From medium to endoplasmic reticulum: Tracing anticancer phenolato titanium(IV) complex by 19F NMR detection.

Titanium(IV) complexes of diaminobis(phenolato)-bis(alkoxo) ligands are promising anticancer drugs, showing marked in-vivo efficacy with no toxic side-effects in mice, hence, it is of interest to elucidate their mechanism of action. Herein, we employed a fluoro-substituted derivative, FenolaTi, for mechanistic analysis of the active species and its cellular target by quantitative 19F NMR detection to reveal its biodistribution and reactivity in extracellular and intracellular matrices. Upon administration to the serum-containing medium, FenolaTi interacted with bovine serum albumin. 20 h post administration, the cellular accumulation of FenolaTi derivatives was estimated as 37% of the administered compound, in a concentration three orders-of-magnitude higher than the administered dose, implying that active membrane transportation facilitates cellular penetration. An additional 19% of the administered dose that was detected in the extracellular environment had originated from post-apoptotic cells. In the cell, interaction with cellular proteins was detected. Although some intact Ti(IV) complex localized in the nucleus, no signals for isolated DNA fractions were detected and no reactivity with nuclear proteins was observed. Interestingly, higher accumulation of FenolaTi-derived compounds in the endoplasmic reticulum (ER) and interaction with proteins therein were detected, supporting the role of the ER as a possible target for cytotoxic bis(phenolato)-bis(alkoxo) Ti(IV) complexes.

Synthesis of asymmetrical diaminobis(alkoxo)-bisphenol compounds and their C1-symmetrical mono-ligated titanium(iv) complexes as highly stable highly active antitumor compounds.

Asymmetrical 2,2'-((ethane-1,2-diylbis((2-hydroxyethyl)azanediyl))bis(methylene))diphenol substituted compounds and their C1-symmetrical diaminobis(phenolato)-bis(alkoxo) titanium(iv) complexes were synthesized, with one symmetrical analogue. X-ray crystallography corroborated tight ligand binding. Different substitutions on the two aromatic rings enabled fine-tuning of the complex properties, giving enhanced solubility, high anticancer activity (IC50 < 4 µM), and significant hydrolytic stability.

Effective Oral Administration of an Antitumorigenic Nanoformulated Titanium Complex.

Orally administered anticancer drugs facilitate treatment, but the acidic conditions in the stomach often challenge their availability. PhenolaTi is a TiIV -based nontoxic anticancer drug with marked in-vivo efficacy. We report that nanoformulation protects phenolaTi from decomposition in stomach-like conditions. This is evidenced by similar NMR characteristics and similar in-vitro cytotoxicity toward murine (CT-26) and human (HT-29) colon cancer cells before and after incubation of nanoformulated phenolaTi (phenolaTi-F) at pH 2, unlike results with the unformulated form of the complex. Furthermore, administration of phenolaTi-F in animal drinking water revealed a notable inhibition of tumor growth in Balb/c and immune-deficient (Nude) mice inoculated with CT-26 and HT-29 cells, respectively. In-vivo efficacy was at least similar to that of the corresponding intraperitoneal treatment with phenolaTi-F and the clinically employed oral drug, capecitabine. No body weight loss or clinical signs of toxicity were evident in the phenolaTi-F-treated animals. These findings demonstrate a new convenient mode of cancer treatment through oral administration by safe titanium-based drugs.