Fluorescent magnetic nanoparticle-labeled mesenchymal stem cells for targeted imaging and hyperthermia therapy of in vivo gastric cancer
© Ruan et al.; licensee Springer. 2012
Received: 15 February 2012
Accepted: 31 May 2012
Published: 18 June 2012
How to find early gastric cancer cells in vivo is a great challenge for the diagnosis and therapy of gastric cancer. This study is aimed at investigating the feasibility of using fluorescent magnetic nanoparticle (FMNP)-labeled mesenchymal stem cells (MSCs) to realize targeted imaging and hyperthermia therapy of in vivo gastric cancer. The primary cultured mouse marrow MSCs were labeled with amino-modified FMNPs then intravenously injected into mouse model with subcutaneous gastric tumor, and then, the in vivo distribution of FMNP-labeled MSCs was observed by using fluorescence imaging system and magnetic resonance imaging system. After FMNP-labeled MSCs arrived in local tumor tissues, subcutaneous tumor tissues in nude mice were treated under external alternating magnetic field. The possible mechanism of MSCs targeting gastric cancer was investigated by using a micro-multiwell chemotaxis chamber assay. Results show that MSCs were labeled with FMNPs efficiently and kept stable fluorescent signal and magnetic properties within 14 days, FMNP-labeled MSCs could target and image in vivo gastric cancer cells after being intravenously injected for 14 days, FMNP-labeled MSCs could significantly inhibit the growth of in vivo gastric cancer because of hyperthermia effects, and CCL19/CCR7 and CXCL12/CXCR4 axis loops may play key roles in the targeting of MSCs to in vivo gastric cancer. In conclusion, FMNP-labeled MSCs could target in vivo gastric cancer cells and have great potential in applications such as imaging, diagnosis, and hyperthermia therapy of early gastric cancer in the near future.
Gastric cancer is currently the second most common cancer and third most common cause of cancer-related death in China [1, 2], and it is still the second most common cause of cancer-related death in the world . Gastric cancer remains difficult to cure because most patients present with advanced disease . Therefore, how to recognize, track, and kill early gastric cancer cells is still one key scientific problem for early diagnosis and therapy of patients with gastric cancer.
Since 1998, we have been trying to establish an early gastric cancer prewarning system [5, 6]. In order to recognize early gastric cancer cells, we selected potential biomarkers associated with gastric cancer, combined nanoparticles and molecular imaging techniques, and tried to identify early gastric cancer cells in vivo[7–15]. Although some differently expressed genes associated with gastric cancer were identified [16, 17], no gene could be confirmed as a specific biomarker of gastric cancer. Therefore, looking for a novel pathway to recognize and treat early gastric cancer cells in vivo has become our major concern.
Stem cell therapy is one emerging potential therapeutic method for cancer therapy following the operation, chemotherapy, and radiotherapy. Mesenchymal stem cells (MSCs) are a subset of nonhematopoietic multipotent cells found primarily within the bone marrow stroma. As one kind of promising seed cells on cancer therapy, MSCs not only have self-renewing and mutlipotent features but can also efficiently carry and deliver genes into a specific location [18–24], have immunomodulatory property, and can home to the sites of active tumorgenesis [25–28]. Therefore, it is possible to use MSCs to target and identify gastric cancer cells in vivo. Furthermore, the combination of nanotechnology and MSCs exhibits great potential in the diagnosis and therapy of early gastric cancer. Up to date, no report fully confirms that MSCs could target imaging and treat gastric cancer.
Herein, we labeled the mouse marrow MSCs with amino-modified fluorescent magnetic nanoparticles (FMNPs) and injected FMNP-labeled MSCs into the mouse model with subcutaneous gastric cancer from the mouse gastric cancer cell line mouse forestomach carcinoma (MFC) cells via the tail vein. Then, we investigated the distribution and targeting ability of the labeled MSCs in nude mice by fluorescence imaging system and magnetic resonance imaging (MRI) system. Then, we irradiated subcutaneous gastric cancer tissues in nude mice by a given external magnetic field and finally explored the possible mechanism of MSCs migrating to in vivo gastric cancer cells. Results showed that FMNP-labeled MSCs could target and recognize in vivo gastric cancer cells and could inhibit the growth of gastric cancer cells under the given external magnetic field. Therefore, FMNP-labeled MSCs have great potential in applications such as targeted imaging and simultaneous therapy of early gastric cancer in the near future.
All animal experiments (NO.SYXK2007-0025) were approved by the Institutional Animal Care and Use Committee of Shanghai Jiao Tong University.
Primary culture and identification of mouse MSCs
MSCs were isolated according to a protocol  and were cultured with Dulbecco's modified Eagle's medium (DMEM; Gibco, Shanghai, China) with 20% fetal bovine serum (FBS; Hyclone, Thermo Scientific, Logan, UT, USA), 100 U/mL penicillin, and 100 mg/mL streptomycin (Gibco) at 37 °C in a 5% CO2 incubator. MSC medium was changed once every 2 days. In order to identify MSCs, passage 3 MSCs were fixed with 4% paraformaldehyde, stained with R-phycoerythrin (PE)-conjugated CD90 antibody (BioLegend, San Diego, CA, USA) and fluorescein isothiocyanate (FITC)-conjugated CD29 antibody (BioLegend), respectively, and observed with a laser confocal scanning microscope (Leica TCS SP5, Leica Microsystems, Shanghai, China). Passage 4 MSCs were detached with 0.05% EDTA in 0.1% phosphate buffered saline (PBS) and rinsed with 0.1% PBS. And then, PE-conjugated CD90 monoclonal antibody, FITC-conjugated CD29 monoclonal antibody, and PE-conjugated CD45 monoclonal antibody were respectively added into cells with 0.1% PBS containing 0.5% BSA (pH 7.2) and incubated at 4 °C for 30 min. Cells were rinsed in 0.1% frozen PBS and observed by a Calibur flow cytometer (Becton-Dickinson, Franklin Lakes, NJ, USA).
MSCs were further characterized by differentiation assays. Passage 3 MSCs were seeded on the 24-well culture plates at a density of 5 × 104/well and incubated at 37 °C in an incubator with 5% CO2. After 24 h, when the confluence of MSCs reached 80%, MSCs were cultured with different kinds of differentiation medium. Osteoblast differentiation culture medium consists of DMEM with 0.1 μmol/L dexamethasone (Sigma-Aldrich, Shanghai, China), 10 mmol/L β-sodium glycerophosphate (Sigma), 50 μmol/L ascorbic acid (Sigma), 100 U/L penicillin-streptomycin, and 10% FBS. Adipocyte differentiation medium consists of DMEM with 10 mg/L insulin (Sigma), 1 μmol/L dexamethasone, 0.5 mmol/L 3-isobutyl-1-methylxanthine (Sigma), and 100 μmol/L indomethacin (Sigma). Chondrocyte differentiation culture medium consists of DMEM with 50 μg/mL ascorbic acid, 40 μg/mL proline (Sigma), 1% insulin-transferrin-selenium (Sigma), 0.1 μM dexamethasone (Sigma), and 10 ng/ml TGF-β (Sigma). Three weeks later, differentiated osteoblasts were stained with alkaline phosphatase (Sigma), differentiated adipocytes were stained with oil red O (Sigma), and differentiated chondrocytes were identified with toluidine blue stain (Ameresco, Solon, OH, USA).
Preparation of FMNP-labeled MSCs
Silica-coated FMNPs were synthesized and characterized according to our previous reports [30, 31]. Ethanol (95 mL) and 2 mL 3-aminopropyltriethoxysilane (APS) were added to form a mixed solution and allowed to react at room temperature for 24 h. The amino-modified FMNPs were separated by permanent magnet and were washed with deionized water three times then saved for further usage. Prepared amino-modified FMNPs were characterized by a transmission electron microscope (TEM). The fluorescent and magnetic properties of the amino-modified FMNPs were characterized by using the photoluminescence (PL) spectra (Perkin Elmer LS 55 spectrofluorimeter, PerkinElmer, Waltham, MA, USA) and superconducting quantum interference device magnetometer (PPMS-9 T, Quantum Design, Beijing, China). Zeta-potential value of amino-modified FMNPs was measured with particle sizing systems (NICOMP 380 ZLS, PSS, Port Richey, FL, USA). Then MSCs were treated with medium containing amino-modified FMNPs (50 μg/mL) for 4 h. Afterward, the cells were stained with Prussian blue and visualized under a light microscope (Olympus IX71, Olympus, Shanghai, China); the labeled MSCs were also stained with 1 mM Hoechst 33258 in PBS (pH 7.4) for 5 min, and fluorescent signal of MSCs was observed by a laser confocal scanning microscope with excitation wavelength of 488 nm (Leica TCS SP5). The labeled MSCs were also embedded with epoxy resin and made into ultra-thin slices and finally observed with a transmission electronic microscope (JEOL JEM2010, JEOL Co. Ltd., Shanghai, China).
In order to confirm whether the MSCs could be labeled up to 14 days, we collected unlabeled MSCs and labeled MSCs at 7 and 14 days into eppendorf tubes to perform the MR imaging. We also examined fluorescence signal of MSCs by a fluorescence microscope.
Cell viability assay
The effect of amino-modified FMNPs on MSCs was evaluated by using the Cell Counting Kit-8 (CCK8) assay. MSCs in 96-well plates (5,000 cells per well) were incubated with MSC medium containing 50 μg/mL of amino-modified FMNPs for 4 h at 37 °C. After replacing with fresh medium, the MSCs continued to culture for 1 to 7 days. The OD values of the cells were measured by using the Multiskan mircoplate reader (Thermo MK3, Thermo Scientific) according to the protocol of the CCK8 assay kit, and the survival rate of the cells was calculated according to the following equation: Cell viability (%) = optical density (OD) of the treated cells/OD of the untreated cells × 100.
Fluorescence imaging and MRI of gastric cancer cells in vivo
All animal experiments complied with the local ethics committee. MFC cells (5 × 106) were injected subcutaneously into the right fore of the nude mice ages 6 to 8 weeks old. When tumors grew to a diameter of approximately 5 mm, 5 × 106 MSCs labeled with FMNPs were intravenously injected into the mouse models with gastric cancer (n = 3) via the tail vein. In the control experiment, FMNPs were intravenously injected into nude mouse models (n = 3) loaded with gastric cancer. These mice were imaged at 7 and 14 days post-injection by using IVIS Lumina imaging system (Xenogen (Caliper Life Sciences), Hopkinton, MA, USA), and MR imaging was performed at 3, 7, 10, and 14 days after post-injection by using GE HDX 3.0 T MR imaging instrument (GE Healthcare, Chalfont St. Giles, UK). The fluorescence signals were acquired at a lateral position on the condition of 465-nm excitation filter and DsRed emission filter. Magnetic resonance signals were obtained with coronal and transected T2-weighted spin echo pulse sequences, and the following imaging parameters were used: TR = 2,500 ms, TE = 80 to approximately 90 ms, FOV = 40 mm, NEX = 2, and slice thickness = 2.0 mm. Then, these mice were killed. Then major organs, such as the liver, heart, lung, brain, and kidney and the tumor, were collected to perform further fluorescence imaging observation.
Immunofluorescence assay, Prussian blue staining, and ICP-MS analysis of major organs
Gastric cancer tissues were harvested, embedded in OCT reagent, and cryosectioned at −20 °C by a cryostat (CM1900, Leica). Twenty micrometer-thick sections from representative areas were directly stained with 1 μg/mL PE-conjugated CD90 antibody for 20 min at room temperature; then, the specimen were rinsed with 0.1% PBS and examined by a fluorescence microscope (Olympus IX71). Tumor specimen intravenously injected FMNPs were used as the negative control. The slices were also stained with Prussian blue and nuclear fast red and visualized under a light microscope (Olympus IX71).
The iron content of gastric cancer tissues with FMNP-labeled MSCs were quantitatively detected by inductively coupled plasma mass spectrometry system (ICP-MS; Thermo Elemental X7, Thermo Scientific). Major organs such as the liver, heart, lung, kidney, and brain and the tumor were excised from the mice, cut into small pieces, weighed separately, and digested by nitric acid (67%, ultrapure reagent grade) and hydrogen peroxide (30%, ultrapure reagent grade). Then, the iron contents in these samples were quantified by ICP-MS.
Hyperthermia therapy for nude mice with gastric cancer cells
Twenty nude mice loaded with gastric cancer were randomly divided into three groups: test group (10 mice, 5 × 106 FMNP-labeled MSCs cells plus external magnetic fields), control group I (10 mice, 5 × 106 FMNP-labeled MSCs cells ), and control group II (10 mice, FMNPs plus external magnetic fields). When the tumor size reached about 5 mm in diameter, nude mice were injected with FMNP-labeled MSCs and FMNPs via the tail vein, respectively. At 7 days post-injection, the mice in the test group and control group II were put under external alternating magnetic field with 63 kHz and 7 kA/m for 4 min  once a week for 1 month. The tumor sizes in the test group and control groups were measured every week.
Analysis of chemokine receptors in MSC cells and chemokine in MFC cells
MSCs with positive CXCR4 and CCR7 were accounted by flow cytometer. FITC-conjugated CXCR4 antibody (BioLegend) and FITC-conjugated CCR7 antibody (BioLegend) were used to sort for MSCs with CXCR4- and CCR7-positive cells. The amounts of CXCL12 and CCL19 in the supernatants of MFC cells were examined by commercial enzyme-linked immunosorbent assay kits (R & D System, Shanghai, China). The migration ability of MSCs was evaluated by using a 48-well modified Boyden chamber [33–35]. The polycarbonate filter (12-μm pore size, CN110416, Neuroprobe, Bethesda, MD, USA) was pre-coated with 5 μg/mL fibronectin (Sigma). MSCs were resuspended at 5 × 105/mL in the medium supplemented with 10% FBS and seeded in the upper chamber. Recombinant CXC ligand 12 (CXCL12; R&D System) and CCL19 (Peprotech, Rocky Hill, NJ, USA) were used as chemoattractants in the lower compartment. The chambers were incubated overnight at 37 °C. Results were expressed as the mean number of net migrated cells over control cells (basal migration without chemotactic stimulus), counted in ten microscope fields at high-power magnification (×1,000). Each experiment was performed in triplicate.
All data are presented in this paper as mean result ± SD. Statistical differences were evaluated using the t test and considered significant at P < 0.05 level. All data in this article were obtained from three independent experiments.
Results and discussion
Identification of cultured MSCs
Characterization of FMNPs
Evaluation of FMNP-labeled MSCs
Cytotoxicity of amino-modified FMNPs
FMNP-labeled MSCs for targeted imaging of gastric cancer cells in vivo
Immunofluorescence staining, Prussian blue staining, and ICP-MS analysis of major organs
The distribution of labeled MSCs in vivo was also analyzed by ICP-MS. The concentration of iron in the tumor tissues of the test group (8.4 μg/mg) was significantly higher than that of the control group (2.7 μg/mg), as shown in Figure 8c. For other organs such as the liver, heart, lung, brain, and kidney, no statistical difference was observed between the test group and the control group (P < 0.05). These data also demonstrate that FMNP-labeled MSCs mainly distribute in the site of gastric cancer tissues in vivo.
Hyperthermia therapy of subcutaneous tumors
Possible molecular mechanism
In conclusion, this study clearly confirms that FMNP-labeled MSCs could target gastric cancer cells in vivo and could be used as dual-modality contrast agents for in vivo gastric cancer's fluorescent imaging and magnetic resonance imaging. The prepared FMNPs had good biocompatibility and could be used for hyperthermia therapy of gastric cancer in vivo under a given external magnetic field. Regarding the mechanism of FMNP-labeled MSCs recognizing in vivo gastric cancer cells, we consider that CCL19/CCR7 and CXCL12/CXCR4 axis loops may be involved in this course. The concrete mechanism is under investigation. Therefore, FMNP-labeled MSCs have great potentials in applications such as detection, fluorescent imaging, magnetic resonance imaging, and simultaneous hyperthermia therapy for early gastric cancer in the near future.
This work is supported by the National Key Basic Research Program (973 Project) (no. 2010CB933901), National Natural Scientific Fund (no. 31100717), Shanghai Science and Technology Fund (10XD1406100), Special Project for Nanotechnology from Shanghai (1052 nm04100), Shanghai Jiao Tong University Innovation Fund for Postgraduates (no. AE340201), Shanghai Jiao Tong University Investment Fund for Excellent Doctoral Dissertation, and Scholarship Award for Excellent Doctoral Student Granted by Ministry of Education.
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