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共价向放射性连接体强化放射性核酸治疗

Xi-Yang Cui^1,2, Zhu Li³, Ziren Kong⁴

¹Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, P. R. China.

|May 22, 2024

概括

一种新的硫 (VI) 化物交换 (SuFEx) 化学策略使放射性药物能够与癌症标结合,改善瘤吸收和保留向放射性核酸治疗. 这种方法提高了成像和治疗效果,同时从健康组织中快速清除.

科学领域:

癌症学
放射化学
医学化学

背景情况:

有针对性的放射性核酸治疗提供局部癌症照射,但在可持续的瘤向和快速的健康组织清除方面面临挑战.
一个关键的限制是放射性药物与向蛋白质的分离,导致治疗结果不理想.
开发持续结合放射性药物与瘤特异性蛋白质的策略对于推进癌症治疗至关重要.

研究的目的:

设计具有新结策略的放射性药物,以实现持续的瘤向和增强治疗效果.
研究使用硫 (VI) 化物交换 (SuFEx) 化学方法对放射性药物与瘤特异性蛋白进行共价结合.
在临床前和试点临床研究中评估SuFEx工程放射性药物的瘤吸收,保留,成像和治疗结果.

主要方法:

在放射性药物上安装基于化学的SuFEx链接器,以便在目标接触时从结合到结合过渡.
通过SuFEx"点击"反应将工程放射性药物与氨酸残留物结合.
在小鼠模型中评估共价结合,解离动力学,瘤吸收,健康组织清除,成像和治疗疗效,并进行试点患者研究.

主要成果:

SuFEx设计的纤维细胞激活蛋白抑制剂 (FAPI) 在六天内显示出超过80%的共价结合和最小的分离.
与原始FAPI相比,SuFEx- FAPI在小鼠中增加了257%的瘤吸收和13倍的瘤保留,并从健康组织中快速清除.
使用SuFEx策略的试验成像研究在癌症患者中发现了更多的瘤病变,使用SuFEx设计的FAPI和前列腺特异性膜抗原 (PSMA) 放射性对象的向治疗导致了小鼠的显著瘤回归.

结论:

SuFEx绑定策略有效地产生持续瘤向和增强保留的放射性药物,克服了当前向放射性核酸治疗的关键局限性.
这种方法显著改善了瘤成像和治疗效果,正如FAPI和PSMA目标所示.
SuFEx化学的适应性表明其可用于广泛的癌症点,为开发下一代放射性药物提供了多功能平台.

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