Avidin-dendrimer-(1B4M-Gd)(254): A tumor-targeting therapeutic agent for gadolinium neutron capture therapy of intraperitoneal disseminated tumor which can be monitored by MRI

Peritoneal carcinomatosis is a late stage in cancer progress, for which no effective therapeutic modality exists. Targeting therapeutic agents to diss eminated lesions may be a promising modality for treating peritoneal. carci nomatosis. Gadolinium (Gd-157,Gd-155) is known to generate Auger and intern al conversion electrons efficiently by irradiation with a neutron beam. Aug er electrons from neutron-activated Gd(III) are strongly cytotoxic, but onl y when Gd(III) atoms have been internalized into the cells. In the present investigation, we have developed a quickly internalizing turner-targeting s ystem to deliver large quantities of Gd(III) atoms into tumor cells to gene rate the Auger emission with an external neutron beam. Simultaneously, one would be able to image its biodistribution by MRI with a shortened T1 relax ation time. Avidin-G6-(1B4M-Gd)(254) (Av-G6Gd) was synthesized from generat ion-6 polyamidoamine dendrimer, biotin, avidin, and 2-(p-isothiocyanatobenz yl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M). The Av-G6Gd was rad iolabeled with Cd(III) doped with Gd-153. All of the 1B4M's on the conjugat e were fully saturated with Gd(III) atoms. An in vitro internalization stud y showed that Av-G6Gd accumulated and was internalized into SHIN3 cells (a human ovarian cancer) 50- and 3.5-fold greater than Gd-DTPA (Magnevist) and G6-(1B4M-Gd)(256) (GGGd). In addition, accumulation of Gd(III) in the cell s was detected by the increased signal on T1-weighted MRI. A biodistributio n study was performed in nude mice bearing intraperitoneally disseminated S HINS tumors. Av-G6Gd showed specific accumulation in the SHIN3 tumor (103% ID/g) 366- and 3.4-fold greater than Gd-DTPA (0.28% ID/g, p < 0.001) and G6 Gd (30% ID/g, p < 0.001) 1 day after i.p. injection. Seventy-eight percent of the tumor-related radioactivity of Av-G6Gd in the SHINS tumor was locate d inside the cells. The SHIN3 tumor-to-normal tissue ratio was greater than 17:1 in all organs and increased up to 638:1 at 1 day after i.p. injection . In conclusion, a sufficient amount (162 ppm) of Av-G6Cd was accumulated a nd internalized into the SHINS cells both in vitro and in vivo to kill the cell using Gd-157/155 With external irradiation with an appropriate neutron beam while monitoring with MRI. Thus, Av-G6Gd may be a promising agent for Gd neutron capture therapy of peritoneal carcinomatosis. This reagent also has the potential to permit monitoring of its pharmacokinetic progress wit h MRI.