, the tumors still could not be eradicated completely. In contrast, tumors treated with Co− P@mSiO2@DOX−MnO2 + NIR irradiation induced controlled drug release and PTT synergetic therapy were deracinated thoroughly without regrowth over a course of 14 days, verifying the excellent treatment effect of chemo-photothermal synergetic therapy. As further proof, the antitumor efficacy of every group was evaluated by hematoxylin and eosin (H&E) staining. As demonstrated in Figure 8e, tumor tissue cells treated with 41655
DOI: 10.1021/acsami.7b10608 ACS Appl. Mater. Interfaces 2017, 9, 41648−41658
Research Article
ACS Applied Materials & Interfaces Co−P@mSiO2@DOX−MnO2 + NIR (group V) exhibted the most obvious apoptosis and necrosis compared to the other groups, proving the high curative effect of PTT and chemotherapy combination. Such significantly improved therapeutic efficacy may be ascribed to the synergetic treatment effect of PTT and chemotherapy. Co−P core-mediated photothermal therapy could not only destroy the cancer cells by local hyperthermia effect but also cause treated cells to be more sensitive to chemotherapy. In addition, DOX release from Co−P@mSiO2@DOX−MnO2 are more efficiently uptaken by cancer cells, leading to improved chemotherapeutic efficacy. Therefore, Co−P@mSiO2@DOX−MnO2 could be expected to be a potential candidate for synergistic chemo-photothermal tumor eradication without recovery. To investigate the long-term toxicity in vivo after administration of Co−P@mSiO2−MnO2, the major organs (heart, spleen, liver, kidney, and lung) of healthy mice (control) and Co−P@mSiO2−MnO2-treated mice were collected after 30 days. No significant tissue damage in both the control group and Co−P@mSiO2−MnO2 group were observed from H&Estained images (Figure S13), further demonstrating that Co− P@mSiO2−MnO2 has barely obvious acute, chronic pathological toxicity to mice.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Ying Tang: 0000-0002-1105-9003 Qinghai Yuan: 0000-0002-8530-960X Hongjie Zhang: 0000-0001-5433-8611 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (Nos. 51502284, 81571737, and 21635007), Project 2016018 Supported by Graduate Innovation Fund of Jilin University, the Program of Science and Technology Development Plan of Jilin Province of China (No. 20180101119JC, 20150520007JH, and 20170101186JC), and Youth Training Foundation by the Health and Family Planning Commission of Jilin Province (No. 2017Q012).
4. CONCLUSIONS In summary, Co−P@mSiO2@DOX−MnO2 was successfully synthesized and served as theranostic agent for pH-triggered T1/T2 dual-modality MRI-guided chemo-photothermal combination therapy for the first time. Co−P@mSiO2@DOX−MnO2 exhibited excellent photothermal performance owing to the strong NIR absorbance of Co−P core. Moreover, introducing MnO2 cap imparts Co−P@mSiO2@DOX−MnO2 with pHresponsive on-demand drug release capacity, and the achieved remarkably improved synergetic treatment effect in vitro and in vivo compared to PTT or chemotherapy alone. The intrinsic magnetic properties of Co−P core and pH-activatable features of MnO2 cap make Co−P@mSiO2@DOX−MnO2 could act as an excellent contrast agent for T1/T2 dual-mode MRI in vitro and in vivo, and offers more comprehensive information for cancer diagnosis. These positive results make this new pHresponsive theranostic agent Co−P@mSiO2@DOX−MnO2 with remarkable MR imaging performance and excellent synergistic anticancer effect potential for cancer theranostics in future oncotherapy.
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MnO2 at 24 h postinjection; cell viability of 4T1 cells incubated with free DOX, Co−P@mSiO2−MnO2, Co− P@mSiO2@DOX−MnO2, Co−P@mSiO2−MnO2 + NIR, and Co−P@mSiO2@DOX−MnO2 + NIR; H&Estained images of healthy mouse and the mouse 30 d postinjection of Co−P@mSiO2−MnO2 (PDF)
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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.7b10608. Quantity of Mn2+ released in different pH; SEM image of Co−P; X-ray diffraction pattern of Co−P; N2 adsorption−desorption isotherm of Co−P@mSiO2; X-ray EDS of Co−P@mSiO2−MnO2; average hydrodynamic diameter of Co−P@mSiO2 and Co−P@mSiO2−MnO2; photographs of Co−P@mSiO2−MnO2 dispersion in PBS and serum; temperature elevation of water and Co−P@mSiO2@DOX−MnO2 aqueous solutions under NIR irradiation; magnetic hysteresis loop of Co−P; in vitro T1-weighted images of Co−P@mSiO2−MnO2 at pH 7.4; in vitro T2-weighted images of Co−P@mSiO2− MnO2 after pH activation and relaxivity plot of r2′ vs concentration of Co; distribution of Co−P@mSiO2− 41656
DOI: 10.1021/acsami.7b10608 ACS Appl. Mater. Interfaces 2017, 9, 41648−41658
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DOI: 10.1021/acsami.7b10608 ACS Appl. Mater. Interfaces 2017, 9, 41648−41658
