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 disseminated lesions may be a promising modality for treating peritoneal carcinomatosis. Gadolinium ((157,155)Gd) is known to generate Auger and internal conversion electrons efficiently by irradiation with a neutron beam. Auger electrons from neutron-activated Gd(III) are strongly cytotoxic, but only when Gd(III) atoms have been internalized into the cells. In the present investigation, we have developed a quickly internalizing tumor-targeting system to deliver large quantities of Gd(III) atoms into tumor cells to generate the Auger emission with an external neutron beam. Simultaneously, one would be able to image its biodistribution by MRI with a shortened T1 relaxation time. Avidin-G6-(1B4M-Gd)(254) (Av-G6Gd) was synthesized from generation-6 polyamidoamine dendrimer, biotin, avidin, and 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M). The Av-G6Gd was radiolabeled with Gd(III) doped with (153)Gd. All of the 1B4M's on the conjugate were fully saturated with Gd(III) atoms. An in vitro internalization study 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) (G6Gd). In addition, accumulation of Gd(III) in the cells was detected by the increased signal on T1-weighted MRI. A biodistribution study was performed in nude mice bearing intraperitoneally disseminated SHIN3 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 G6Gd (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 SHIN3 tumor was located 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-G6Gd was accumulated and internalized into the SHIN3 cells both in vitro and in vivo to kill the cell using (157/155)Gd 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 with MRI.
Kobayashi
H
H
Hitachi Medical Co., chaired, Department of Diagnostic and Interventional Imagiology, and Department of Nuclear Medicine and Diagnostic Imaging, Kyoto University, Kyoto 606-8507, Japan. hisataka@kuhp.kyoto-u.ac.jp
Kawamoto
S
S
Saga
T
T
Sato
N
N
Ishimori
T
T
Konishi
J
J
Ono
K
K
Togashi
K
K
Brechbiel
M W
MW
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001360:Avidin / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D050091:Dendrimers; D005260:Female; D005682:Gadolinium / Q000008:administration & dosage; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017247:Neutron Capture Therapy; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004369:Pentetic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis; D010534:Peritoneal Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D011073:Polyamines / Q000138:chemical synthesis; D011868:Radioisotopes / Q000737:chemistry; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D050091:Dendrimers; D009942:Organometallic Compounds; C104700:PAMAM Starburst; D011073:Polyamines; D011868:Radioisotopes; C436395:avidin-dendrimer-(1B4M-Gd)(254); D001360:Avidin; C077295:2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid; D004369:Pentetic Acid; D005682:Gadolinium