Manganese Oxide-Coated Carbon Nanotubes As ... - ACS Publications

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Manganese oxide-coated carbon nanotubes as dual-modality lymph mapping agents for photothermal therapy of tumor metastasis Sheng Wang, Qin Zhang, Peng Yang, Xiangrong Yu, Li-Yong Huang, Shun Shen, and Sanjun Cai ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.5b08087 • Publication Date (Web): 10 Dec 2015 Downloaded from http://pubs.acs.org on December 10, 2015

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ACS Applied Materials & Interfaces

Manganese oxide-coated carbon nanotubes as dual-modality lymph mapping agents for photothermal therapy of tumor metastasis Sheng Wang,†,# Qin Zhang,‡,# Peng Yang,& Xiangrong Yu,§ Li-Yong Huang†, Shun Shen,¶,*and Sanjun Cai†,* †

Department of Colorectal Surgery, Fudan University Shanghai Cancer Center,

Shanghai 200032, China. ‡Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China. &Department of Macromolecular Science, Fudan University, Shanghai 200433, China. §Department of Radiology, Huashan Hospital, Fudan University, Shanghai, 200032, China. ¶School of Pharmacy & Key Laboratory of Smart Drug Delivery, Fudan University, Shanghai 201203, China. # Both authors contributed equally to this work. *Corresponding author, Address: Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong-an Road, Xu-Hui District, Shanghai 200032, China. Phone: +86-21-64175590. Fax: +86-21-64035387.

E-mail: [email protected] (S.J. Cai); [email protected] (S. Shen)

Abstract: Lymph nodes (LNs) status is a major indicator of stage and survival of lung cancer patients. LNs dissection is a primary option for lung cancer LNs metastasis;

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however, this strategy elicits adverse effects and great trauma. Therefore, developing a minimally invasive technique to cure LNs metastasis of lung cancer is desired. In this study, multi-walled carbon nanotubes (MWNTs) coated with manganese oxide (MnO) and polyethylene glycol (PEG) (namely MWNTs–MnO-PEG) was employed as a lymphatic theranostic agent to diagnose and treat metastatic LNs. After single local injection and lymph drainage were performed, regional LNs were clearly mapped by T1-weighted magnetic resonance (MR) of MnO and dark dye imaging of MWNTs. Meanwhile, metastatic LNs could be simultaneously ablated by near-infrared (NIR) irradiation under the guidance of dual-modality mapping. The excellent photothermal therapy (PTT) was obtained in mice bearing LNs metastasis models, showing that MWNTs–MnO–PEG as a multifunctional theranostic agent was competent for dual-modality mapping guided photothermal therapy of metastatic LNs. Keywords: manganese oxide, multi-walled carbon nanotubes, lymph nodes metastasis, dual-modality mapping, theranostics, photothermal therapy

INTRODUCTION Lung cancer is one of the most common cancer types and remains as the leading cause of cancer mortality worldwide.1 Approximately 85% of lung cancer patients manifest non-small cell lung cancer; five-year survival rate remains poor in spite of early resection and combination therapy. Various clinical factors and pathological markers have been used to identify patients at high risk of recurrence.2-5 Among them, nodal involvement is an important prognostic factor to determine cancer stage and


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patient survival.6-8 LNs status is also a major indicator of survival in patients with lung cancer.9 As is known to all, lung cancer spreads mainly by lymphatic metastasis. Surgeons always perform radical LNs resection to treat lung cancer. A high number of resected LNs correspond to a high chance of survival.10,11 Therefore, initial identification and eradication of LNs are the key to prevent lung cancer recurrence. Although surgical dissection is a primary option to treat LNs metastasis, this technique is invasive and associated with adverse effects. So, developing a visual and minimally invasive method for the treatment of LNs metastasis is desired. PTT has been extensively investigated in nanomedicine because this technique is minimally invasive, controllable, and highly efficient. NIR light-absorbing agents are applied to generate heat from optical energy, resulting in the thermal therapy.12-14 Various types of NIR-absorbing nanoagents, such as gold-based nanomaterials,14-18 copper sulfide nanoparticles19,20 and graphene,13,21-23 as well as organic polymers24-27 have been widely explored. MWNTs have also been considered as promising materials in various biomedical applications because of their unique physical and chemical properties.28-31 MWNTs exhibit remarkable optical absorbance in NIR region and convert NIR laser radiation into heat, which is a transparency window for biological tissues.21,32,33 By the use of photothermal absorbing agents, PTT has been successfully utilized to ablate solid tumors in animal models. However, the application of PTT to treat metastatic LNs has been occasionally reported. The main reason is that, to ensure the safety and efficacy of the photothermal ablation, the location

of

LNs

metastasis

must

be

accurately


identified

in

the


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full course of treatment. With inherent black imaging, MWNTs are used as natural lymph tracers displaying T1- and T2-weighted magnetic resonance (MR) contrast effects when the nanomaterials are attached to metallic catalyst nanoparticles produced

via

carbon

nanotubes

synthesis.30,33 Contrast

agents,

such

as

superparamagnetic iron oxides with high T2 relaxivities, are widely used in tumor targeting and imaging. Unfortunately, T2-weighted imaging (dark regions) usually produces confusion with signals from hemorrhage and blood clots.34,35 Therefore, “positive” contrast agents need to be developed and investigated. For example, gadolinium (Gd)-based complexes as positive contrast agents can generate hyper intense regions resulting from predominant effects on longitudinal (T1) relaxation time of water protons in tissues.26,36-40 However, Gd-based contrast agents are associated with nephrogenic systemic fibrosis. As a result, these agents are less favorable than other contrast materials34 such as T1-MRI contrast of manganese oxide.34,35,41,42 In this work, we developed dual-modality tracer of MWNTs–MnO–PEG for guided PTT of metastatic LNs, reducing tumor recurrence in mice lung cancer metastasis models (Fig. 1). Multifunctional MWNTs–MnO–PEG nanocomposites were synthesized by a one-pot microwave synthesis in a polar solvent[41]. Applying inherent black appearance and MR contrast effect, we could accurately map the regional lymphatic system via lymphatic circulation of MWNTs–MnO–PEG. Our imaging result provided valuable information for surgeons to prepare preoperative plans and intraoperatively distinguish regional LNs from surrounding tissues. Regional LNs


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were ablated through NIR laser irradiation in which MWNTs were utilized as a NIR light-absorbing agent under the guidance of dual-modality mapping. Moreover, MWNTs–MnO–PEG exhibited low bio-toxicity, and PTT had highly efficient in eradicating metastatic LNs with satisfactorily safe to neighboring normal tissues. EXPERIMENTAL SECTION Materials.

Manganese (II) 2, 4-pentanedionate [Mn(acac)2] was purchased from

Alfa Aesar. Tiethylene glycol (TREG) was purchased from Shanghai Reagent Company (Shanghai, China). NH2-polyethylene glycol 5000 (NH2-PEG5000) was purchased from Seebio Biotech, Inc. (Shanghai, China). Cell counting kit-8 (CCK-8), calcein AM, and propidium iodide (PI) were purchased from KeyGen BioTech (Nanjing,

China).

RPMI

1640

medium,

fetal

bovine

serum

(FBS),

penicillin–streptomycin solution, and trypsin–EDTA solution were purchased from Gibco (Tulsa, OK, USA). MWNTs were purchased from Nanjing XFNANO Materials Tech Co., Ltd. (Nanjing, China). All other chemicals were of analytical grade. Purified water was produced by a Millipore water purification system. Synthesis of MWNTs–MnO–PEG. MWNTs–MnO was synthesized in accordance with previously described methods.41 In a typical procedure, 60 mg of Mn(acac)2 and 30 mg of MWNTs were placed in a flask containing 20 mL of TREG solution. The resulting solution was stirred in an oil bath at 135 °C for half an hour, sealed and maintained in a microwave synthesis system (Discovery, CEM Corp, USA) at 250 °C for 10 min. Afterward, the solution was quickly cooled down to room temperature. The reaction product was centrifuged and then washed several times with ethanol and



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deionized water to remove ions and possible remnants. To increase hydrophilicity and biocompatibility, we further modified the MWNTs–MnO with NH2-PEG5000 by applying a covalently linked method, as described in previous reports.13 Material characterization. The samples were characterized using a transmission electron microscope (TEM) (JEOL-2010). Manganese concentration was determined by inductively coupled plasma atomic emission spectroscopy (ICP–AES) (P-4010 spectrometer, Hitachi, Japan). Fourier transform infrared (FTIR) spectra were obtained using a Magna-550 spectrometer (Nicolet, USA). T1-weighted images of MWNTs–MnO nanocomposites with different iron concentrations were obtained using a 3-T clinical MRI scanner. In vitro temperature evaluation caused by NIR laser irradiation. 1 mL of aliquots with 40 µg of MWNTs–MnO–PEG and NS was deposited in a quartz tube and illuminated with 808 nm of continuous-wave NIR laser (Changchun New Industries Optoelectronics Technology, Changchun, China) at the laser power density of 2 and 3 W/cm2 for 5 min. Pre- and post-illumination temperatures were recorded using an IR thermal camera (InfraTec, VarioCAM®hr Research, Germany). In vitro cytotoxicity and photothermal cell death induction. The A549 cells (human lung cancer cells) were plated in 96-well plates at 37 °C with 5% CO2 and 95% air atmosphere at >95% humidity for 24 h. The cells were then incubated with various concentrations of MWNTs–MnO–PEG. After 24 h of incubation, each well was washed twice with PBS. Afterward, 10 µL of CCK-8 solution and 100 µL of RPMI-1640 cell medium were added to each and incubated for another 2 h. Finally,


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the OD value at 450 nm was read using a microplate reader (Synergy TM2, BIO-TEK Instruments Inc., USA). A549 cells (1.0 × 105 cells per well) were seeded in 20 mm glass-bottom culture dish (NEST, China) and incubated with 40 µg/mL of MWNTs–MnO–PEG at 37 °C for 2 h to directly observe photothermal therapeutic efficacy. The cells were then irradiated by NIR laser (2 and 3 W/cm2) for 5 min. Afterward, the cells were stained with 1 µM calcein-AM and 4 µM PI in PBS for 30 min. The staining solution was aspirated and replaced with PBS. The staining cells were observed using a ZEISS LSM710 live cell confocal laser imaging system (Carl Zeiss, Germany). Animal model. Nude male mice were obtained from Shanghai BK Laboratory Animal Co., Ltd. (Shanghai, China) and used under protocols approved by the Ethics Committee of Fudan University. A549 LNs metastases were induced by subcutaneous injection of 3 × 106 A549 cells suspended in 50 µL of PBS via the right hind foot pad of nude mice. At 60 d after inoculation, the mice with spherical hard lumps in their popliteal fossa were selected for our experiments. In vivo dual-modality mapping. For the dual-modality mapping studies, mice manifesting LNs metastases were randomly divided into two groups (n=4 per group). One group was injected with NS into the right hind footpad. The second group was injected with 50 µL of MWNTs–MnO–PEG (3 mg/mL). At approximately 90 min after injection, the mice were anesthetized and then imaged by using a 3-T clinical MRI scanner equipped with a small animal coil under the T1 weighted model. At the



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same time, popliteal and sciatic LNs were exposed by ca. 0.5 cm skin incision of the corresponding region through MRI and then photographed. Photothermal ablation of popliteal LNs. In this experiment, popliteal LNs were designated as a therapeutic target of metastatic LNs to expound the feasibility of PTT. A total of 20 mice exhibiting LNs metastases were randomly divided into four groups (n=5 per group). One group was injected with NS into the right hind footpad without laser irradiation. The second group was injected with NS and then irradiated with laser at power density of 2 W/cm2 for 5 min. The third group was injected with 50 µL of MWNTs–MnO–PEG (3 mg/mL) without laser irradiation. The fourth group was injected with 50 µL of MWNTs–MnO–PEG (3 mg/mL) and then irradiated with laser at power density of 2 W/cm2 for 5 min. Temperature changes were subsequently recorded using an IR thermal camera. At 15# d, the main organs were collected and analyzed to evaluate the safety of PTT. The weight and the histopathological characteristics of popliteal LNs were examined to assess therapeutic efficacy. Statistical analysis. Unpaired student’s t test was used for between two-group comparison and one-way ANOVA with Fisher’s LSD for multiple-group analysis. A probability (P) less than 0.05 was considered statistically significant. Results were expressed as mean ± standard deviation (SD) unless otherwise indicated. RESULTS AND DISCUSSION Characterization of MWNTs–MnO–PEG. As shown in Fig. 2b, numerous dark nanodots of MnO with diameters of 10 nm uniformly grew on the MWNTs surface. There were no dark nanodots on the primary MWNTs by comparison in Fig. 2a. The energy-dispersive X-ray analysis (EDXA) spectrum of the obtained MWNTs–MnO


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nanomaterial revealed the existence of Mn, C, and O elements, confirming the growth of MnO onto the surface of MWNTs (Fig. 2d). As determined by ICP–AES, the weight ratio of Mn in the MWNTs–MnO nanocomposites was ca. 12.35%, which met a requirement of MRI diagnosis. FTIR spectra were recorded to verify PEGylated result (Fig. S1 in the Supporting Information). After carboxyl and amino condensation reaction was completed, the characteristic peak of the carboxyl group became weak and underwent a minor red shift to 1688 cm−1, which confirmed the successful modification of polyethylene glycol (PEG). The peak of ether bond in PEG at 1010 cm−1 also showed that some PEG molecules conjugated to MWNTs–MnO. To demonstrate the T1-enhancing capability in vitro, we determined T1 signal with different concentrations of MWNTs–MnO by a 3.0T clinical MRI system. An obviously bright T1-MRI was observed with increasing Mn concentration (Fig. 1c), indicating our MWNTs–MnO could be used as MRI contrast agents. An NIR thermal imaging camera was performed to investigate the photothermal properties of MWNTs–MnO–PEG and the photothermal efficiency of the aqueous solution (40 µg/mL) irradiated by NIR laser (λ=808 nm, 2 and 3 W/cm2). The temperature of laser-irradiated MWNTs–MnO–PEG increased dependently on laser power density (Fig. 3a). The temperature increased 20.34 and 40.08 °C at the power density of 2 and 3 W/cm2, respectively (Fig. 3d). In contrast, the temperature of normal saline (NS) slightly changed. The result illustrated MWNTs–MnO–PEG could act as an efficient photothermal converter.



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Intracellular PTT. WNTs–MnO–PEG was applied for imaging and therapy, the toxicity of photothermal converter was firstly evaluated. The cell viability of A549 cells incubated with various MWNTs–MnO–PEG concentrations for 24 h was not significantly decreased (Fig. 4a), indicating our as-prepared nanomaterials had no inherent toxicity. Cell viability was quantitatively evaluated by CCK-8 assay for PTT efficiency. The A549 cells were incubated with MWNTs–MnO–PEG at the concentration of 40 µg/mL for 2 h and then irradiated by NIR laser at the power density of 0, 2, 3 W/cm2 for 5 min. The relative cell viabilities were 98.02%, 51.79%, and 11.59%, respectively, demonstrating that the increase of laser power density could significantly increase the therapeutic effect (Fig. 4b). Cell viability was also qualitatively evaluated by calcein AM (green, live cells) and PI (red, dead cells) co-staining assay (Fig. 4c). A549 cells exhibited bright green fluorescence and no red fluorescence without NIR illumination. After the NIR illumination at power density of 2 W/cm2, a large amount of red fluorescence emitting from dead cells was observed. Highest rate of killing A549 cell was obtained exposed to laser illumination with a power density of 3 W/cm2, indicating almost no cell survived. Dual-model Mapping of Regional LNs. In clinical practice, cancer cells initially metastasize to sentinel LNs; these cells quickly and latently spread to other nearby LNs (called regional LNs). Thus, regional LNs resection is the basis of tumor treatment. However, accurate diagnosis and localization of regional LNs is difficult in clinical treatment. MRI combined with contrast agents is one of the most widely used clinical imaging techniques to diagnose tumor and LNs. For example, Chen et al.36,43


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have developed Gd-based, magnetite-based dual-modality MRI for LNs mapping and treatment. Our groups have successfully fabricated magnetic graphenes to perform dual-modality (dye and T2-MRI) mapping guided PTT in regional LNs metastasis of pancreatic and acquire encouraging therapeutic outcomes.13 However, T2-weighted MRI exhibits some disadvantages, which are mainly associated with confusion with other hypointense areas and hardly find the subclinical lymph node metastases for its intrinsic dark signals. In contrast, the T1-MRI mapping can provide valuable information for surgeons to prepare preoperative plans and intraoperatively distinguish regional LNs from surrounding tissues. Although gadolinium (Gd)-based complexes as positive contrast agents have been widely applied for the disease diagnosis, they are associated with nephrogenic systemic fibrosi and less favorable than T1-MRI contrast of manganese oxide. In our work, MWNTs–MnO–PEG with a high r1 relaxivity was exploited as a strong contrast agent in T1-weighted MRI. The mice with LNs metastases were imaged using a 3.0T MRI system. After normal saline (NS) was injected into the right hind footpad, the MRI result showed that regional LNs were hardly distinguished from their surrounding tissues for the same signal-to-noise ratio (Fig. 5a). The relative signal intensity was 1.02±0.07 (n=3). The mice were anesthetized, and the right popliteal and sciatic LNs in the corresponding surgically incised skin region were examined by snaked eye. We found that the LNs were difficult to discriminate from the surrounding normal tissues because of the same color (Fig. 5b). On the other hand, remarkably enhanced T1-weighted MR signals were observed in regional LNs after MWNTs–MnO–PEG (3 mg/mL, injection



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volume of 50 µL) was injected into the right hind footpad (Fig. 5c). The relative signal intensity was 1.91±0.26 (n=3). Simultaneously, the popliteal and sciatic LNs were labeled in black by MWNTs and easily distinguished compared with those in the NS group (Fig. 5d). PTT of Metastatic LNs. Radical LNs dissection is the first choice for the treatment of lymphatic metastasis in clinical practice. However, it is always associated with time consuming, infection, bleeding and intractable diarrhea for injury of innocent abdominal vagus nerve. The therapeutic effect by PTT with high efficient, minimally invasive treatment characteristics happens only at the tumor site where both light-absorbent and localized photo-irradiation coexist. Thus, the PTT of metastatic LNs has a good prospect, which not only can effectively reduce the side effects of the operation, but also the treatment process is simple and effective. Subsequently, we further investigated the in vivo mapping-guided invasive photothermal treatment of metastatic LNs. The mice bearing LNs metastases were established by subcutaneous injection of A549 cells suspended in PBS via the right hind foot pad of nude mice (male, aging 6–8 weeks). When the tumors of popliteal LNs reached the longest dimension of 5.0 mm, the mice were randomly placed in four treatment groups (n=5 per group): NS treatment (Group I), NS with laser treatment (Group II), MWNTs–MnO–PEG treatment (Group III), and MWNTs–MnO–PEG with laser treatment (Group IV). Laser irradiation was carried out 90 min after the right hind footpad was injected with MWNTs–MnO–PEG. During PTT, temperature changes on the popliteal LNs surface were recorded by using an IR thermal camera. The


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temperature rapidly increased from 25.28 °C to 55.64 °C in 5 min (Fig. 6). By contrast, the surface temperatures of popliteal LNs hardly changed in Group II, in which temperature increased only 7 °C. Changes in the temperature of the irradiated region showed a cliff drop from the popliteal LNs to the surrounding normal tissues (Fig. 6, 3D), causing minimal damage for normal tissues. The anti-cancer effects of MWNTs–MnO–PEG with laser treatment on mice bearing LNs metastases were examined (Fig. 7). Obviously, the antitumor efficiency of Group IV was particularly prominent and was superior to all the other groups (P

Manganese Oxide-Coated Carbon Nanotubes As ... - ACS Publications

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