High Antitumor Activity of Highly Resistant Salan-Titanium(IV) Complexes in Nanoparticles: An Identified Active Species

摘要

Titanium(IV)-based anticancer complexes were the first to enter clinical trials after platinum compounds.'11 In particular, budotitane ([(bzac)2Ti(OEt)2]; bzac = benzoylacetonate) and titanocene dichloride ([Cp2TiCl2]; Cp = cyclopentadienyl) demonstrated high antitumor activity with reduced toxicity toward a range of cancer cells; however, use of these complexes, which both bear two labile ligands, was limited by their instability in water.'2' Therefore, mechanistic aspects remained unresolved, including the nature of the active species and its identification from the multiple hydrolysis products that were formed. We have recently introduced cytotoxic salan-Ti~(IV) complexes, which are: a) substantially more hydrolytically stable than known Ti~(IV) complexes, and b) markedly more active than [(bzac)2Ti(OiPr)2], [Cp2TiCl2], and cis-platin toward a variety of cancer-derived cell lines. Structure-activity-relationship studies based on both salan and labile ligand variations revealed that reduced steric bulk is favored for cytotoxicity. Additionally, all cytotoxic complexes slowly gave defined oxo-bridged polynuclear hydrolysis products. Particularly, N-methy-lated complexes produced well-defined trinuclear clusters, which were stable for weeks in water. Several observations indicated that the hydrolysis products play a meaningful role in the cytotoxicity mechanism; nevertheless, direct measurements on the isolated clusters showed no activity. Herein we address the hypothesis that cellular penetration, which is size-dependent, and/or impaired solubility were limiting factors, and that labile ligands may actually not be required for cytotoxicity of Ti~(IV) complexes, unlike for cis-platin. This paper presents the high activity of a hydrolysis product and other particularly resistant Ti~(IV) complexes, the solubility and cell-penetration of which are improved through the reduction of their particle size to the nanoscale dimension. Reduction of the particle size to the nanometric region accelerates intercellular permeability and increases the solubility and dissolution rate.Nanoparticles of salan-Ti~(IV) complexes were obtained by a rapid conversion of a volatile oil-in-water microemulsion into a dry powder composed of nanoparticles. Rapid evaporation of the volatile droplets that contain the complex gave a powder that was easily dispersible in aqueous media to form a dispersion of stable nanoparticles. Notably, the surfactants used are approved by the Food and Drug Administration (FDA) for incorporation into pharmaceutical dosage forms.