Inorganic Drug Release from Mesoporous Silica Nanoparticles for Cancer Treatment

Carla Caramella ^1*

The study demonstrated that controlled synthesis of mesoporous silica nanoparticles enables efficient, targeted cancer treatment with reduced toxicity.

Abstract

Mesoporous Silica Nanoparticles (MSNs) were synthesized via a modified sol-gel Stöber process. The effect of various parameters - sodium hydroxide concentration, co-solvent, stirring rate, aging time and stirring time – on the size, morphology and monodispersity of the particles was investigated. The reproducible MSNs developed were spherical, 80.24 ± 11.80 nm in size, monodispersed, had a large surface area (690.34 m2/g) and pore volume (0.89 cm3/g). These properties deemed our MSNs ideal carriers for the delivery of therapeutic ions to cancer cells. Zinc and iron were incorporated, together and separately, into the silica network via a post-synthetic incorporation technique followed by calcination. Zinc ions have a preferential toxicity towards cancer cells, which leads to a pH-triggered release. The addition of ions to the particles did not affect their size or morphology. The washing step was proven crucial to preserve the monodispersity of the particles. Results suggest that zinc is probably acting as a network modifier (decreases network connectivity) and iron as a network former (increases network connectivity). The behaviour of iron(III) chloride and iron(III) nitrate as precursors was compared. Iron(III) chloride produced predominantly large localized hematite crystals (25.75 ± 3.19 nm). Iron(III) nitrate gave rise to mainly small homogeneously-spread magnetite crystals (2.70 ± 0.50 nm), which is desired. The incorporation of iron into to the MSN-Zn network slowed down the release of zinc, making the release less toxic. Iron tightens the silica network and it does not get released.

Keywords: Mesoporous Silica Nanoparticles (MSNs), Drug Delivery Systems, Cancer Therapy, Zinc and Iron Ions, Controlled Release Mechanism

References

Bharti, C., Nagaich, U., Pal, A. K., Gulati, N. (2016). Mesoporous silica nanoparticles in target drug delivery system: A review. International Journal of Pharmaceutical Investigation, 6(1), 14-24. https://doi.org/10.4103/2230-973X.176455

Bhattacharyya, S., Khan, M. A., & Singh, B. (2014). Mesoporous silica nanoparticles in targeted drug delivery system: A review. Journal of Chemical and Pharmaceutical Research, 6(4), 2169-2178.

Brayner, R., Ferrari-Iliou, R., Brivois, N., Djediat, S., Benedetti, M. F., & Fiévet, F. (2006). Toxicological impact studies based on Escherichia coli bacteria in ultrafine ZnO nanoparticles colloidal medium. Nano Letters, 6(4), 866-870. https://doi.org/10.1021/nl052326h

Cai, W., & Chen, X. (2007). Nanoplatforms for targeted molecular imaging in living subjects. Small, 3(11), 1840-1854. https://doi.org/10.1002/smll.200700296

Du, X., He, J., Wang, G., Hu, L., Wang, W., & Gu, Z. (2013). Mesoporous silica nanoparticles as a delivery system for improving anticancer efficiency of cisplatin. Journal of Colloid and Interface Science, 388(1), 82-89. https://doi.org/10.1016/j.jcis.2012.08.047

Froba, M., Estournes, C., Livage, J., & Sanchez, C. (1999). Mesoporous silica nanoparticles incorporating transition metal ions for selective catalysis. Chemistry of Materials, 11(10), 3140-3146. https://doi.org/10.1021/cm991042m

He, Q., Gao, Y., Zhang, L., Zhang, Z., Gao, F., & Li, Y. (2009). A pH-responsive mesoporous silica nanoparticles-based multi-drug delivery system for overcoming multidrug resistance. Biomaterials, 31(12), 3084-3096. https://doi.org/10.1016/j.biomaterials.2009.12.010

Huh, S., Chen, H. T., Wiench, J. W., Pruski, M., & Lin, V. S. Y. (2005). Cooperative catalysis by general acid and base bifunctionalized mesoporous silica nanoparticles. Angewandte Chemie International Edition, 44(12), 1826-1830. https://doi.org/10.1002/anie.200462058

Jiang, J., Pi, J., & Cai, J. (2008). The Advancing of Zinc Oxide Nanoparticles for Biomedical Applications. Bioinorganic Chemistry and Applications, 2008, Article 457104. https://doi.org/10.1155/2008/457104

Kim, J., Kim, H. S., Lee, N., Kim, T., Kim, H., Yu, T., ... & Hyeon, T. (2008). Multifunctional uniform nanocomposite particles with a magnetite nanocrystal core and a mesoporous silica shell for magnetic resonance and fluorescence imaging and for drug delivery. Angewandte Chemie International Edition, 47(44), 8438-8441. https://doi.org/10.1002/anie.200802234

Kresge, C. T., Leonowicz, M. E., Roth, W. J., Vartuli, J. C., & Beck, J. S. (1992). Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism. Nature, 359(6397), 710-712. https://doi.org/10.1038/359710a0

Lee, J. H., Ju, E. J., Kim, B. I., Pak, P. J., Choi, E. K., Lee, H. S., & Lee, S. C. (2011). Magnetic mesoporous silica nanoparticle-based macrophage delivery of therapeutic agents to brain tumors. Journal of the National Cancer Institute, 103(22), 1670-1681. https://doi.org/10.1093/jnci/djr379

Mamaeva, V., Sahlgren, C., & Lindén, M. (2013). Mesoporous silica nanoparticles in medicine—recent advances. Advanced Drug Delivery Reviews, 65(5), 689-702. https://doi.org/10.1016/j.addr.2012.07.018

Meng, H., Xue, M., Xia, T., Zhao, Y. L., Tamanoi, F., Stoddart, J. F., ... & Nel, A. E. (2010). Autonomous in vitro anticancer drug release from mesoporous silica nanoparticles by pH-sensitive nanovalves. Journal of the American Chemical Society, 132(36), 12690-12697. https://doi.org/10.1021/ja1033633

Paris, J. L., Cabañas, M. V., Manzano, M., & Vallet-Regí, M. (2015). Polymer-grafted mesoporous silica nanoparticles as ultrasound-responsive drug carriers. ACS Nano, 9(11), 11083-11093. https://doi.org/10.1021/acsnano.5b04045

Rasmussen, J. W., Martinez, E., Louka, P., & Wingett, D. G. (2010). Zinc oxide nanoparticles for selective destruction of tumor cells and potential for drug delivery applications. Expert Opinion on Drug Delivery, 7(9), 1063-1077. https://doi.org/10.1517/17425247.2010.502560

Slowing, I. I., Trewyn, B. G., Giri, S., & Lin, V. S. Y. (2007). Mesoporous silica nanoparticles for drug delivery and biosensing applications. Advanced Functional Materials, 17(8), 1225-1236. https://doi.org/10.1002/adfm.200601191

Slowing, I. I., Vivero-Escoto, J. L., Wu, C. W., & Lin, V. S. Y. (2008). Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers. Advanced Drug Delivery Reviews, 60(11), 1278-1288. https://doi.org/10.1016/j.addr.2008.03.012

Stöber, W., Fink, A., & Bohn, E. (1968). Controlled growth of monodisperse silica spheres in the micron size range. Journal of Colloid and Interface Science, 26(1), 62-69. https://doi.org/10.1016/0021-9797(68)90272-5

Tang, F., Li, L., & Chen, D. (2012). Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery. Advanced Materials, 24(12), 1504-1534. https://doi.org/10.1002/adma.201104763

Vallet-Regí, M., & Balas, F. (2008). Silica materials for medical applications. Open Biomedical Engineering Journal, 2(1), 1-9. https://doi.org/10.2174/1874120700802010001

Van Speybroeck, M., Barillaro, V., Huygens, C., Pinna, C., de Belder, S., Ludovico Martinez, L., ... & Mellaerts, R. (2009). Ordered mesoporous silica material SBA-15: A broad-spectrum formulation platform for poorly soluble drugs. Journal of Pharmaceutical Sciences, 98(8), 2648-2658. https://doi.org/10.1002/jps.21640

Zhang, L., Jiang, Y., Ding, Y., Daskalakis, N., Jeuken, L., Povey, M., ... & Hao, T. (2014). Mechanistic investigation into antibacterial behavior of zinc oxide nanoparticles against Escherichia coli. Journal of Nanoparticle Research, 16(1), 1-12. https://doi.org/10.1007/s11051-014-2257-y

Zhao, X. S., Lu, G. Q., & Whittaker, A. K. (1998). Synthesis and characterization of ordered mesoporous silica materials. Chemistry of Materials, 10(4), 902-908. https://doi.org/10.1021/cm970731r

Zhu, Y., Ikoma, T., Hanagata, N., Kaskel, S. (2010). Rattle-type Fe3O4@SiO2 hollow mesoporous spheres as carriers for drug delivery. Small, 6(3), 471-478. https://doi.org/10.1002/smll.200901717