A new generation of anticancer drugs: mesoporous materials modified with titanocene complexes.
Dehydroxylated MCM-41 and SBA-15 surfaces were modified by the grafting of two different titanocene complexes ([Ti(eta(5)-C(5)H(4)Me)(2)Cl(2)] and [Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)]) 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 Q(50) values for these samples, which is the number of particles required to inhibit normal cell growth by 50%. In addition, M(50) 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 Q(50) values correspond to titanocene functionalized MCM-41 surfaces (MCM-41/[Ti(eta(5)-C(5)H(4)Me)(2)Cl(2)] (1) and MCM-41/[Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (2)) with Q(50) values between 3.8+/-0.6x10(8) and 24.5+/-3.0x10(8) particles. Titanocene functionalized SBA-15 surfaces (SBA-15/[Ti(eta(5)-C(5)H(4)Me)(2)Cl(2)] (3) and SBA-15/[Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (4)) gave higher Q(50) values, showing lower activity from 73.2+/-9.9x10(8) to 362+/-7x10(8) particles. The best response of the studied materials in terms of M(50) values was observed against Fem-x (309+/-42 microg for 4) and K562 (338+/-18 microg for 2), whereas moderate activities were observed in HeLa cells (from 508+/-63 microg of 2 to 912+/-10 microg 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(eta(5)-C(5)H(4)Me)(2)Cl(2)] and [Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] and the corresponding titanocene functionalized materials is also described.
Departamento de Química Inorgánica y Analítica, E.S.C.E.T. Universidad Rey Juan Carlos, 28933 Móstoles, Madrid, Spain.
Damian
D
Pérez-Quintanilla
Santiago
S
Gómez-Ruiz
Zeljko
Z
Zizak
Isabel
I
Sierra
Sanjiv
S
Prashar
Isabel
I
del Hierro
Mariano
M
Fajardo
Zorica D
ZD
Juranić
Goran N
GN
Kaluderović
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012822:Silicon Dioxide / Q000737:chemistry
D000970:Antineoplastic Agents; C509968:MCM-41; D009942:Organometallic Compounds; C509969:SBA-15; C406884:titanocene; D012822:Silicon Dioxide