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生物分布驱动的发现确定了一个可切割的糖化酶连接器来重新编程放射性无线电学

Woonghee Lee¹, Sai Reddy Doda², Kwamena E Baidoo¹

¹Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bethesda, MD 20895, USA.

bioRxiv : the preprint server for biology

|September 26, 2025

概括

新的可切割连接剂可以改善晚期癌症的放射性药物治疗 (RPT). 这些链接器增强瘤向性并减少脏毒性,为更有效的癌症治疗提供了有希望的策略,副作用更少.

科学领域:

在瘤学瘤学.
放射性药物化学放射性药物化学
分子成像学分子成像学

背景情况:

放射性药物治疗 (RPT) 是晚期前列腺癌和神经内分泌瘤 (NETs) 的标准,但治疗因正常组织毒性而受到限制.
酶可切割的链接剂提供了一种策略,通过向瘤特异性酶来提高RPT的治疗指数.

研究的目的:

设计,合成和评估用于RPT剂DOTA-TATE的新型可切割链接剂.
在临床前模型中评估可切割链接剂对瘤吸收,脏保留和治疗疗效的影响.

主要方法:

合成了一系列具有多种可切割链接器的DOTA-TATE类似物.
在小鼠神经内分泌瘤模型中使用86Y标记剂进行正子发射断层扫描 (PET) 成像.
进行了体外和体外酶裂解研究.
使用225Ac标记的药物进行治疗疗效研究.

主要成果:

与DOTA-TATE相比,两个可切割的链接剂DOTA-MVK(ε) -TATE和DOTA-β-Gal-TATE减少了脏保留.
86Y-DOTA-β-Gal-TATE显示了瘤吸收的增强,瘤与脏的比率提高了10倍.
这两种被标记为225Ac的可切割剂都表现出治疗疗效,改善了生存率和降低了毒性.
225Ac-DOTA-β-Gal-TATE表现出明显较低的毒性.

结论:

可切割链接体化学是一种可行的策略,可以增强RPT剂的药理动力学并降低毒性.
DOTA-β-Gal-TATE是一种有前途的下一代RPT药物,具有改进的瘤向性和安全性.
这种方法有可能在开发改进的放射性药物治疗中得到更广泛的应用.

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