A ubiquitous metal, difficult to track: towards an understanding of the regulation of titanium(iv) in humans

Abstract

Despite the ubiquitous nature of titanium(IV) and several examples of its beneficial behavior in different organisms, the metal remains underappreciated in biology. There is little understanding of how the metal might play an important function in the human body. Nonetheless, new insight is obtained regarding the molecular mechanisms that regulate the blood speciation of the metal to maintain it in nontoxic and potentially bioavailable form for use in the body. This review surveys the literature on Ti(IV) application in prosthetics and in the development of anticancer therapeutics to gain insight into soluble Ti(IV) influx in the body and its long-term impact. The limitation in analytical tools makes it difficult to depict the full picture of how Ti(IV) is transported and distributed throughout the body. Improved understanding of Ti function and its interaction with biomolecules will be helpful in developing future technologies for its imaging in the body.

Expanding the Therapeutic Potential of the Iron Chelator Deferasirox in the Development of Aqueous Stable Ti(IV) Anticancer Complexes

“…8 Modifications made include substitutions with less labile ligands and with ligands that allow for higher cellular specificity and biocompatibility. 9–21 McGowan and Lord have also synthesized and characterized a library of second-generation budotitane complexes.…”

In Vivo Anticancer Activity of a Nontoxic Inert Phenolato Titanium Complex: High Efficacy on Solid Tumors Alone and Combined with Platinum Drugs

“…However, development of resistance to these drugs and the toxicity of the Pt ion led to a search for other metal‐based drugs. Among the transition metals tested, two titanium‐based complexes—budotitane and titanocene dichloride—reached clinical trials, but failed due to rapid hydrolysis and the formation of undefined aggregates . To overcome these obstacles, our laboratory developed a new family of titanium(IV) complexes based on phenolato ligands .…”

“…Amongt he transition metalstested, two titanium-based complexes-budotitane and titanocene dichloride-reached clinical trials, but failed due to rapid hydrolysis and the formation of undefineda ggregates. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] To overcome these obstacles, our laboratory developed an ew family of titanium(IV) complexes based on phenolato ligands. [30][31][32][33][34][35][36][37][38][39][40][41][42] In particular,d iaminobis(phenolato)-bis(alkoxo)Ti IV (phenolaTi,F igure 1) demonstrated remarkable stability in aqueous media and an extended shelf life, along with enhanced in vitro cytotoxicity toward various cancer cell types.…”

Study of the anticancer properties of optically active titanocene oximato compounds

“…The titanium derivatives titanocene dichloride ([(η 5 -C H 5 ) 2 TiCl 2 ], TDC) [8,9] and budotitane ([cisdiethoxybis(1-phenylbutane-1,3-dionato)titanium(IV)]) [10,11] were the first metal compounds to enter clinical trials after platinum complexes. Although these derivatives showed promising properties in preliminary studies, they failed advanced clinical trials due to low antitumor efficacy in vivo, rapid hydrolysis and limited solubility in biological media [12][13][14][15][16][17][18][19]. Since then, a plethora of modified titanium based compounds have been synthesized and studied as potential antitumor agents [17][18][19][20][21][22][23][24][25][26][27][28][29].…”

“…Comparison of IC 50 values (µM) of 1b, b•HCl, TDC and TDC+b•HCl in prostate cancer PC-3, DU-145 and non-tumorigenic RWPE-1 cell lines a (after 72 h of exposure to the drug).To date, various distinct mechanisms have been proposed for titanium-based therapeutics. DNA binding is still thought to be one important potential mode of action for titanocene compounds, although interactions with DNA have been found to be generally very weak at physiological pH conditions[16,17]. The study of DNA interactions for these particular metal complexes does often represent an experimental challenge, since the compounds can easily hydrolyse in water solutions.…”