Upsalite® is a mesoporous magnesium carbonate synthesized without using surfactants and therefore highly attractive from environmental and production economy points of view. The material has recently been suggested as drug delivery vehicle and as topical bacteriostatic agent. In order to continue exploring these and other bio-related applications of the material, primary biocompatibility studies are needed. Herein we present the first in vivo acute systemic toxicity and skin irritation analyses as well as in vitro cytotoxicity evaluations of Upsalite®. The material was found to be non-toxic for human dermal fibroblasts cells up to a concentration of 1000 μg/ml and 48 h exposure in contrast to the mesoporous silica material SBA-15, used as reference, which significantly affected cell viability at particle concentration of 500 and 1000 μg/ml after the same exposure time. Topical application of Upsalite® resulted in negligible cutaneous reactions in a
References
[1]
Lu, G.Q. and Zhao, X.S. (2004) Nanoporous Materials: Science and Engineering. World Scientific.
[2]
Fadeel, B., Kasemo, B., Malmsten, M. and Stromme, M. (2010) Nanomedicine: Reshaping Clinical Practice. Journal of Internal Medicine, 267, 2-8. http://dx.doi.org/10.1111/j.1365-2796.2009.02186.x
[3]
Vallet-Regí, M. (2010) Nanostructured Mesoporous Silica Matrices in Nanomedicine. Journal of Internal Medicine, 267, 22-43. http://dx.doi.org/10.1111/j.1365-2796.2009.02190.x
[4]
Vallhov, H., Kupferschmidt, N., Gabrielsson, S., Paulie, S., Stromme, M., Garcia-Bennett, A.E., et al. (2012) Adjuvant Properties of Mesoporous Silica Particles Tune the Development of Effector T Cells. Small, 8, 2116-2124.
http://dx.doi.org/10.1002/smll.201102620
[5]
Vallhov, H., Gabrielsson, S., Stromme, M., Scheynius, A. and Garcia-Bennett, A.E. (2007) Mesoporous Silica Particles Induce Size Dependent Effects on Human Dendritic Cells. Nano Letters, 7, 3576-3582.
http://dx.doi.org/10.1021/nl0714785
[6]
Zhang, P., Forsgren, J. and Stromme, M. (2014) Stabilisation of Amorphous Ibuprofen in Upsalite, a Mesoporous Magnesium Carbonate, as an Approach to Increasing the Aqueous Solubility of Poorly Soluble Drugs. International Journal of Pharmaceutics, 472, 185-191. http://dx.doi.org/10.1016/j.ijpharm.2014.06.025
[7]
Stromme, M., Brohede, U., Atluri, R. and Garcia-Bennett, A.E. (2009) Mesoporous Silica-Based Nanomaterials for Drug Delivery: Evaluation of Structural Properties Associated with Release Rate. Wiley Interdisciplinary Reviews Nanomedicne Nanobiotechnology, 1, 140-148.
[8]
Brohede, U., Atluri, R., Garcia-Bennett, A.E. and Stromme, M. (2008) Sustained Release from Mesoporous Nanoparticles: Evaluation of Structural Properties Associated with Release Rate. Current Drug Delivery, 5, 177-185.
http://dx.doi.org/10.2174/156720108784911686
[9]
Hudson, S.P., Padera, R.F., Langer, R. and Kohane, D.S. (2008) The Biocompatibility of Mesoporous Silicates. Biomaterials, 29, 4045-4055. http://dx.doi.org/10.1016/j.biomaterials.2008.07.007
[10]
Liong, M., Lu, J., Kovochich, M., Xia, T., Ruehm, S.G., Nel, A.E., et al. (2008) Multifunctional Inorganic Nanoparticles for Imaging, Targeting, and Drug Delivery. ACS Nano, 2, 889-896. http://dx.doi.org/10.1021/nn800072t
[11]
Peters, K., Unger, R. and Kirckpatrick, C. (2009) Biocompatibility Testing. In: Narayan, R., Ed., Biomedical Materials, Springer Science & Business Media, New York, 261-292. http://dx.doi.org/10.1007/978-0-387-84872-3_10
[12]
Tang, F., Li, L. and Chen, D. (2012) Mesoporous Silica Nanoparticles: Synthesis, Biocompatibility and Drug Delivery. Advanced Materials, 24, 1504-1534. http://dx.doi.org/10.1002/adma.201104763
[13]
Vallet-Regí, M., Balas, F. and Arcos, D. (2007) Mesoporous Materials for Drug Delivery. Angewandte Chemie International Edition, 46, 7548-7558. http://dx.doi.org/10.1002/anie.200604488
[14]
Kresge, C.T., Leonowicz, M.E., Roth, W.J., Vartuli, J.C. and Beck, J.S. (1992) Ordered Mesoporous Molecular Sieves Synthesized by a Liquid-Crystal Template Mechanism. Nature, 359, 710-712. http://dx.doi.org/10.1038/359710a0
[15]
Beck, J.S., Vartuli, J.C., Roth, W.J., Leonowicz, M.E., Kresge, C.T., Schmitt, K.D., et al. (1992) A New Family of Mesoporous Molecular Sieves Prepared with Liquid Crystal Templates. Journal of the American Chemical Society, 114, 10834-10843. http://dx.doi.org/10.1021/ja00053a020
[16]
Wan, Y. and Zhao, D. (2007) On the Controllable Soft-Templating Approach to Mesoporous Silicates. Chemical Reviews, 107, 2821-2860. http://dx.doi.org/10.1021/cr068020s
[17]
Garcia-Bennett, A.E. (2011) Synthesis, Toxicology and Potential of Ordered Mesoporous Materials in Nanomedicine. Nanomedicine, 6, 867-877. http://dx.doi.org/10.2217/nnm.11.82
[18]
Baù, L., Bártová, B., Arduini, M. and Mancin, F. (2009) Surfactant-Free Synthesis of Mesoporous and Hollow Silica Nanoparticles with an Inorganic Template. Chemical Communications, 28, 7584-7586.
http://dx.doi.org/10.1039/b917561j
[19]
Atluri, R., Hedin, N. and Garcia-Bennett, A.E. (2009) Nonsurfactant Supramolecular Synthesis of Ordered Mesoporous Silica. Journal of the American Chemical Society, 131, 3189-3191. http://dx.doi.org/10.1021/ja8096477
[20]
Forsgren, J., Frykstrand, S., Grandfield, K., Mihranyan, A. and Stromme, M. (2013) A Template-Free, Ultra-Adsorbing, High Surface Area Carbonate Nanostructure. PLoS ONE, 8, e68486. http://dx.doi.org/10.1371/journal.pone.0068486
[21]
Frykstrand, S., Forsgren, J., Mihranyan, A. and Stromme, M. (2014) On the Pore Forming Mechanism of Upsalite, a Micro- and Mesoporous Magnesium Carbonate. Microporous and Mesoporous Materials, 190, 99-104.
http://dx.doi.org/10.1016/j.micromeso.2013.12.011
[22]
US Food and Drug Administration. U.S. Department of Health & Human Services.
[23]
WHO Department of Essential Medicines and Health Products (2014) The International Pharmacopedia. Fourth Edition, WHO, Geneva.
[24]
Brunauer, S., Emmett, P.H. and Teller, E. (1938) Adsorption of Gases in Multimolecular Layers. Journal of the American Chemical Society, 60, 309-319. http://dx.doi.org/10.1021/ja01269a023
[25]
ISO 10993-10 (2010) Biological Evaluation of Medical Devices. Part 10: Tests for Irritation and Skin Sensitization.
[26]
ISO 10993-11 (2010) Biological Evaluation of Medical Devices. Part 11: Tests for Systemic Toxicity.
[27]
Temenoff, J.S. and Mikos, A.G. (2008) Biomaterials: The Intersection of Biology and Materials Science. Prentice Hall, Upper Saddle River.
[28]
Zhou, Z., Zhu, S. and Zhang, D. (2007) Grafting of Thermo-Responsive Polymer inside Mesoporous Silica with Large Pore Size Using ATRP and Investigation of Its Use in Drug Release. Journal of Materials Chemistry, 17, 2428-2433.
http://dx.doi.org/10.1039/b618834f
[29]
Yang, Q., Wang, S., Fan, P., Wang, L., Di, Y., Lin, K., et al. (2005) pH-Responsive Carrier System Based on Carboxylic Acid Modified Mesoporous Silica and Polyelectrolyte for Drug Delivery. Chemistry of Materials, 17, 5999-6003.
http://dx.doi.org/10.1021/cm051198v
[30]
López, T., Basaldella, E., Ojeda, M., Manjarrez, J. and Alexander-Katz, R. (2006) Encapsulation of Valproic Acid and Sodic Phenytoin in Ordered Mesoporous SiO2 Solids for the Treatment of Temporal Lobe Epilepsy. Optical Materials, 29, 75-81. http://dx.doi.org/10.1016/j.optmat.2006.03.017
[31]
ISO 10993-5 (2009) Biological Evaluation of Medical Devices. Part 5: Tests for in Vitro Cytotoxicity.
[32]
Zhang, P., de la Torre, T.Z.G., Forsgren, J., Bergstrom, C. and Stromme, M. (2015) Diffusion-Controlled Drug Release from the Mesoporous Magnesium Carbonate Upsalite®. Journal of Pharmaceutical Sciences, In Press.
http://dx.doi.org/10.1002/jps.24553
[33]
Heikkila, T., Santos, H.A., Kumar, N., Murzin, D.Y., Salonen, J., Laak-sonen, T., et al. (2010) Cytotoxicity Study of Ordered Mesoporous Silica MCM-41 and SBA-15 Microparticles on Caco-2 Cells. European Journal of Pharmaceutics and Biopharmaceutics, 74, 483-494. http://dx.doi.org/10.1016/j.ejpb.2009.12.006
