A New Generation of Anticancer Drugs: Mesoporous Materials Modified with Titanocene Complexes

Abstract

Dehydroxylated MCM-41 and SBA-15 surfaces were modified by the grafting of two different titanocene complexes ([Ti(Tη5-C5H 4Me)2Cl2] and [Ti(Me2Si(η 5-C5Me4) (η5-C5H 4)}Cl2]) to give new materials, which have been characterized by powder X-ray diffraction, X-ray fluorescence, nitrogen gas sorption, MAS-NMR spectroscopy, thermogravimetry, SEM, and TEM. The toxicity of the resulting materials toward human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x, and normal immunocompetent cells, such as peripheral blood mononuclear cells PBMC has been studied. Estimation of the number of particles per gram of material led to the calculation of O 50 values for these samples, which is the number of particles required to inhibit normal cell growth by 50%. In addition, M50 values (quantity of material needed to inhibit normal cell growth by 50%) of the studied surfaces is also reported. Nonfunctionalized MCM-41 and SBA-15 did not show notable antiproliferative activity, whereas functionalization of these materials with different titanocene based anticancer drugs led to very promising antitumoral activity. The best Q50 values correspond to titanocene functionalized MCM-41 surfaces (MCM-41/[Ti(η5C5H 4Me)2Cl2] (1) and MCM-41/[TiIMe 2Si(Tf-C5Me4)(Tf-C5H 4)(Cl2] (2)) with Q50 values between 3.8 ± 0.6 x 108 and 24.5 ±3.0 x 108 particles. Titanocene functionalized SBA-15 surfaces (SBA-15/[Ti(η5-C 5H4Me)2Cl2] (3) and SBA-15/[Ti{Me2Si(η5-C5Me 4)(η5C5H4)}Cl2] (4)) gave higher Q50 values, showing lower activity from 73.2 ± 9.9 x 108 to 362±7×l08 particles. The best response of the studied materials in terms of M50 values was observed against Fem-x (309 ± 42 g for 4) and K562 (338±18 g for 2), whereas moderate activities were observed in HeLa cells (from 508±63g of 2 to 912 ± 10g of 1). In addition, the analyzed surfaces presented only marginal activity against unstimulated and stimulated PBMC, showing a slight selectivity on human cancer cells. Comparison of the in vitro cytotoxicity in solution of the titanocene complexes/[Ti(η5-C5H 4Me)2Cl2] (3) and SBA-15/[Ti{Me 2Si(η5-C5Me4) (η5C5H4)}Cl2] (4)) gave higher Q50 va and the corresponding titanocene functionalized materials is also described.