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

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• 作者：Hisataka Kobayashi ; Satomi Kawamoto ; Tsuneo Saga ; Noriko Sato ; Takayoshi Ishimori ; Junji Konishi ; Koji Ono ; Kaori Togashi ; and Martin W. Brechbiel
• 刊名：Bioconjugate Chemistry
• 出版年：2001
• 出版时间：July 2001
• 年：2001
• 卷：12
• 期：4
• 页码：587 - 593
• 全文大小：114K
• 年卷期：v.12,no.4(July 2001)
• ISSN：1520-4812

文摘

Peritoneal carcinomatosis is a late stage in cancer progress, for which no effective therapeutic modalityexists. Targeting therapeutic agents to disseminated lesions may be a promising modality for treatingperitoneal carcinomatosis. Gadolinium (^157,155Gd) is known to generate Auger and internal conversionelectrons 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 thepresent investigation, we have developed a quickly internalizing tumor-targeting system to deliverlarge quantities of Gd(III) atoms into tumor cells to generate the Auger emission with an externalneutron beam. Simultaneously, one would be able to image its biodistribution by MRI with a shortenedT1 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 ¹⁵³Gd. All of the 1B4M'son the conjugate were fully saturated with Gd(III) atoms. An in vitro internalization study showedthat Av-G6Gd accumulated and was internalized into SHIN3 cells (a human ovarian cancer) 50- and3.5-fold greater than Gd-DTPA (Magnevist) and G6-(1B4M-Gd)₂₅₆ (G6Gd). In addition, accumulationof Gd(III) in the cells was detected by the increased signal on T1-weighted MRI. A biodistributionstudy was performed in nude mice bearing intraperitoneally disseminated SHIN3 tumors. Av-G6Gdshowed specific accumulation in the SHIN3 tumor (103% ID/g) 366- and 3.4-fold greater thanGd-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 insidethe cells. The SHIN3 tumor-to-normal tissue ratio was greater than 17:1 in all organs and increasedup to 638:1 at 1 day after i.p. injection. In conclusion, a sufficient amount (162 ppm) of Av-G6Gd wasaccumulated and internalized into the SHIN3 cells both in vitro and in vivo to kill the cell using^157/155Gd 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.