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. 2018 Jan 31;11(2):224.
doi: 10.3390/ma11020224.

Anticancer Applications of Nanostructured Silica-Based Materials Functionalized with Titanocene Derivatives: Induction of Cell Death Mechanism through TNFR1 Modulation

Santiago Gómez-Ruiz  1 , Alberto García-Peñas  2   3 , Sanjiv Prashar  4 , Antonio Rodríguez-Diéguez  5 , Eva Fischer-Fodor  6   7
Affiliations

Anticancer Applications of Nanostructured Silica-Based Materials Functionalized with Titanocene Derivatives: Induction of Cell Death Mechanism through TNFR1 Modulation

Santiago Gómez-Ruiz et al. Materials (Basel). .

Abstract

A series of cytotoxic titanocene derivatives have been immobilized onto nanostructured silica-based materials using two different synthetic routes, namely, (i) a simple grafting protocol via protonolysis of the Ti-Cl bond; and (ii) a tethering method by elimination of ethanol using triethoxysilyl moieties of thiolato ligands attached to titanium. The resulting nanostructured systems have been characterized by different techniques such as XRD, XRF, DR-UV, BET, SEM, and TEM, observing the incorporation of the titanocene derivatives onto the nanostructured silica and slight changes in the textural features of the materials after functionalization with the metallodrugs. A complete biological study has been carried out using the synthesized materials exhibiting moderate cytotoxicity in vitro against three human hepatic carcinoma (HepG2, SK-Hep-1, Hep3B) and three human colon carcinomas (DLD-1, HT-29, COLO320) and very low cytotoxicity against normal cell lines. In addition, the cells' metabolic activity was modified by a 24-h exposure in a dose-dependent manner. Despite not having a significant effect on TNFα or the proinflammatory interleukin 1α secretion, the materials strongly modulated tumor necrosis factor (TNF) signaling, even at sub-cytotoxic concentrations. This is achieved mainly by upregulation of the TNFR1 receptor production, something which has not previously been observed for these systems.

Keywords: TNFR1 modulation; anticancer; cytotoxicity; nanostructured silica; titanocene; tumor necrosis factor.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Synthesis of S1–S4.
Figure 1
Figure 1
Functionalization species: (A) by the elimination of ethanol groups; (B) by the elimination of ethanol groups and a thiolate ligand, which leads to the formation of a Ti–O–Si bond; and (C) by the elimination of both thiolate ligands, which leads to the formation of two Ti–O–Si ligands. The figure also represents the proposed release species in simulated body fluid.
Figure 2
Figure 2
XRD diffraction patterns of SBA-15, S1–S4.
Figure 3
Figure 3
Nitrogen adsorption/desorption isotherms of SBA-15, S1–S4.
Figure 4
Figure 4
13C CP MAS NMR spectra of SBA-15, S1–S4.
Figure 5
Figure 5
29Si MAS NMR spectra of SBA-15, S1–S4.
Figure 6
Figure 6
SEM images of S1–S4.
Figure 7
Figure 7
TEM images of S1–S4.
Figure 8
Figure 8
Binding study of S1 upon increasing concentrations of DNA.
Figure 9
Figure 9
Quantitative evaluation of soluble IL-1α in hepatic HepG2, Hep3B, SK-Hep1, and colon DLD-1, HT-29 and COLO320 tumor cells, at the EC50 concentration of titanocene-functionalized materials S1–S4.
Figure 10
Figure 10
The concentration of tumor necrosis factor receptor 1 (TNFR1) in hepatic and colon cancer cell lines, after in vitro treatment with S1–S4 at their EC50 concentrations.
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