Key Laboratory of Radiation Physics and Technology of the Ministry of Education, Institute of Nuclear Science and Technology, Sichuan University, Chengdu, 610064, China.
Department of Nuclear Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
Eur J Med Chem. 2024 Dec 5;279:116919. doi: 10.1016/j.ejmech.2024.116919. Epub 2024 Sep 26.
Fibroblast activation protein-α (FAPα) is highly expressed in tumor-associated cells and has become one of the most attractive targeting sites in cancer diagnosis and therapy. To ameliorate the rapid metabolism of FAPα inhibitor (FAPI), here, a multifunctional binding agent was introduced to simultaneously achieve At radiolabeling and tumor retention prolongation of corresponding radiolabeled drug. At-APBA-FAPI was successfully synthesized by conjugating At with the designed FAPI carrier in satisfactory radiochemical yield (>60 %). At-APBA-FAPI exhibited excellent in vitro stability, significant tumor affinity and specific killing effect on FAPα-positive U87MG cells. Molecular docking reveals that FAPI decorated with albumin binder can bind with FAPα protein via multiple intermolecular interactions with a considerable binding energy of -9.66 kcal/mol At-APBA-FAPI exhibits good targeting in murine xenograft models, showing obviously longer tumor retention than previously-reported radioastatinated compound. As a result, At-APBA-FAPI presents pronounced therapeutic effect with ignorable normal organs/tissues biotoxicity. All these indicate that introducing a multifunctional binding agent can effectively enhance the availability of FAPI for At conjugation and tumoricidal effect, providing vital hints for the translation of targeted-alpha therapy based on radiolabeled FAPI derivatives.
成纤维细胞激活蛋白-α（FAPα）在肿瘤相关细胞中高度表达，已成为癌症诊断和治疗中最有吸引力的靶向位点之一。为了改善 FAPα抑制剂（FAPI）的快速代谢，本文引入了一种多功能结合剂，以同时实现放射性标记的 At 和相应放射性标记药物在肿瘤中的滞留延长。通过将 At 与设计的 FAPI 载体缀合，成功合成了 At-APBA-FAPI，放射化学收率>60%。At-APBA-FAPI 表现出优异的体外稳定性、对 FAPα阳性 U87MG 细胞的显著肿瘤亲和力和特异性杀伤作用。分子对接表明，通过与 FAPα 蛋白的多种分子间相互作用，用白蛋白结合剂修饰的 FAPI 可以与 FAPα 蛋白结合，结合能为-9.66 kcal/mol。At-APBA-FAPI 在小鼠异种移植模型中具有良好的靶向性，与之前报道的放射性标记化合物相比，肿瘤滞留时间明显延长。结果表明，At-APBA-FAPI 具有明显的治疗效果，正常器官/组织的生物毒性可忽略不计。所有这些都表明，引入多功能结合剂可以有效地提高 FAPI 与 At 缀合和杀肿瘤效果的可用性，为基于放射性标记 FAPI 衍生物的靶向-α治疗的转化提供了重要线索。
