Synthesis and characterization of silica nanoparticles functionalized with titanocene derivatives

Introduction: Titanocene dichloride is a well-known organometallic compound that has been tested in Phase II clinical trials in patients with metastatic breast carcinoma and advanced renal cell carcinoma. However, its activity was not very good due to the low solubility and stability of the compound in physiological medium. Therefore, the incorporation of this complex in nanoparticles could be an alternative to improve its pharmacokinetics. In this work, the design of systems based on mesoporous silica nanoparticles (MSNs) was carried out, as well as biological assays in order to compare the biological activity with the isolated complex and the influence of the chlorine atoms. Materials & Methods: MSNs were synthesized by the sol-gelmethod when tetraethyl orthosilicate was used as silica precursor and hexadecyltrimethylammonium bromide was applied as surfactant. Titanocene derivatives were covalently incorporated on the surface of MSNs through grafting reactions trough mercapto ligand. Synthesized MSNs were characterized by analytical techniques such as FTIR spectroscopy (analysis of chemical bonds), TEM analysis (morphology of MSNs), BET analysis (texturalproperties), and ICP-MS analysis (content of functionalized metal). The biological effects of synthesized MSNs were tested on MDA-MB-231 and MDA-MB-468 triple-negative breast cancer cell lines by metabolic assay, CM-H2DCFDA assay, immunochemical analysis, and cell cycle analysis. Results: Treatment of MSNs functionalized with titanocene derivatives caused a decrease in the viability, mainly in MDA-MB-468 cells. Further, the application of synthesized MSNs introduced ROS production with influenced cell cycle progression manifested by significant increase of the sub-G1 population after treatment with functionalized MSNs. Subsequent analysis of proteins involved in key signalling pathways revealed increased level of LC3B, the protein associated with the induction of autophagy. Conclusion: MSNs were synthesized to determine how theappearance, or absence, of the chlorine atom influences the activity of titanocene derivatives and to compare the biological activity with respect to the isolated complex. The biological experiments showed that the chlorine atom is not necessary for titanocene dichloride activity, but its occurrence contributes to it. This information could be applied in future research focused on the development of novel and more efficient derivatives of titanocene dichloride supported on nanomaterials.