Europium-doped amorphous calcium phosphate porous nanospheres: preparation and application as luminescent drug carriers
© Chen et al; licensee Springer. 2011
Received: 11 June 2010
Accepted: 12 January 2011
Published: 12 January 2011
Calcium phosphate is the most important inorganic constituent of biological tissues, and synthetic calcium phosphate has been widely used as biomaterials. In this study, a facile method has been developed for the fabrication of amorphous calcium phosphate (ACP)/polylactide-block-monomethoxy(polyethyleneglycol) hybrid nanoparticles and ACP porous nanospheres. Europium-doping is performed to enable photoluminescence (PL) function of ACP porous nanospheres. A high specific surface area of the europium-doped ACP (Eu3+:ACP) porous nanospheres is achieved (126.7 m2/g). PL properties of Eu3+:ACP porous nanospheres are investigated, and the most intense peak at 612 nm is observed at 5 mol% Eu3+ doping. In vitro cytotoxicity experiments indicate that the as-prepared Eu3+:ACP porous nanospheres are biocompatible. In vitro drug release experiments indicate that the ibuprofen-loaded Eu3+:ACP porous nanospheres show a slow and sustained drug release in simulated body fluid. We have found that the cumulative amount of released drug has a linear relationship with the natural logarithm of release time (ln(t)). The Eu3+:ACP porous nanospheres are bioactive, and can transform to hydroxyapatite during drug release. The PL properties of drug-loaded nanocarriers before and after drug release are also investigated.
The development of multifunctional nanosystems, for maximum therapeutic benefit including early diagnoses of the diseases and delivery of suitable therapeutic drugs, holds a promise for the future of clinical treatment to enhance therapeutic efficacy [1, 2]. Therefore, it is highly desirable to develop novel methods that can achieve simultaneous in vivo imaging and treatment based on nanotechnology. Nanoparticles show unique size-dependant physical and chemical properties and have great potential for clinical use [3, 4]. Dual or multifunctional nanosystems can be constructed based on nanostructures with well-designed structures and constituents, which are simultaneously capable of diagnosis and treatment . Many kinds of nanostructures have been fabricated from a multitude of materials and used in bio-imaging, including quantum dots [6–8], silica particles , gold , carbon nanotubes , dendrimers [12–14], magnetic nanoparticles [15–18], and so on. However, in the search for the nanosystems for bio-imaging and therapy, a couple of the major concerns are their biodegradability and toxicity [19–21]. To date, the development of multifunctional inorganic nanosystems with both biocompatible and biodegradable properties has been little reported, and more research is needed in this regard.
Calcium phosphates including hydroxyapatite (HAp) are the most important inorganic constituents of biological tissues such as bone and tooth [22–25]. Thus, synthetic calcium phosphates are of great significance because of their biodegradability and biocompatibility, and have been investigated for applications in bone repair/tissue engineering [26, 27], drug loading and release [28, 29], gene delivery [30, 31], and other biomedical areas. Owing to its chemical nature, calcium phosphate nanostructures may serve as an ideal candidate for both bio-imaging and drug delivery. The investigation on rare earth-doped calcium phosphates has become a hot research topic [32–37]. However, up to now, little work has been reported on dual or multifunctional calcium phosphate nanostructures for biomedical applications. HAp, a kind of chemically stable calcium phosphate, has been used for drug storage and luminescence . The development of bi-functional nanosystems of other calcium phosphates such as amorphous calcium phosphate (ACP) is still scarce. Compared with HAp, ACP is bioactive with better biodegradability, and can promote osteoblast adhesion and osteoconductivity [39, 40].
In this article, the authors report a facile method for the fabrication of ACP/polylactide-block-monomethoxy(polyethyleneglycol) (PLA-mPEG) hybrid nanoparticles and ACP porous nanospheres. ACP is an important kind of calcium phosphate and is present in natural bone . PEG and PLA are widely used as biocompatible polymers and currently possess the approval of the US Food and Drug Administration for use in a variety of biomaterials applications [42, 43]. Europium doping was performed to enable photoluminescence (PL) function of ACP porous nanospheres. In vitro cytotoxicity experiments showed that the as-prepared porous nanospheres were biocompatible. In vitro drug loading and release experiments indicated that ibuprofen-loaded europium-doped ACP (Eu3+:ACP) porous nanospheres had a slow and sustained drug release profile in simulated body fluid (SBF). The cumulative amount of the released drug had a linear relationship with the natural logarithm of release time (ln(t)). The Eu3+:ACP porous nanospheres were bioactive, and could transform to HAp after drug release.
The block copolymer PLA-mPEG (M w = 8000 Da) was purchased from Jinan Daigang Co., Ltd., Jinan, China, and the molecular weight of the PEG segment was 5000 Da. Other chemicals were purchased from Sinopharm Chemical Reagent Co., Shanghai, China, and used as received without further purification. For the preparation of ACP/PLA-mPEG hybrid nanoparticles, 1.775 g of Na2HPO4 12H2O and 0.025 g of PLA-mPEG was dissolved in 60 mL of distilled water, and the pH value was adjusted to 10 using ammonia, followed by magnetic stirring for 1 h to form a clear solution. Then, 60 mL of calcium chloride aqueous solution containing 0.33 g of CaCl2 and 0.025 g of PLA-mPEG was added dropwise (10 mL/min) to the above solution, and the pH value was maintained at 10 by slow addition of ammonia. The white precipitate was collected and washed by centrifugation-redispersion cycles with distilled water and ethanol. For the preparation of ACP porous nanospheres, 0.1 g of the as-obtained precipitate was transferred into a 70-mL Teflon autoclave with 50 mL N, N-dimethylformamide (DMF) and treated at 200°C for 1 h by a microwave-solvothermal system (MDS-10, Sineo, Shanghai, China). The product was washed with distilled water and ethanol and dried at 60°C. For the preparation of europium-doped Eu3+:ACP porous nanospheres, europium nitrate aqueous solution was added into the calcium source solution before mixing with phosphate source solution. The doping concentration of Eu3+ was 1, 5, and 10 mol% relative to Ca2+.
PL measurements of Eu3+:ACP porous nanospheres were carried out on a spectrofluorometer (Fluorolog-3, Jobin Yvon, France) at room temperature.
Porcine iliac artery endothelial cells (PIECs) were obtained from the Institute of Biochemistry and Cell Biology (Chinese Academy of Sciences). All the culture media and reagents used in cytotoxicity tests were purchased from Gibco Life Technologies (USA). PIECs were seeded in 96-well flat-bottom microassay plates at a concentration of 2 × 104 cells/mL and cultured with 200 μL/well Dulbecco's Modified Eagle's Medium (DMEM) with 10% fetal serum, 100 U/mL penicillin, and 100 U/mL streptomycin for 48 h in a humidified incubator (BB-15, Heraeus, Germany) with 5% CO2 at 37°C. The samples were diluted with DMEM without fetal bovine serum at a concentration of 6 mg/mL. Then, 50, 100, and 150 μL of each sample solution was added into each well, and the cells were cultured for 24 h. To evaluate cytotoxicity, cell viability was quantified using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (Sigma, USA) and Enzyme-labeled Instrument (MK3, Thermo, USA). Data were measured in three independent parallel experiments, and all data points were plotted as means ± standard deviation (SD) (n = 3).
The typical drug loading and in vitro drug release experiments were performed as follows: 0.5 g of dried powder of Eu3+:ACP porous nanospheres was added into 50 mL hexane solution with an ibuprofen concentration of 40 mg/mL. The suspension was then stirred for 24 h in a sealed vessel at 37°C. The Eu3+:ACP porous nanospheres with loaded drug was centrifuged, and 2 mL supernatant was analyzed by UV-Vis absorption spectroscopy at a wavelength of 263 nm to calculate the ibuprofen storage. The drug loaded Eu3+:ACP porous nanospheres were washed with fresh hexane, dried at 60°C in air, and compacted into disks (0.3 g each, diameter 10 mm) at a pressure of 3 MPa. Each disk was immersed into 200 mL of SBF at 37°C under shaking at a constant rate using a desk-type oscillator (THI-92A, China). Two milliliter of solution was removed for UV-Vis analysis at 263 nm at given time intervals to measure the amount of ibuprofen released, and this quantity of solution was replaced with the same volume of fresh SBF.
Transmission electron microscopy (TEM) micrographs were obtained using a JEOL JEM 2100 field emission electron microscope. X-ray diffraction (XRD) patterns were recorded using a Rigaku D/max 2550 V X-ray diffractometer with a graphite monochromator (Cu K α radiation, λ = 1.54178 Å). Thermogravimetry (TG) curves were obtained at a heating rate of 10°C in nitrogen using a STA 409/PC simultaneous thermal analyzer (Netzsch, Germany). The Brunauer-Emmett-Teller (BET) surface area and pore size distribution were measured with an accelerated surface area and porosimetry system (ASAP 2010).
Results and discussion
We investigated the drug loading and release behaviors of Eu3+:ACP porous nanospheres using a typical anti-inflammatory drug, ibuprofen. The drug loading capacity of Eu3+:ACP porous nanospheres was calculated from the absorbance values of ibuprofen hexane solution before and after drug loading. The drug loading capacity of Eu3+:ACP porous nanospheres reached 70 mg/g carrier.
This result is similar to that of our previous report on the drug release system of porous microspheres of calcium silicate hydrate . For the drug delivery system of Eu3+:ACP porous nanospheres, the constant values of A and k are determined to be 15.47 and 19.46, respectively, with a regression factor of 0.999. Figure 8b shows the XRD pattern of the drug delivery system of Eu3+:ACP porous nanospheres after drug release in SBF, from which one can see that the product after drug release was HAp instead of ACP, indicating that the phase transformation from ACP to HAp occurred during the drug release process in SBF.
It is well acknowledged that the Higuchi model (C = K·t 1/2) can well describe the kinetics of drug release from carrier materials [49–51], with a linear relationship between the cumulative amount of the released drug (C) and the square root of time (t 1/2), and that the drug release is governed by a diffusion process. However, for the drug delivery system of Eu3+:ACP porous nanospheres, Eu3+:ACP porous nanospheres are bioactive, and they can transform from ACP to HAp in SBF solution during the drug release process. Therefore, for the drug delivery system of Eu3+:ACP porous nanospheres in SBF, the drug release kinetics is different from that of the model for common carrier materials.
In a previous study , the authors prepared HAp nanostructured porous hollow ellipsoidal capsules which were constructed by nanoplate networks using inorganic CaCO3 template. CaCO3 ellipsoids were synthesized by the reaction between Ca(CH3COO)2 and NaHCO3 in mixed solvents of water and ethylene glycol at room temperature, and they were used as the Ca2+ source and cores. Then, the PO4 3- source was added to react with CaCO3 to form a HAp shell on the surface of CaCO3 ellipsoids. Dilute acetic acid was used to remove the remaining CaCO3 cores. The drug loading and release behaviors of HAp hollow ellipsoidal capsules were also investigated. The ibuprofen-loaded HAp hollow ellipsoidal capsules showed a slow and sustained release of ibuprofen in SBF. A linear relationship between the cumulative amount of the released ibuprofen and the square root of time was found for the first 12 h. Compared with HAp nanostructured hollow ellipsoidal capsules, the Eu3+:ACP porous nanosphere drug delivery system also showed a slow and sustained drug release profile. However, the IBU/Eu3+:ACP porous nanosphere drug delivery system exhibited a faster drug release rate than that of HAp nanostructured hollow ellipsoidal capsules. On the other hand, the drug release kinetics is different for the two drug delivery systems. For the IBU/Eu3+:ACP porous nanosphere drug delivery system, the cumulative amount of the released drug has a linear relationship with the natural logarithm of release time (ln(t)), instead of the square root of time. However, for IBU/HAp nanostructured hollow ellipsoidal capsule drug delivery system, a linear relationship between the cumulative amount of the released ibuprofen and the square root of time was found. The different drug release properties for the two drug delivery systems may be explained by the different chemical compositions, structures, and morphologies of the two samples.
Figure 8c shows PL emission spectra of drug-loaded Eu3+:ACP porous nanospheres before and after drug release. The characteristic emission peaks are still obvious in the emission spectra for both the samples. There were essentially no shifts in the spectral positions for the characteristic emission peaks, but the PL peak relative intensity and the shape of peaks changed after drug loading. The change of PL properties may be explained by the effect of ibuprofen. However, after in vitro drug release, it is worth noting that the intensities of the emission peaks increased. This phenomenon may be explained by the transformation of carrier material from ACP to HAp during the process of drug release in SBF.
The as-prepared Eu3+:ACP porous nanospheres have a porous structure, which is favorable for a sustained drug release. The Eu3+:ACP porous nanospheres empowered by luminescent properties show a great potential for applications in both drug delivery and in vivo bioimaging. Considering the biocompatible and biodegradable nature, Eu3+:ACP porous nanospheres are a new kind of promising biomaterial.
Calcium phosphate is the most important inorganic constituent of biological hard tissues. ACP, as one of the most important calcium phosphates, is bioactive with biocompatibility and biodegradability. In this study, the authors report a facile method for the preparation of ACP/PLA-mPEG hybrid nanoparticles, which were successfully used as the precursor for the preparation of ACP porous nanospheres. PL function of ACP porous nanospheres was achieved by europium doping. The BET-specific surface area, the BJH-desorption cumulative pore volume, and the average pore size were 126.7 m2/g, 0.53 cm3/g, and 16.7 nm, respectively, for the Eu3+:ACP porous nanospheres. The experimental results of PL, cytotoxicity, as well as in vitro drug loading and release showed that the as-prepared Eu3+:ACP porous nanospheres were biocompatible and bioactive with favorable properties of PL, drug loading and drug release, implying that Eu3+:ACP porous nanospheres are a new kind of promising biomaterial with bi-functions of both luminescence and drug delivery.
amorphous calcium phosphate
porcine iliac artery endothelial cells
simulated body fluid.
Financial supports from the Science and Technology Commission of Shanghai (1052nm06200), Shanghai-Unilever Research and Development Fund (09520715200), the National Natural Science Foundation of China (50772124, 50821004), and the State Key Laboratory of High Performance Ceramics and Superfine Microstructure are gratefully acknowledged.
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