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Avidin-biotin system pretargeting radioimmunoimaging and radioimmunotherapy and its application in mouse model of human colon carcinoma

机译:靶向放射免疫成像和放射免疫疗法的抗生物素蛋白-生物素系统及其在人结肠癌小鼠模型中的应用

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摘要

AIM: To evaluate the multi-step pretargeting radioimm-unoimaging (RII) and radioimmunotherapy (RIT) in nude mice bearing human colon carcinoma with avidin-biotin system labeled with 153Sm.METHODS: Two- and three-step strategies for avidin-biotin system pretargeting techniques were established. In a three-step procedure, human colon carcinoma bearing nude mice were first injected with biotinylated monoclonal antibody (McAb-Bt) followed by cold avidin (Av) 48 h later and then 153Sm-DB2 24 h thereafter; whereas the two-step procedure consisted of injection of 153Sm-SA 48 h after pretargeting with biotinylated anti-CEA monoclonal antibody (CEA McAb-Bt). SPECT imaging and biodistribution were performed at 4, 24, 48, or 72 h after injection of 153Sm-labeled compounds. Five groups of nude mice subcutaneously grafted with human colon carcinoma were treated 3 d after grafting. One group received the injection with 100 μg CEA McAb-Bt followed by cold avidin (80 μg) after 2 d and 11.1 MBq 153Sm-DB2 after 1 d. Four control groups were treated respectively with 11.1 MBq 153Sm-CEA McAb, 11.1 MBq 153Sm-nmIgG, 11.1 MBq 153Sm-DB2, 100 μL normal saline. Toxicity was evaluated by changes of leukocyte count, and the efficacy by variation in tumor volume. Histological analyses of tumors were performed.RESULTS: The three-step procedure allowed faster blood clearance and yielded higher tumor blood ratios (5.76 at 4 h and 12.94 at 24 h) of the 153Sm-DB2. The tumor was clearly visualized at 4 h in γ-imaging after the injection of 153Sm-DB2, while a significant accumulation of 153Sm-SA in the tumor was observed only 24 h after the injection and tumor blood ratios at 4 and 24 h were 1.00 and 2.03, respectively, in the two-step procedure. Pretargeting RIT and 153Sm-CEA McAb had a strong tumor-inhibiting effect. The tumor inhibitory rate was 80.67% and 78.44%, respectively, five weeks after therapy. Histopathological evidence also indicated radioactive damage in tumor tissues as necrosis of tumor cells, while in the other organs such as liver and kidney no radioactive damage was observed. Leukocyte counts showed significant decrease after treatment in groups of 153Sm-CEA McAb and 153Sm-nmIgG.CONCLUSION: The two kinds of pretargeting strategies can elevate the target-to-nontarget ratio, decrease the blood background and shorten the imaging time compared to 153Sm-CEA McAb. Three-step pretargeting RIT is as efficient as 153Sm-CEA McAb, but markedly less toxic. This study provides experimental evidence for the clinical application of pretargeting RII and RIT.
机译:目的:评估带有人结肠癌的裸鼠的多步骤预靶向放射免疫成像(RII)和放射免疫疗法(RIT),该裸鼠具有标有 153 Sm的抗生物素蛋白-生物素系统。方法:二和三建立了抗生物素蛋白-生物素系统预靶向技术的分步策略。通过三步过程,首先在48小时后向带有人结肠癌的裸鼠注射生物素化单克隆抗体(McAb-Bt),然后注射抗生物素蛋白(Av),然后在24小时内 153 Sm-DB2之后;而分两步进行的步骤是在预先靶向生物素化抗CEA单克隆抗体(CEA McAb-Bt)48小时后注射 153 Sm-SA。在注射 153 Sm标记的化合物后的4、24、48或72 h进行SPECT成像和生物分布。在移植后3天对五组皮下移植人结肠癌的裸鼠进行治疗。一组在注射后2 d注射100μgCEA McAb-Bt,然后注射冷抗生物素蛋白(80μg),在注射1 d后接受11.1 MBq 153 Sm-DB2。四个对照组分别接受11.1 MBq 153 Sm-CEA单克隆抗体,11.1 MBq 153 Sm-nmIgG,11.1 MBq 153 Sm-DB2, 100μL生理盐水。通过白细胞计数的变化评估毒性,通过肿瘤体积的变化评估疗效。结果:通过三步法可以更快地清除血液并产生更高的 153 Sm-DB2肿瘤血液比率(4 h为5.76,24 h为12.94)。注射 153 Sm-DB2后第4小时在γ成像中清晰可见肿瘤,而仅观察到 153 Sm-SA在肿瘤中大量积聚。注射后24小时,在两步程序中,第4小时和第24小时的肿瘤血液比率分别为1.00和2.03。预靶向RIT和 153 Sm-CEA单克隆抗体具有很强的抑瘤作用。治疗5周后,肿瘤抑制率分别为80.67%和78.44%。组织病理学证据还表明,肿瘤组织中的放射性损伤为肿瘤细胞坏死,而在其他器官如肝和肾中,未观察到放射性损伤。结论: 153 Sm-CEA单克隆抗体和 153 Sm-nmIgG组治疗后白细胞计数显着下降。结论:两种预靶向策略可以将靶点提高至与 153 Sm-CEA单克隆抗体相比,非靶标比率降低了血液背景并缩短了成像时间。三步预靶向RIT与 153 Sm-CEA McAb一样有效,但毒性明显较低。这项研究为预靶向RII和RIT的临床应用提供了实验证据。

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