Recently there has been a wide concern on inorganic nanoparticles as drug delivery carriers. CaCO 3 particles have shown promising potential for the development of carriers for drugs, but little research had been performed regarding their safe dosage for maximizing the therapeutic activity without harming biosystems. In this study, we assessed the biological safety of porous spherical CaCO 3 microparticles on Hela cells. The reactive oxygen species (ROS), glutathione (GSH), carbonyl content in proteins (CCP), DNA-protein crosslinks (DPC) and cell viability were measured. Results showed that with the exposure concentration increase, ROS and CCP in Hela cells presented a significant increase but GSH contents in Hela cells and cell viability showed a significant decrease respectively compared with the control. DPC coefficient ascended, but no statistically significant changes were observed. The results indicated that porous spherical CaCO 3 microparticles may induce oxidative damage to Hela cells. But compared with other nanomaterials, porous spherical CaCO 3 appeared to have good biocompatibility. The results implied that porous spherical calcium carbonate microparticles could be applied as relatively safe drug vehicles, but with the caveat that the effect of high dosages should not be ignored when attempting to maximize therapeutic activity by increasing the concentration.
M. P. Ginebra, T. Traykova and J. A. Planell, “Calcium Phosphate Cements as Bone Drug Delivery Systems: A Review,” Journal of Controlled Release, Vol. 113, No. 2, 2006, pp. 102-110. doi:10.1016/j.jconrel.2006.04.007
G. F. Paciotti, D. G. I. Kingston and L. Tamarkin, “Colloidal Gold Nanoparticles: A Novel Nanoparticle Platform for Developing Multifunctional Tumor-Targeted Drug Delivery Vectors,” Nanobiotechnology, Drug Development Research, Vol. 67, No. 1, 2006, pp. 47-54.
A. Bianco, K. Kostarelos and M. Prato, “Applications of Carbon Nanotubes in Drug Delivery,” Current Opinion in Chemical Biology, Vol. 9, No. 6, 2005, pp. 674-679. doi:10.1016/j.cbpa.2005.10.005
E. J. Anglin, L. Cheng, W. R. Freeman and M. J. Sailor, “Porous Silicon in Drug Delivery Devices and Materials,” Advanced Drug Delivery Reviews, Vol. 60, No. 11, 2008, pp. 1266-1277. doi:10.1016/j.addr.2008.03.017
T. K. Jain, M. A. Morales, S. K. Sahoo, D. L. Leslie-Pelecky and V. Labhasetwar, “Iron Oxide Nanoparticles for Sustained Delivery of Anticancer Agents,” Molecular pharmaceutics, Vol. 2, No. 3, 2005, pp. 194-205. doi:10.1021/mp0500014
Y. Li, D. Liu, H. Ai, Q. Chang, D. Liu, Y. Xia, S. Liu, N. Peng, Z. Xi and X. Yang, “Biological Evaluation of Layered Double Hydroxides as Efficient Drug Vehicles,” Nanotechnology, Vol. 21, No. 10, 2010, p. 105101.
W. Wei, G. Ma, G. Hu, D. Yu, T. Mcleish, Z. Su and Z. Shen, “Preparation of Hierarchical Hollow CaCO3 Particles and the Application as Anticancer Drug Carrier,” Journal of the American Chemical Society, Vol. 130, No. 47, 2008, pp. 15808-15810. doi:10.1021/ja8039585
Q. Zhao, B. Han, Z. Wang and C. Gao, “Hollow Chitosan-Alginate Multilayer Microcapsules as Drug Delivery Vehicle: Doxorubicin Loading and in Vitro and in Vivo Studies,” Nanomedicine: Nanotechnology, Biology, and Medicine, Vol. 3, No. 1, 2007, pp. 63-74. doi:10.1016/j.nano.2006.11.007
G. B. Sukhorukov, D. V. Volodkin and A. M. Günther, A. I. Petrov, D. B. Shenoy and H. M?hwald, “Porous Calcium Carbonate Microparticles as Templates for Encapsulation of Bioactive Compounds,” Journal of Materials Chemistry, Vol. 14, 2004, pp. 2073-2081. doi:10.1039/b402617a
Y. Ueno, H. Futagawa, Y. Takagi, A. Ueno and Y. Mizushima, “Drug-Incorporating Calcium Carbonate Nanoparticles for a New Delivery System,” Journal of Controlled Release, Vol. 103, No. 1, 2005, pp. 93-98. doi:10.1016/j.jconrel.2004.11.015
C. Wang, C. He, Z. Tong, X. Liu, B. Ren and F. Zeng, “Combination of Adsorption by Porous CaCO3 Microparticles and Encapsulation by Polyelectrolyte Multilayer Films for Sustained Drug Delivery,” International Journal of Pharmaceutics, Vol. 308, No. 1-2, 2006, pp. 160-167. doi:10.1016/j.ijpharm.2005.11.004
C. Peng, Q. Zhao and C. Gao, “Sustained Delivery of Doxorubicin by Porous CaCO3 and Chitosan/Alginate Multilayers-Coated CaCO3 Microparticles,” Colloids and Surfaces A: Physicochemical and Engineering, Vol. 353, No. 2-3, 2010, pp. 132-139. doi:10.1016/j.colsurfa.2009.11.004
C. Buzea, I. I. Pacheco and K. Robbie, “Nanomaterials and Nanoparticles: Sources and Toxicity,” Biointerphases, Vol. 2, No. 4, 2007, pp. 17-71. doi:10.1116/1.2815690
I. Linkov, F. Kyle and M. Lisa, “Nanotoxicology and Nanomedicine: Making Hard Decisions,” Nanomedcine, Vol. 2, No. 2, 2008, pp. 167-171. doi:10.1016/j.nano.2008.01.001
H. Meng, Z. Chen, G. Xing, H. Yuan, C. Chen, F. Zhao, C. Zhang and Y. Zhao, “Ultrahigh Reactivity Provokes Nanotoxicity: Explanation of Oral Toxicity of Nano-Copper Particles,” Toxicology Letters, Vol. 175, No. 1-3, 2007, pp. 102-110. doi:10.1016/j.toxlet.2007.09.015
W. Lin, Y. W. Huang, X. D. Zhou and Y. Ma, “In Vitro of Silica Nanoparticles in Human Lung Cancer Cells,” Toxicology and Applied Pharmacology, Vol. 217, No. 3, 2006, pp. 252-259. doi:10.1016/j.taap.2006.10.004
K. Govindaraju, J. Shan, K. Levesque, S. N. A. Hussain, W. S. Powell and D. H. Eidelman, “Nitration of Respiratory Epithelial Cells by Myeloperoxidase Depends on Extracellular Nitrite,” Nitric Oxide, Vol. 18, No. 3, 2008, pp. 184-194. doi:10.1016/j.niox.2008.01.004
M. Audebert, B. Salles and P. Calsou, “Effect of Double-Strand Break DNA Sequence on the PARP-1 NHEJ Pathway,” Biochemical and Biophysical Research Communications, Vol. 369, No. 3, 2008, pp. 982-988. doi:10.1016/j.bbrc.2007.11.132
S. A. Mouron, C. A. Grillo, F. N. Dulout and C. D. Golijow, “Induction of DNA Strand Breaks, DNA-Protein Crosslinks and Sister Chromatid Exchanges by Arsenite in a Human Lung Cell Line,” Toxicology in Vitro, Vol. 20, No. 3, 2006, pp. 279-285. doi:10.1016/j.tiv.2005.07.005
K. Pulskamp, S. Diabate and H. F. Krug, “Carbon Nanotubes Show No Sign of Acute Toxicity but Induce Intracellular Reactive Oxygen Species in Dependence on Contaminants,” Toxicology Letters, Vol. 168, No. 1, 2007, pp. 58-74. doi:10.1016/j.toxlet.2006.11.001
Y. S. Liu, C. M. Li, Z. S. Lu and S. M. Ding, “Studies on Formation and Repair of Formaldehyde-Damaged DNA by Detection of DNA-Protein Crosslinks and DNA Breaks,” Frontiers in Bioscience, Vol. 11, 2006, pp. 991-997. doi:10.2741/1856
A. R. Collins, “The Comet Assay for DNA Damage and Repair,” Molecular Biotechnology, Vol. 26, No. 3, 2004, pp. 249-261. doi:10.1385/MB:26:3:249
S. Chen, L. S. Chang and Y. Wei, “Oxidative Damage to Proteins and Decrease of Antioxidant Capacity in Patients with Varicocele,” Free Radical Biology & Medicine, Vol. 30, No. 11, 2001, pp. 1328-1334. doi:10.1016/S0891-5849(01)00536-6
G. Oberdorster, E. Oberdorster and J. Oberdorster, “Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles,” Environ Health Perspect, Vol. 113, 2005, pp. 823-839. doi:10.1289/ehp.7339
D. K. Das, N. Maulik, M. Sato and P. S. Ray, “Reactive Oxygen Species Function as Second Messenger during Ischemic Preconditioning of Heart,” Molecular and Cellular Biochemistry, Vol. 196, No. 1-2, 1999, pp. 59-67. doi:10.1023/A:1006966128795
V. E. Kagan, Y. Y. Tyurina, V. A. Tyurin, N. V. Konduru, A. I. Potapovich, A. N. Osipov, E. R. Kisin, D. Schwegler-Berry, R. Mercer, V. Castranova and A. A. Shvedova, “Direct and Indirect Effects of Single Walled Carbon Nanotubes on RAW 264.7 Macrophages: Role of Iron,” Toxicology Letters, Vol. 165, No. 1, 2006, pp. 88-100. doi:10.1016/j.toxlet.2006.02.001
M. T. Zhu, W. Y. Feng, B. Wang, T. C. Wang, Y. Q. Gu, M. Wang, H. Q. Yang, Y. L. Zhao and Z. F. Chai, “Comparative Study of Pulmonary Responses to Nano-and Submicron-Sized Ferric Oxide in Rats,” Toxicology, Vol. 247, No. 2-3, 2008, pp. 102-111. doi:10.1016/j.tox.2008.02.011
T. C. Long, N. Saleh, R. D. Tilton, G. V. Lowry and B. Veronesi, “Titanium Dioxide (P25) Produces Reactive Oxygen Species in Immortalized Brain Microglia (BV2): Implications for Nanoparticle Neurotoxicity,” Environmental Science and Technology, Vol. 40, No. 14, 2006, pp. 4346-4352. doi:10.1021/es060589n
B. Wang, W. Y. Feng, M. Wang, T. C. Wang, Y. Q. Gu, M. T. Zhu, H. Q. Yang, J. W. Shi, F. Zhang, Y. L. Zhao, Z. F. Chai, H. F.Wang and J. Wang, “Acute Toxicological Impact of Nano- and Submicro-Scaled Zinc Oxide Powder on Healthy Adult Mice,” Journal of Nanoparticle Research, Vol. 10, No. 2, 2008, pp. 263-276. doi:10.1007/s11051-007-9245-3
Y. Li, X. Tian, Z. Lu, C. Yang, G. Yang, X. Zhou, H. Yao, Z. Zhu, Z. Xi and X. Yang, “Mechanism for α-MnO2 Nanowire Induced Cytotoxicity in Hela Cells,” Journal of Nanoscience and Nanotechnology, Vol. 10, No. 1, 2010, pp. 1-8. doi:10.1166/jnn.2010.1719
B. P. Yu, “Cellular Defenses against Damage from Reactive Oxygen Species,” Physiological Reviews, Vol. 74, No. 1, 1994, pp. 139-162.
W. S. Lin, Y. W. Huang, X. D. Zhou and Y. F. Ma, “In Vitro Toxicity of Silica Nanoparticles in Human Lung Cancer Cells,” Toxicology and Applied Pharmacology, Vol. 217, No. 3, 2006, pp. 252-259. doi:10.1016/j.taap.2006.10.004
S. M. Hussain, K. L. Hess, J. M. Gearhart, K. T. Geiss and J. J. Schlager, “In Vitro Toxicity of Nanoparticles in BRL 3A Rat Liver Cells,” Toxicology in Vitro, Vol. 19, No. 7, 2005, pp. 975-983. doi:10.1016/j.tiv.2005.06.034
A. Mozumder, “Early Production of Radicals from Charged Particle Tracks in Water,” Radiation Research, Vol. 104, 1985, pp. S33-S39. doi:10.2307/3576629
S. Barker, M. Weinfeld and D. Murray, “DNA-Protein Crosslinks: Their Induction, Repair, and Biological Consequences,” Mutation Research, Vol. 589, No. 2, 2005, pp. 111-135. doi:10.1016/j.mrrev.2004.11.003
M. O. Bradley, I. C. Hsu and C. C. Harris, “Relationship between Sister Chromatid Exchange and Mutagenicity, Toxicity and DNA Damage,” Nature, Vol. 282, 1979, pp. 318-320. doi:10.1038/282318a0
M. O. Bradley and K. W. Kohn, “X-Ray Induced DNA Double Strand Break Production and Repair in Mammalian Cells as Measured by Neutral Filter Elution,” Nucleic Acids Research, Vol. 7, No. 3, 1979, pp. 793-804. doi:10.1093/nar/7.3.793
A. J. Fornace and J. B. Little, “Malignant Transformation by the DNA-Protein Crosslinking Agent Trans-Pt (II) Diamminedichloride,” Carcinogenesis, Vol. 1, No. 12, 1980, pp. 989-994. doi:10.1093/carcin/1.12.989
A. J. Fornace, “Detection of DNA Single-Strand Breaks Produced during the Repair of Damage by DNA-Protein Crosslinking Agents,” Cancer Research, Vol. 42, 1982, pp. 145-149.
O. Merk and G. Speit, “Significance of Formaldehyde-Induced DNA-Protein Crosslinks for Mutagenesis,” Environmental and Molecular Mutagenesis, Vol. 32, No. 3, 1998, pp. 260-268. doi:10.1002/(SICI)1098-2280(1998)32:3 3.0.CO;2-M
B. Halliwell and J. Gutteridge, “Free Radicals in Biology and Medicine,” Oxford University, Oxford, 1999.
I. D. Donnea, R. Rossib, D. Giustarinib, A. Milzania and R. Colomboa, “Protein Carbonyl Groups as Biomarkers of Oxidative Stress,” Clinica Chimica Acta, Vol. 329, No. 1-2, 2003, pp. 23-38. doi:10.1016/S0009-8981(03)00003-2