Chem-Eur J.2013 Jan;19(3):981-987

Highly stable amorphous calcium phosphate porous nanospheres: microwave-assisted rapid synthesis using ATP as phosphorus source and stabilizer, and their application in anticancer drug delivery.

Qi C, Zhu YJ*, Zhao XY, Lu BQ, Tang QL, Zhao J, Chen F.

State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China

 

ABSTRACT

Highly stable amorphous calcium phosphate (ACP) porous nanospheres with a relatively uniform size and an average pore diameter of about 10 nm have been synthesized by using a microwave-assisted hydrothermal method with adenosine 5’-triphosphate disodium salt (ATP) as the phosphorus source and stabilizer. The as-prepared ACP porous nanospheres have a high stability in the phosphate buffer saline (PBS) solution for more than 150 h without phase transformation to hydroxyapatite, and the morphology and size were essentially not changed. The important role of ATP and effects of experimental conditions on the formation of ACP porous nanospheres were also investigated. The ACP porous nanospheres were characterized by X-ray powder diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). This method is facile, rapid, surfactant-free and environmentally friendly. The as-prepared ACP porous nanospheres are efficient for anticancer drug (docetaxel) loading and release. The ACP porous nanosphere drug-delivery system with docetaxel shows a high ability to damage tumor cells, thus, is promising for the application in anticancer treatment.

PMID: 23180605

 

SUPPLEMENTS

Calcium phosphates, such as hydroxyapatite (HAP), as the main inorganic constituents of biological hard tissues such as bone and tooth, are important biomaterials with excellent biocompatibility.1 In recent years, calcium phosphate nanostructured materials with various morphologies have been prepared and investigated for applications in drug and gene delivery, tissue engineering and bone repair, and other biomedical areas.

Adenosine 5’-triphosphate disodium salt (ATP), as the most common energy carrier of the cell in biological systems, is advantageous in the synthesis of nanostructured biomaterials. It is now recognized that nucleic acids have the ability to control the growth and morphology of inorganic nanocrystals. These biomolecules are particularly appealing as a template and provide the means to modulate the growth and properties of the resulting nanocrystals. In recent years, the nucleic acid- and nucleotide-mediated synthesis of inorganic nanoparticles has been reported.2 ATP was used as a reactant to synthesize rodlike HAP nanocrystals by the hydrothermal method.3 ATP was also employed as a stabilizer for amorphous calcium phosphate (ACP) to inhibit the transformation from ACP to HAP in aqueous solution by poisoning
heterogeneous nucleation sites and/or binding to embryonic HAP nuclei to prevent their growth to the critical nucleus size.4 We have demonstrated surfactant-free microwave-assisted hydrothermal rapid synthesis of ACP porous nanospheres using ATP biomolecules as both a phosphorus source and a stabilizer. ATP biomolecules hydrolyze to produce PO43 ions in aqueous solution that react with Ca2+ ions to form ACP porous nanospheres under microwave hydrothermal conditions. ATP biomolecules can also act as a stabilizer for ACP nanostructures to inhibit the conversion of ACP to crystalline HAP. The reported synthetic strategy is facile, rapid, surfactant-free, and environmentally friendly.

 

Ying-Jie Zhu-1

Ying-Jie Zhu-2Figure 1. (a) SEM micrograph of ACP porous nanospheres synthesized using CaCl2·2H2O as the calcium source and ATP as both a phosphorus source and stabilizer by the microwave-assisted hydrothermal method at 120 oC for 10 min. (b) Docetaxel drug release curve in phosphate buffered saline (PBS) solution of docetaxel-loaded ACP porous nanospheres. The inset shows the cumulative drug-release percentage as a function of the natural logarithm of release time for the ACP porous nanosphere drug-delivery system. Reprinted from Chem. Eur. J. 2013, 19, 981-987.

 

Following this work, this research group has expanded the research and developed a new general synthetic strategy for a variety of calcium phosphate nanostructured materials using a variety of biocompatible phosphorus-containing biomolecules as the organic phosphorus sources.5–11 It is well known that the inorganic phosphorus sources such as phosphate ions are usually adopted for the synthesis of calcium phosphate materials. However, in the precursor solution with supersaturated calcium ions and phosphate ions, rapid nucleation and disordered growth of calcium phosphates may occur, and it is difficult to control the morphology and size of the products. Compared with the inorganic phosphorus sources, the use of phosphorus-containing biomolecules as the organic phosphorus sources has many advantages. Firstly, the phosphorus source exists in biomolecules and no phosphate ions exist in the pre-reaction solution, thereby avoiding the fast nucleation and disordered growth of calcium phosphates. Secondly, phosphorus-containing biomolecules generally require certain conditions such as heating in aqueous solution to hydrolyze for the formation of phosphate ions, and the hydrolysis conditions can be adjusted to control the hydrolysis rate of biomolecules, which determines the morphology, size, and structure of the products. Thirdly, phosphorus-containing biomolecules hydrolyze to form phosphate ions in a progressive manner, thereby avoiding the fast nucleation and disordered growth of calcium phosphates. On the other hand, the biomolecules can regulate the crystal growth of calcium phosphates. Fourthly, phosphorus-containing biomolecules are essentially non-toxic with high biocompatibility.

By adopting this new general synthetic strategy, this research group has synthesized various kinds of calcium phosphate nanostructured materials by the microwave-assisted hydrothermal method or the conventional hydrothermal method using a variety of biomolecues such as ATP,5,6 fructose 1,6-bisphosphate trisodium salt,7 creatine phosphate disodium salt,8,9 pyridoxal-5’-phosphate,10 and riboflavin-5’-phosphate monosodium salt.11 The as-prepared calcium phosphate nanostructured materials have a relatively high drug loading capacity and protein adsorption ability, as well as good sustained drug and protein release behaviors; thus they are promising for applications as anticancer drug carriers for controlled drug delivery.

 

References:

1. Dorozhkin, S. V.; Epple, M., Biological and Medical Significance of Calcium Phosphates. Angew. Chem. Int. Ed. 2002, 41, 3130-3146.

2. Berti, L.; Burley, G. A., Nucleic acid and nucleotide-mediated synthesis of inorganic nanoparticles. Nature Nanotechnol. 2008, 3, 81-87.

3. Cao, H.; Zhang, L.; Zheng, H.; Wang, Z., Hydroxyapatite Nanocrystals for Biomedical Applications. J. Phys. Chem. C 2010, 114, 18352–18357.

4. Posner, A. S.; Betts, F.; Blumenthal, N. C., Role of ATP and Mg in the stabilization of biological and synthetic amorphous calcium phosphates. Calcif. Tissue Res. 1976, 22, 208-212.

5. Qi, C.; Tang, Q.-L.; Zhu, Y. J.; Zhao, X. Y.; Chen, F., Microwave-assisted hydrothermal rapid synthesis of hydroxyapatite nanowires using adenosine 5′-triphosphate disodium salt as phosphorus source. Mater. Lett. 2012, 85, 71-73.

6. Zhao J.; Zhu Y. J.; Zheng J. Q.; Chen F.; Wu J., Microwave-assisted hydrothermal preparation using adenosine 5’-triphosphate disodium salt as a phosphate source and characterization of zinc-doped amorphous calcium phosphate mesoporous microspheres. J. Micropor. Mesopor. Mater. 2013,180:79-85.

7. Qi, C.; Zhu, Y. J.; Chen, F., Fructose 1,6-Bisphosphate Trisodium Salt as A New Phosphorus Source for the Rapid Microwave Synthesis of Porous Calcium-Phosphate Microspheres and their Application in Drug Delivery. Chem. Asian J. 2013, 8 (1), 88-94.

8.         Qi, C.; Zhu, Y.-J.; Lu, B.-Q.; Zhao, X.-Y.; Zhao, J.; Chen, F.; Wu, J., Hydroxyapatite Hierarchically Nanostructured Porous Hollow Microspheres: Rapid, Sustainable Microwave-Hydrothermal Synthesis by Using Creatine Phosphate as an Organic Phosphorus Source and Application in Drug Delivery and Protein Adsorption. Chem. Eur. J. 2013, 19 (17), 5332-5341.

9. Chen F.; Zhu Y. J.; Zhao X. Y.; Lu B. Q.; Wu J., Solvothermal synthesis of oriented hydroxyapatite nanorod/nanosheet arrays using creatine phosphate as phosphorus source. CrystEngComm 2013,15, 4527–4531.

10.       Zhao, X. Y.; Zhu, Y. J.; Qi, C.; Chen, F.; Lu, B. Q.; Zhao, J.; Wu, J., Hierarchical Hollow Hydroxyapatite Microspheres: Microwave-Assisted Rapid Synthesis by Using Pyridoxal-5′-Phosphate as a Phosphorus Source and Application in Drug Delivery. Chem. Asian J. 2013, 8 (6), 1313-1320.

11.       Zhao, X. Y.; Zhu, Y. J.; Chen, F.; Lu, B. Q.; Qi, C.; Zhao, J.; Wu, J., Hydrothermal synthesis of hydroxyapatite nanorods and nanowires using riboflavin-5′-phosphate monosodium salt as a new phosphorus source and their application in protein adsorption. CrystEngComm 2013, 15 (39), 7926-7935.

 

*Address for correspondence:

Shanghai Institute of Ceramics, Chinese Academy of Sciences

1295 Ding-Xi Road

Shanghai 200050

China

Tel: 0086-21-52413122

Fax: 0086-21-52413122

E-mail: y.j.zhu@mail.sic.ac.cn

Website: http://people.ucas.ac.cn/~yjzhu?language=en

 

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