MnO2-Functionalized CoâP Nanocomposite: A New Theranostic

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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 ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b10608 • Publication Date (Web): 08 Nov 2017 Downloaded from http://pubs.acs.org on November 9, 2017

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ACS Applied Materials & Interfaces

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,ǁ Tianqi Zhang,† Qinghai Yuan,*,† Yinghui Wang,‡ Hongjie Zhang ‡

†

Department of Radiology, 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) ǁ

Department of Pathology, The Second Hospital of Jilin University, Changchun 130041, (P. R.

China)

Address correspondence to [email protected]

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ABSTRACT Construction of stimuli-responsive theranostic nanoagents that can increase the accuracy of imaging diagnosis and boost the therapeutic efficacy has been demonstrated to 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 NIR 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 T1-weighted 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 agent for tumor diagnosis and treatment, and stimulate interest in exploration novel stimuli responsive 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

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1. INTRODUCTION Cancer, as one of the major diseases, has become the leading killer of human health.1-3 Recent advance 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 of gold nanostructures,13-16 copper sulfide nanoparticles,17-18 carbon nanomaterials,11, 19-20 palladium nanosheets21-22 and organic polymers.23 However, the inhomogeneous heat distribution within tumor tissue make PTT alone hardly achieve the desired curative effect for cancer therapy.24-26 In view of this inadequacy, there is urgent need to design multifunctional nanocomposites which can 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 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 to 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 3



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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 cancer early 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 T2-weighted MRI contrast agents (CAs) for improving image contrast and sensitivity, i.e. iron oxide, manganese oxide, and gadolinium complexes. Despite every MRI mode has its advantage, e.g. T1-weighted MRI has excellent resolution in displaying normal soft-tissue anatomy, and T2-weighted MRI is more outstanding in softer tissue imaging with high sensitivity to detect lesions such as tumors and inflammation,39-40 single MRI mode cannot meet the high diagnostic requirements owing to their inherent defects.41-42 Importantly, most of 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 our best knowledge, rare work has been focusing on exploring stimuli activated T1/T2 dual-mode CAs so far,44-46 to say nothing of incorporation 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 behaviour, which is feasible to act as contrast agent for T2-weighted MRI. Recently, MnO2 nanosheets have been employed successfully as pH-responsive activated T1-weighted MRI 4


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CAs owing to the generation of paramagnetic Mn2+ ions in acidic environment of tumors by MnO2 nanosheets disintegration. Along this line, if MnO2 nanosheets, that 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 is combined with Co-P nanocomposites, the scaffolds will not only serve as pH-triggered T1/T2 dual modal CAs for MRI, also improve the therapeutic effect.

Building from these ideas, we have successfully developed the 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). Employing the strong NIR absorbance of Co-P@mSiO2-MnO2, effective PTT could be realized. MnO2 as the “gatekeeper” can prevent the drug early 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 as not only“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 MRI CAs around tumor environment, providing more comprehensive diagnostic information for tumor with high target-to-background ratios. Such findings validated that our nanotheranostic agents are promising for pH-triggered T1/T2 dual MRI guidance combined cancer treatments.

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Scheme 1. Schematic illustration of (a) synthetic process of Co-P@mSiO2@DOX-MnO2, (b) mechanism

of cellular uptake process and

pH-triggered

T1/T2 dual MRI and

chemo-photothermal synergetic therapy. 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), MES, methanol (AR), n-hexane (AR), acetone (AR), and ethanol (AR) were purchased from Aladdin. Cetyltrimethylammonium chloride (CTAC) and 6


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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 details, 1.2 mmol of Co(ac)2 was mixed with 2.4 mmol of TPP and 21 mL OM in a 100 mL three-necked flask. The mixture was heated to 110 ℃ for 30 min under an argon flow to exclude the water as well as oxygen, and then heated up to 290℃ 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 washed with a mixed solution of hexane, acetone and ethanol for several times, and dispersed in 30 mL cyclohexane. Synthesis of Co-P@mSiO2. Co-P@mSiO2 were prepared according to previous litrature.52 5 mL cyclohexane of Co-P nanocomposites was added into 10 mL deionized water, followed by injecting 40 µL HCl (37 wt%). After stirring for 2 h, almost all Co-P nanoparticles were transferred from cyclohexane to water. Then the ligand-free Co-P nanoparticles were centrifuged and washed by water for three times, and finally dispersed in 15 mL deionized water. 2g CTAC and 18 µL TEA were mixed in a flask with 20 mL deionized water, then kept intense stirring for 1 h. Then 15 mL ligand-free Co-P nanocomposites solution was added and maintained sonicating for 1.5 h. Afterwards, 100 µL TEOS was dropwise added under stirring, then the mixture was heated to 80 ℃ for 1 h. After washing with ethanol for several times, Co-P@mSiO2 products were extracted with the mixture of 0.3g NaCl and 30 mL methanol for 3 h. In order to remove the template CTAC, the extraction process was performed for several times, and the obtained Co-P@mSiO2 products were finally dispersed in 10 mL deionized 7



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water for future use. Synthesis of MnO2-modified Co-P@mSiO2(Co-P@mSiO2-MnO2). Co-P@mSiO2 were dispersed in 5 mL MES (100 mM, pH 6.0) and stirred for 2 hours. 0.5 mL 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 were washed with water for three times to remove the free manganese ions and superfluous potassium, 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 DOX (1 mg/mL) with 12 mg Co-P@mSiO2 in phosphate buffer solution (PBS). Then kept stirring for 24 h at 37℃ in the dark. After centrifugation, Co-P@mSiO2@DOX was gently washed with PBS for 3 times. All the washing supernatant liquid were 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 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 added diverse 8


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concentrations of Co-P@mSiO2-MnO2, Co-P@mSiO2@DOX-MnO2, and free DOX for another

4

h.

Subsequently,

the

cells

incubated

with

Co-P@mSiO2-MnO2

and

Co-P@mSiO2@DOX-MnO2 were washed with PBS for 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 Center for Experimental Animals, Jilin University (Changchun, China), and all mouse experiments were operated complying to institutional and national guidelines. The xenograft model 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 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 tumor (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, then the mixtures were heated to 70 ℃ until the solutions became clear. The concentrations of Co ions in each solution were determined by inductively coupled

plasma

mass

spectrometry

(ICP-MS),

afterwards

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the

concentrations

of


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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 time (s-1) vs. the Co and Mn concentration (mM), respectively.

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: The repetition time (TR) = 569 ms, The echo time (TE) = 20.7 ms, Field of view (FOV) = 200 × 200 mm, slice thickness = 2.0 mm. T2-weighted imaging parameters: TR = 3000 ms, TE = 104.6 ms, FOV = 200 × 200 mm, slice thickness = 2.0 mm.

In Vivo Long-term Toxicity Evaluation. The histological analysis was performed for evaluation the toxicity in vivo. After intravenous injection with Co-P@mSiO2-MnO2 for 30

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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 statistical significance and extreme significance. 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 Figures S1, in 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 (Figures 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 were capped with MnO2 layer as the “gatekeeper” to block drug release from the mesopores. The morphology of Co-P@mSiO2 and Co-P@mSiO2-MnO2 still kept uniform as revealed in the transmission electron microscope (TEM) images (Figure 1b and 1c). X-ray energy-dispersive spectroscopy (EDS) illustrates the coexistence of the Co, P, Si, and Mn elements (Figure S4), which certifies the success of 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 throughout the surface of Co-P nanocomposites, which clearly demonstrates their core-shell structure (Figure 1d–g).

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The the average hydrodynamic diameter of Co-P@mSiO2-MnO2 became larger than that of Co-P@mSiO2, further proving the scucessuful caoting of MnO2 (Figure S5). Obvious characteristic peaks of Co2p3/2 at 778.2 eV and P2p 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 Si2p and Mn2p further confirm the successful coating the mesoporous silica and MnO2 shells on Co-P nanocomposites (Figure 2b).

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.

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Figure 2. XPS spectra of Co-P nanocomposites (a) and Co-P@mSiO2-MnO2 (b).

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 calculate to be 404.98 mg g-1. Such pH values were selected to mimic the normal physological microenvironment (pH 7.4) and tumor acidic microenvironment (pH 5.0~6.5). Figure 3a shows that Co-P@mSiO2@DOX-MnO2

exhibit

low

release

rate

in

normal

physological

microenvironment, while the release rate enhances as pH decrease, especially in pH 5.0 and 5.4.

Such

results

clearly

demonstrate

the

pH-triggered

release

properties

of

Co-P@mSiO2@DOX-MnO2. Furhtermore, the content of Mn2+ releasing in different pH

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certified that Co-P@mSiO2@DOX-MnO2 could be acted as a controlled drug release system for chemotherapy (Table S1).

The Co-P@mSiO2-MnO2 shows good dispersion stability in 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 by with 808 nm NIR laser were detected by 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 ℃ at a concentration of 2 mM (Figure 3b and 3c) in contrast to water. Such outstanding photothermal effect enable Co-P@mSiO2@DOX-MnO2 as excellent photothermal agent for PTT.

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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 ℃, (b) Plots of temperature change (∆T) with 300 s vs. the concentration of Co-P@mSiO2@DOX-MnO2, (c) Infrared thermal images of Co-P@mSiO2@DOX-MnO2 at timed intervals in vitro.

The different structural and physicochemical properties of Co-P@mSiO2-MnO2 under the different pH conditions were expected to influence on the proton relaxation in a magnetic field (Figure 4a). In normal blood circulation, Co-P@mSiO2-MnO2 can just serve 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 were dispersed in pH 5.0 buffer solution (imitate acidic microenvironment of tumor) for different concentration. 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 buffer solution comparing to that at pH 7.4, the r2' value was determined to be 253. 44 mM-1 s-1 (Figure S10). Such greatly enhanced of MR relaxivities maybe 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 removing the MnO2 shells, more water molecules could faster and easier access the Co-P core, thereby improving T2-weighted MRI performance; and iii) 15



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The reduced proton relaxation interference futher improve 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 has the capacity to be applied as pH-responsive T1/T2 dual mode MRI CAs in vivo.

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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 vs. 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.

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. Firstly, 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 comparing to the pre-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 were intravenously injection 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 provide both T1- and T2-weighted contrast enhancement in MR imaging within 24 h post-injection. 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 high-efficiency 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 17



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tissues by enhanced permeability and retention (EPR) effect after dministration in the blood circulation.54-55 The biodistribution of Co-P@mSiO2-MnO2 in major organs and tumor after 24 h of injection was detected by ICP-MS analysis (Figure S11). The result further demonstrated Co-P@mSiO2-MnO2 could accumulate at tumor tissues after injection 24 h. 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.

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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.

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 chemotheray 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, then co-stained with the nucleic acid specific dyes acridine orange (AO) / ethidium bromide (EB) (AO can stain the nuclei of live cells and give green fluorescence, EB can stain the nuclei of dead cells and give red fluorescence). As shown in Figure 6, cells treated laser alone exhibited negligible cell death. In contrst, 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). Although 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

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therapy could significantly improve therapic effect, thereby reducing drug dose and mitigating the side effect.

Figure 6. Confocal images of Co-P@mSiO2@DOX-MnO2,

4T1 cells treated with PBS (control), NIR, 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).

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. Firstly, 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 tumor promptly increased to ≈55.4 ℃ after irradiating with 808 nm NIR laser (1.5 W cm-2) for 5 min, which was high enough to killing cancer cells and restricting its malignant proliferation. In 20


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contrast, tumors injected with PBS shown 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.

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).

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@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 treatment (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 meanwhile, although the single chemotherapy or PTT (group III and IV) exhibited notably 21



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enhanced tumor growth inhibition respectively, 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 a further proof, the anti-tumor efficacy of every group was evaluated by hematoxylin and eosin (H&E) staining. As demonstrated in Figure 8e, tumor tissue cells treated with Co-P@mSiO2@DOX-MnO2 + NIR (gourp V) exhibted 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 ascribe to the synergetic treatment effect of PTT and chemotherapy. Co-P core-mediated photothermal therapy could not only destory 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 uptaked 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 eradiation without recovery.

22


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Figure 8. (a) The 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

and

V.

Co-P@mSiO2@DOX-MnO2 + NIR, *p < 0.05 and **p < 0.01 by the student’s two-tailed ttest). 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 23



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in both the control group and Co-P@mSiO2-MnO2 group were observed from H&E stained images (Figure S13), further demonstrating that Co-P@mSiO2-MnO2 have barely obvious acute, chronic pathological toxicity to mice. 4. CONCLUSIONS In summary, Co-P@mSiO2@DOX-MnO2 were successfully synthesised 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 pH-responsive on-demanded 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. Theses positive results make this new pH-responsive theranostic agent Co-P@mSiO2@DOX-MnO2 with remarkable MR imaging performance and excellent synergistic anticancer effect potential for cancer theranostics in future oncotherapy. ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website at The quantity of Mn2+ released in different pH; The SEM image of Co-P; The X-ray diffraction pattern of Co-P; N2 adsorption–desorption isotherm of Co-P@mSiO2; X-ray energy-dispersive

spectroscopy

(EDS)

of

Co-P@mSiO2-MnO2;

24


The

the

average

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hydrodynamic diameter of Co-P@mSiO2 and Co-P@mSiO2-MnO2; The 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-MnO2 at 24 h after injection; 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&E stained images of healthy mouse and the mouse 30 d after injection of Co-P@mSiO2-MnO2. 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). REFERENCES (1) Liu, Y.; Ai, K.; Liu, J.; Deng, M.; He, Y.; Lu, L., Dopamine-melanin colloidal nanospheres: an efficient near-infrared photothermal therapeutic agent for in vivo cancer therapy. Advanced materials (Deerfield Beach, Fla.) 2013, 25 (9), 1353-1359. (2) Liu, D.; Poon, C.; Lu, K.; He, C.; Lin, W., Self-assembled nanoscale coordination polymers with trigger release properties for effective anticancer therapy. Nature communications 2014, 5, 4182. (3) Siegel, R.; Naishadham, D.; Jemal, A., Cancer statistics, 2013. CA: a cancer journal for clinicians 2013, 63 (1), 11-30. (4) Chen, Y.; Tan, C.; Zhang, H.; Wang, L., Two-dimensional graphene analogues for biomedical applications. Chemical Society reviews 2015, 44 (9), 2681-2701. (5) Wei, A.; Mehtala, J. G.; Patri, A. K., Challenges and opportunities in the advancement of nanomedicines. 25



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MnO2-Functionalized CoâP Nanocomposite: A New Theranostic

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MnO2-Functionalized CoâP Nanocomposite: A New Theranostic