Abstract：
Targeted radionuclide therapy (TRT) is an effective treatment for tumors. Self-condensation strategies can enhance the retention of radionuclides in tumors and enhance the anti-tumor effect. Considering legumain is overexpressed in multiple types of human cancers, a 131I-labeled radiopharmaceutical ([131I]MAAN) based on the self-condensation reaction between 2-cyanobenzothiazole (CBT) and cysteine (Cys) was developed by us recently for treating legumain-overexpressed tumors. However, liver enrichment limits its application. In this study, a new radiopharmaceutical [131I]IM(HE)3AAN was designed and synthesized by introducing a hydrophilic peptide sequence His-Glu-His-Glu-His-Glu ((HE)3) into [131I]MAAN to optimize the pharmacokinetics. Upon activation by legumain under a reducing environment, hydrophilic [131I]IM(HE)3AAN could react with its precursor to form heterologous dimer [131I]H-Dimer that is highly hydrophobic. Cerenkov imaging revealed that [131I]IM(HE)3AAN displayed superior tumor selectivity and longer tumor retention time as compared with [131I]MAAN, with a significant reduction in the liver uptake. After an 18-day treatment with [131I]IM(HE)3AAN, the tumor proliferation was obviously inhibited, while no obvious injury was observed in the normal organs. These findings suggest that [131I]IM(HE)3AAN could serve as a promising drug candidate for treating legumain-overexpressed tumors.
摘要：
靶向放射性核素治疗（TRT）是一种有效的肿瘤治疗方法。自缩合策略可以增强放射性核素在肿瘤中的保留并增强抗肿瘤效果。考虑到legumain在几种类型的人类癌症中过度表达，我们报道了一种131I标记的放射性药物([131I]MAAN),其基于2-氰基苯并噻唑(CBT)和半胱氨酸(Cys)的自缩合反应,用于体内治疗豆科蛋白酶过表达的肿瘤.然而,肝脏富集限制了它的应用。在这项研究中,通过将亲水肽序列His-Glu-His-Glu-His-Glu-Glu-Glu((HE)3)引入[131I]MAAN以优化药代动力学,合成了一种新的放射性药物[131I]IM(HE)3AAN.在还原环境下被生肉激活后，亲水性[131I]IM(HE)3AAN可以与其前体反应形成高度疏水的异源二聚体([131I]H-二聚体)。切伦科夫成像显示，与[131I]MAAN相比，[131I]IM（HE）3AAN显示出更高的肿瘤选择性和更长的肿瘤保留时间，肝脏摄取显着减少。在用[131I]IM(HE)3AAN治疗18天后，肿瘤增殖受到明显抑制,治疗过程中正常器官未见明显损伤。这些发现表明[131I]IM（HE）3AAN成为治疗豆科蛋白过表达肿瘤的有希望的候选者。
