Biocompatibility of hydrophilic silica-coated CdTe quantum dots and magnetic nanoparticles
© Ruan et al; licensee Springer. 2011
Received: 28 December 2010
Accepted: 6 April 2011
Published: 6 April 2011
Fluorescent magnetic nanoparticles exhibit great application prospects in biomedical engineering. Herein, we reported the effects of hydrophilic silica-coated CdTe quantum dots and magnetic nanoparticles (FMNPs) on human embryonic kidney 293 (HEK293) cells and mice with the aim of investigating their biocompatibility. FMNPs with 150 nm in diameter were prepared, and characterized by high-resolution transmission electron microscopy and photoluminescence (PL) spectra and magnetometer. HEK293 cells were cultured with different doses of FMNPs (20, 50, and 100μ g/ml) for 1-4 days. Cell viability and adhesion ability were analyzed by CCK8 method and Western blotting. 30 mice were randomly divided into three groups, and were, respectively, injected via tail vein with 20, 60, and 100 μg FMNPs, and then were, respectively, raised for 1, 7, and 30 days, then their lifespan, important organs, and blood biochemical parameters were analyzed. Results show that the prepared water-soluble FMNPs had high fluorescent and magnetic properties, less than 50 μg/ml of FMNPs exhibited good biocompatibility to HEK293 cells, the cell viability, and adhesion ability were similar to the control HEK293 cells. FMNPs primarily accumulated in those organs such as lung, liver, and spleen. Lung exposed to FMNPs displayed a dose-dependent inflammatory response, blood biochemical parameters such as white blood cell count (WBC), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), displayed significant increase when the FMNPs were injected into mice at dose of 100μg. In conclusion, FMNPs exhibit good biocompatibility to cells under the dose of less than 50 μg/ml, and to mice under the dose of less than 2mg/kg body weight. The FMNPs' biocompatibility must be considered when FMNPs are used for in vivo diagnosis and therapy.
Up to date, nanomaterials and nanotechnology have shown great potentials in disease diagnosis and therapy [1–7]. For example, a broad range of nanoscale inorganic particles including magnetic nanoparticles (MNPs) and quantum dots (QDs) have been systematically investigated for their unique physical, chemical properties, and their potential application in bio-detection, molecular imaging, and photothermal therapy of tumors [8–16]. Especially, MNPs have been used for magnetic resonance imaging (MRI), gene delivery, cell separation and cancer hyperthermia [17–19], and magnetic targeting, which provides an alternative method for targeted drug delivery systems to the desired location [20–22]. Up to date, QDs have been subjected to intensive investigations due to their unique properties and potential application prospect [23, 24]. Several methods have been developed to synthesize water-soluble QDs for use in biological relevant studies [25, 26]. For example, QDs have been used successfully in cellular imaging , immunoassays , DNA hybridization , optical barcoding , and drug carrier . QDs provide a new functional platform for bioanalytical sciences and biomedical engineering.
In our previous study, we successfully prepared fluorescent MNPs composed of silica-coated CdTe QDs and magnetic nanoparticles (FMNPs), and used as-prepared FMNPs to label biomolecules for tumor imaging and hyperthermia therapy, and actively investigated their potential applications in bio-labeling, bio-separation, immunoassay, target imaging, and pathogenic detection [32–36]. Up to date, there were many reports which closely associated with preparation of fluorescent MNPs and their applications in biomedical engineering [37–47]. However, few report is closely associated with biocompatibility of fluorescent MNPs [48, 49]. With the rapid development of nanotechnology, nanomaterials' biosafety has attracted more and more attention [50–56].
Herein, we investigated the effects of hydrophilic silica-coated CdTe QDs and magnetic nanoparticles (FMNPs) on human embryonic kidney 293 cells (HEK293) and mice with the aim of evaluating biocompatibility of prepared FMNPs. Our results showed that prepared FMNPs exhibited good biocompatibility under a special dose, and display great potential in applications such as in vivo molecular imaging, and hyperthermia therapy as well as in vitro pathogen separation and detection.
Synthesis and characterization of FMNPs
FMNPs were prepared using improved method based on our previous reported method . First, Fe3O4@Polystyrene (Fe3O4/PS) nanospheres were prepared according to Ref. , CdTe QDs were prepared according to our previous method , then CdTe QDs were modified to the surface of Fe3O4@Polystyrene (Fe3O4/PS) nanospheres, resultant CdTe QDs-covered MNPs were modified with silica shell using reverse microemulsion method, finally prepared FMNPs were washed with PBS (pH 7.4), isolated, and then saved for usage. Prepared FMNPs were characterized using scanning electron microscopy (SEM), high-resolution transmission electron microscopy (TEM, JEOL JEM2010, at 200 kV), the photoluminescence (PL) spectra (Perkin Elmer LS 55 spectrofluorimeter), and superconducting quantum interference device (SQUID) magnetometer (Quantum Design, PPMS-9T).
Observation of cells incubated with FMNPs
HEK293 cells were seeded on cover slips for overnight, and were treated with medium with FMNPs (50 μg/ml) for 3 h. Then, the cells were rinsed with distilled water and stained with Prussian blue according to protocol. The HEK 293 cells were not treated with medium with FMNPs as the control. Then, the samples were attached to glass plates using mounting medium, and then were observed under an optical microscope (Olympus IX71).
Fluorescent microscopy observation
HEK293 cells incubated with FMNPs (50 μg/ml) were collected, and fixed with 2.5% glutaraldehyde for 30 min, then, were incubated with 1 mM Hoechst 33258 in PBS (pH 7.4) for 5 min, and then were washed with PBS (pH 7.4) for three times, finally these cells were observed under fluorescence microscope (NIKON TS100-F).
Flow cytometry analysis
HEK293 cells were treated without or with 20 μg/ml of FMNPs for 24 h, and were collected. After washing with PBS (pH 7.4), these cells were fixed with 70% ethanol/PBS for 30 min on ice. Approximately, 4 × 105 cells were centrifuged and re-suspended with PBS (pH 7.4), and then were analyzed by Calibur Flow Cytometers (BD Biosciences, Sunnydale, CA), the number of cells labeled with FMNPs were counted on.
TEM observation of endocytosis course of FMNPs
HEK 293 cells were treated with 50 μg/ml FMNPs for 24 h. Then these cells were collected and fixed with 2.5% glutaraldehyde solution, and then embedded with epoxy resin, finally, these cells were made into the ultra-thin slices, and then observed with TEM.
Effects of FMNPs on HEK 293 cells viability and proliferation assay
Detection of cell adhesion ability
Western blotting analysis of adhesive proteins
HEK293 cells were, respectively, incubated with FMNPs (20, 50, and 100 μg/ml) for 4 days, then they were collected and lysed in protein lysis buffer. Equal amounts of sample lysates were separated by sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and electrophoretically transferred onto polyvinylidene difluoride (PVDF) membranes (Millipore). The membrane was blocked with 0.1% BSA in Tris-Buffered Saline Tween-20 (TBST) buffer, and incubated overnight at 4°C with specific primary antibodies such as anti-fibronectin monoclonal antibody, anti-cyclin D3 antibody, anti-laminin antibody, anti-FAK antibody, and anti-β-actin antibody. Subsequently, the membrane was washed with TBST buffer and incubated with horseradish peroxidase-conjugated secondary antibodies. Enhanced chemiluminescence kits were used (Amersham, ECL kits) .
Effects of FMNPs on mice
All animal experiments were performed in compliance with the local ethics committee. Kunming mice (female 28-30 g, 4-5 weeks old) were obtained from the Shanghai LAC Laboratory Animal Co. Ltd., Chinese Academy of Sciences (Shanghai, China) and housed in positive-pressure air-conditioned units (25°C, 50% relative humidity) on a 12:12-h light/dark cycle. The mice were allowed to acclimate at this facility for 1 week before being used in the experiment. All mice were divided into three test groups with FMNPs (20, 60, and 100 μg), and one control group (0 μg), and each mouse was injected with the suspension with FMNPs via tail vein. Those mice were, respectively, killed at No. 1-, 7- and 30-day post-injection, their organs such as heart, liver, spleen, stomach, kidneys, lungs, and brain were collected immediately. Then, those organs were fixed with 10% formaldehyde, embedded in paraffin, were cut into 20-μm section, stained with hematoxylin and eosin, and were observed by light microscopy. Three mice without FMNPs treatment were used as control.
After mice treated with different doses of FMNPs (20, 60, and 100 μg) for 1, 7, and 30 days, the blood were, respectively, collected in potassium EDTA collection tubes using a standard saphenous vein blood collection technique and were analyzed for standard hematology markers: red blood cell count (RBC), hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count, and white blood cell count (WBC). In order to separate serum, blood samples were centrifuged twice at 3000 rpm for 10 min. Liver function was evaluated with serum levels of total bilirubin levels (TBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkalinephosphatase (ALP). Nephrotoxicity was determined by blood urea nitrogen (BUN) and creatinine (Cr). The enzyme of lactate dehydrogenase (LDH) was assayed for evaluating cardiac damage. Albumin (ALB) was assayed as one parameter of damage of tissue or inflammation. These parameters were all assayed using a Hitachi 7600 Automatic Biochemical Autoanalyzer.
Each experiment was repeated three times in duplicate. The results were presented as mean ± SD. Statistical differences were evaluated using the t test and considered significance at P< 0.05.
Results and discussion
Characterization of FMNPs
It is well known that MNPs can quench the fluorescent signal of QDs, which is because MNPs can absorb strongly the light emitted by QDs [42–44]. How to obtain FMNPs with high fluorescent signal and magnetic intensity is a great technical challenge. In order to prepare high performance of FMNPs, we improved the synthesis method based on our previous method . We selected Fe3O4/PS nanospheres to replace Fe3O4 nanoparticles with the aim of reducing the QDs' fluorescence quenching caused by MNPs. The main procedure is as follows: first, fully mix Fe3O4/PS (100 nm average diameter) with CdTe QDs (3.5 nm average diameter) according to the ratio of 10:1, secondly, use ammonia-catalyzed hydrolysis method of tetraethyl orthosilicate (TEOS) to prepare silica-covered on the nano-composites composed of Fe3O4/PS MNPs and CdTe QDs. We optimized the FMNPs' reaction condition based on reverse micro-emulsion method through the Ternary phase diagram [48–50], finally obtained hydrophilic silica-coated CdTe QDs and MNPs with high fluorescent signal and magnetic intensity.
Localization of FMNPs inside cells
Effects of FMNPs on cell viability
Effects of FMNPs on cell adhesion
Effects of FMNPs on lifespan of mice
Regarding the effects of FMNPs on lifespan of mice, we used tail vein injection pathway to evaluate the in vivo toxicity of FMNPs. The mice were injected with 200 μl of FMNPs with the concentrations of 0 mg/ml (control group), 0.1 mg/ml (low dose group, LD), 0.3 mg/ml (medium dose group, MD), and 0.5 mg/ml (high dose group, HD). After cultured for 1 day, 1 week, and 1 month, the mice were killed by the method of cervical vertebra displace, and then used histopathology to evaluate inflammation degree of the mouse organs.
When the mice were injected with FMNPs of 20 and 60 μg, mice did not die, also did not show obvious clinical toxic signs, and then the body weight also increased accordingly. However, 3 of 9 mice injected with 100 μg FMNPs died (0 in the 1-day group, 2/3 in the 7-day group and 1/3 in the 30-day group). All mice deaths occurred in No. 1-30days after injection of the FMNPs. Before death, mice appeared lethargy, inactivity, and body-weight losses. In addition, the mice treated with 100 μg of FMNPs for 1day appeared weakness, and lost 10% of body weights within first week, these symptoms disappeared after 1week, mice could eat food normally, and their body-weight increased.
Effects of FMNPs on important organs
Regarding the biodistribution of FMNPs in mice, as we observed, FMNPs mainly located in lung, liver, and spleen, no FMNPs was found in the brain tissues, which highly suggest that FMNPs cannot get through blood-brain barrier. Few FMNPs was observed in kidney of mice, which highly suggest that FMNPs is very difficult to be exited out by pathway of kidney, we speculate that FMNPs are mainly expelled out by liver secretion into bile tract system as shown in Figure 10c.
Effects of FMNPs on blood biochemical parameters
Blood biochemical parameters that reflect the hepatic function and renal function were further investigated on No. 1, 7 and 30 days. Serum ALT or AST levels were increased with FMNPs' administration at 100 μg, while no increase was observed at 20 and 60 μg (Figure 11b, c). It illustrated that higher dose (100 μg, 2mg/kg body weight) of FMNPs influence the hepatic functions of mice. There were no significant changes for renal functions parameters such as urea nitrogen and others biochemical indexes after administration of FMNPs.
In this study, we also investigated the effects of as-prepared FMNPs on human fibroblast cells, gastric cancer MGC803 cells, and gastric mucous GES-1 cells, and obtained similar results, therefore, in this article, we did not display all data.
FMNPs were successfully prepared by improved reverse micro-emulsion method. The prepared FMNPs possess strong fluorescent signal and high magnetization saturation intensity. FMNPs exhibited good biocompatibility to human normal cells with the concentration of 50 μg/ml FMNPs in cell medium, and to mice injected within the dose of 60 μg(2mg/kg. body weight) FMNPs. Conversely, when the dose of FMNPs reach or overrun 100 μg/ml in cell medium, or 60 μg to be injected into mice, cells and mice exhibited obvious toxic signs. Therefore, we strongly suggest that FMNPs can be safely used for cell labeling and in vivo tracking and imaging within 60 μg, and do not affect cell function and mice lifespan. Further work will focus on the surface modification of prepared FMNPs to enhance their biocompatibility. We believe that these prepared FMNPs have great potential in applications such as bio-labeling, bio-separation, immunoassay, in vivo targeting imaging and pathogenic detections.
blood urea nitrogen
Dulbecco's Phosphate Buffered Saline
human embryonic kidney 293
magnetic resonance imaging
mean corpuscular hemoglobin
mean corpuscular hemoglobin concentration
mean corpuscular volume
red blood cell count
scanning electron microscopy
sodium dodecylsulfate polyacrylamide gel electrophoresis
superconducting quantum interference device
total bilirubin levels
Tris-Buffered Saline Tween-20
white blood cell count.
This work was supported by the National Natural Science Foundation of China (No. 20803040 and No. 20471599), Chinese 973 Project (2010CB933901), New Century Excellent Talent of Ministry of Education of China (NCET-08-0350), Doctorial Position Budget (20070248050), Special Infection Diseases Key Project of China (2009ZX10004-311), Shanghai Science and Technology Fund (10XD1406100 and 1052nm04100) and Shanghai Jiao Tong University Innovation Fund for Postgraduates.
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