Anti‐cancer Applications of Titanocene‐Functionalised Nanostructured Systems: An Insight into Cell Death Mechanisms

Abstract

A series of alkenyl-substituted titanocene compounds have been supported on the mesoporous silica-based material KIT-6. The corresponding functionalised materials were completely characterised by different techniques (solid-state multinuclear NMR spectroscopy, IR spectroscopy, N2 adsorption-desorption isotherms, X-ray fluorescence and diffraction, SEM and TEM) to observe the incorporation of the titanocene derivatives on the external surface of the material KIT-6. Both the titanocene compounds and the materials were tested in vitro against a wide variety of human cancer and normal cell lines. A very high cytotoxicity of the synthesised titanocene derivatives (IC50 values in the range of those described in the literature for the most active cytotoxic titanocene compounds), with selectivity towards cancer cell lines was observed. The cytotoxic activity of the materials is the highest reported to date for titanocene-functionalised materials. In addition, higher Ti uptake (from 4 to 23% of the initial amount of Ti) of the cells treated with materials was observed with respect to those treated with "free" titanocene derivatives (which gave Ti uptake values from 0.4 to 4.6% of the initial amount of Ti). Additional experiments with the titanocene derivatives and the functionalised materials revealed that changes to the morphological and functional dynamics of apoptosis occurred when the active titanocene species were incorporated into mesoporous materials. In addition, the materials could induce programmed cell death in tumour cell populations by impairing the damaged DNA repair mechanisms and by upregulation of intrinsic and extrinsic apoptotic signalling pathways.

Evaluating Ligand Modifications of the Titanocene and Auranofin Moieties for the Development of More Potent Anticancer Drugs

“…This study reveals a route for titanocenyl uptake through a plasma membrane estrogen receptor. In a series of studies, a different approach was taken to functionalize the titanocene moiety to not only stabilize the compound and enhance its cellular uptake but to also apply it to specific cancers [69][70][71][72]. Titanocene and select derivatives were grafted onto the surface of ceramic materials, including mesoporous silicas, alumina, and hydroxyapatite, that can be used as components of synthetic hard tissues, such as bone fillers or prosthetics ( Figure 8).…”

“…The cytotoxicity of the ceramic materials and their titanocenyl grafted counterparts are measured in terms of M 50 values, the quantity of material in µg/mL necessary to reduce the cell population's growth by 50%. The ceramic materials alone exhibit very weak antiproliferative behavior, whereas the titanocene grafted material are moderately to strongly antiproliferative [69][70][71][72]. Ceballos-Torres et al conducted a study of titanocenes grafted onto the mesoporous silica-based material KIT-6 [74].…”

Multifunctional Silica-Based Nanoparticles with Controlled Release of Organotin Metallodrug for Targeted Theranosis of Breast Cancer

“…In this sense, nanomaterials can act as suitable vectors for metallodrug delivery by (i) protecting the active species from degradation, (ii) enhancing their therapeutic activity [26], (iii) increasing drug bioavailability and specificity, or (iv) increasing the solubility [23,[27][28][29][30]. Because of its synthetic flexibility and biocompatibility, mesoporous silica-based nanostructured materials (MSN) represent one of the most used nanovectors in biomedicine, with special importance in metallodrug-based drug delivery systems [23,[31][32][33][34][35][36][37][38]. Consequently, the MSNs have stood out in different biomedical fields such as molecular imaging (fluorescence and magnetic resonance imaging) and drug delivery [39][40][41][42][43][44][45].…”

Nano-Based Systems and Biomacromolecules as Carriers for Metallodrugs in Anticancer Therapy

“…The advantages of silica carriers include chemical stability, ease of surface modification with different functional groups for subsequent drug conjugation, as well as a tunable pore diameter [95]. Gomes-Ruiz's group employed mesoporous silica nanoparticles as carriers for tin, titanium, and ruthenium complexes [34,[96][97][98][99][100][101][102][103]. Interestingly, they observed that the entire nanostructure of mesoporous silica-drug conjugate was involved in triggering cancer cell apoptosis, and only a small release of the encapsulated metallodrug was contributing to cytotoxic effects.…”