H(4) octapa-trastuzumab:用于111In和177Lu成像和治疗的多功能无环酸系统
Eric W Price1, Brian M Zeglis, Jacqueline F Cawthray
1Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada, V6T 1Z1.
Journal of the American Chemical Society
|August 2, 2013
概括
一种新的双功能合剂,p-SCN-Bn-H4octapa,被合成并与trastuzumab结合用于向癌症治疗. 与DOTA-trastuzumab相比,这种H4octapa-trastuzumab合物显示了较好的放射标记和体内性能.
科学领域:
- 放射化学 放射化学是指辐射化学.
- 免疫结合体的发展
- 在瘤学瘤学.
背景情况:
- 针对性放射性药物的开发对于有效的癌症诊断和治疗至关重要.
- 抗体与药物联合体 (ADCs) 和放射性免疫联合体 (RICs) 利用抗体的特异性进行向传递.
- 像DOTA这样的常规化剂在放射性标记效率和抗体完整性保护方面存在局限性.
研究的目的:
- 为了合成和表征一种新的双功能合剂,p-SCN-Bn-H4octapa.
- 评估H4octapa结合的trastuzumab (一种HER2/neu向抗体) 对于放射性标记和体内应用的性能.
- 为了比较H4octapa-trastuzumab放射性免疫结合物的疗效与基于已确定的DOTA化剂的疗效.
主要方法:
- 合成双功能的化剂p-SCN-Bn-H4octapa. 这种组合.
- 结合化剂到特拉斯图祖马布的结合.
- 使用印-111 ((111) In) 和-177 ((177) Lu) 进行放射性标记.
- 在卵巢癌异种移植小鼠模型中的体内研究.
- 生物分布,SPECT成像和抗体完整性与DOTA-trastuzumab合物的比较.
主要成果:
- 与DOTA-trastuzumab相比,H4octapa-trastuzumab在较温和的条件下 (15分钟,RT,~94-95%) 显示出更快,更可重复的放射标记动力学 (60分钟,37°C,~50-88%).
- 抗体完整性在H4octapa-trastuzumab构造物 (免疫反应分数为0.99) 与DOTA-trastuzumab (0.93-0.95) 相比更好地保持.
- 与DOTA-trastuzumab RIC相比,H4octapa-trastuzumab RIC在SPECT成像中表现出改善的体内生物分布,更高的瘤吸收率和更好的瘤与组织比率.
结论:
- 新的p-SCN-Bn-H4octapa化剂在开发基于trastuzumab的放射性免疫结合物方面比DOTA具有显著的优势.
- H4octapa-trastuzumab结合物提供了增强的放射标记效率,更好的抗体完整性,并改善了卵巢癌异种移植的体内向.
- 这种双功能化剂代表了推进向放射性核素治疗和成像的有希望的工具.
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