Mechanistic studies of titanium anti-cancer drugs utilizing radionuclidic techniques.

摘要

Titanium(IV) complexes, particularly titanocene complexes, have been shown to exhibit high antitumor activity against a range of tumors in animals with less toxic side-effects than cisplatin. Titanocene dichloride (TDC) is currently in phase II clinical trials as an anticancer agent. Although the aqueous chemistry of titanium compounds has been explored, the biological chemistry and mechanism of action of such drugs remain undetermined. Under physiological conditions, titanium(IV) is readily taken up by human transferrin from titanocene dichloride suggesting that it may mediate the uptake of titanium from anti-cancer drugs.; The preparation of 45Ti was pursued and validated for microPET imaging. By inducing a 45Sc (p,n) 45Ti nuclear reaction on a cyclotron, sufficient yields of 45Ti were produced and isolated from the target material with 99.8% radionuclidic purity. MicroPET images showed excellent resolution down to a diameter of 1.25 mm.; Titanium-45 formed a complex with apotransferrin that remained intact in vivo. Results from biodistribution studies in mice showed high tumor uptake relative to non-target organs (e.g., muscle). These findings were consistent with the biodistribution data of 67Ga-citrate, which is known to be transported via the transferrin pathway. The tumors can be clearly delineated from the surrounding tissue in microPET images. Titanocene dichloride synthesis has been successfully adapted for carrier-added incorporation of 45 Ti. MicroPET images of 45Ti-TDC show similar uptake to that of 45Ti-transferrin, although with higher standard uptake values. Ex vivo analysis showed incorporation of 45Ti into serum transferrin.; Receptor-specific MRI agents are used to delineate changes in tumor vasculature, however they are not currently approved for clinical use due to their overwhelming toxicity. Ga-68-citrate has been used to evaluate pulmonary vascular permeability, but the current study employed 45Ti-Tf was used to take advantage of the longer half-life (45Ti-t½ = 3.09 h) and lower positron energy (1.04 MeV). Preliminary microPET imaging data demonstrated higher uptake of 45Ti-Tf into tumor tissue in the treated animals over untreated controls.