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.
Highlights
Since the discovery of cisplatin (cis-diamminedichloridoplatinum (II)) by Rosenberg and coworkers [1], a wide variety of metal complexes for medicinal applications, such as diagnosis or Materials 2018, 11, 224; doi:10.3390/ma11020224 www.mdpi.com/journal/materialsMaterials 2018, 11, 224 therapy, have been designed [2,3]
The second method is a tethering reaction of a titanocene derivative containing triethoxysilyl fragments [Ti(η5 -C5 H5 )2 {SCH2 CH2 CH2 Si(OEt)3 }2 ] (4) with SBA-15 to give the material SBA-15/[Ti(η5 -C5 H5 )2 {SCH2 CH2 CH2 Si(OEt)3 }2 ] (S4)
Spacing values of ca. 73 Å (Table 2). These results suggest that the structural order of the synthesized material is maintained after functionalization with the titanocene derivatives
Summary
Since the discovery of cisplatin (cis-diamminedichloridoplatinum (II)) by Rosenberg and coworkers [1], a wide variety of metal complexes for medicinal applications, such as diagnosis or Materials 2018, 11, 224; doi:10.3390/ma11020224 www.mdpi.com/journal/materialsMaterials 2018, 11, 224 therapy, have been designed [2,3]. In many cases, metallodrugs change their structure in the previous steps of passive or active transportation to the cell and membrane crossing, leading to a transformation of the coordination sphere of the metal and/or decomposition of the complex which makes them act more as a prodrug than, as a drug [7]. In this context, the use of encapsulators or carrier vehicles for the protection of the actives species and subsequent delivery to cancer cells is an approach of current interest for the scientific community [8,9]. One of the most interesting scaffolds for metallodrug-loading is nanostructured mesoporous silica which, loaded with titanium [9,10,11,12,13,14,15], tin [16,17], or other metallodrugs [8], has been shown to be highly effective against cancer cell lines
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