Graduate School of Medical Sciences, Kanazawa University, Kakuma-Machi, Kanazawa, 920-1192, Ishikawa, Japan.
Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.
Eur J Nucl Med Mol Imaging. 2024 Jul;51(9):2663-2671. doi: 10.1007/s00259-024-06695-w. Epub 2024 Apr 4.
A probe for targeted alpha therapy (TAT) using the RGD peptide (Ga-DOTA-K([At]APBA)-c(RGDfK) ([At]1)) with albumin-binding moiety (ABM) was recently developed. [At]1 highly accumulated in tumors and significantly inhibited tumor growth in U-87 MG tumor-bearing mice. However, high [At]1 retention in blood may cause critical adverse events, such as hematotoxicity. Therefore, we attempted to accelerate the blood clearance of [At]1 by competitively inhibiting the binding of [At]1 to albumin to modulate the pharmacokinetics of the former.
To evaluate the effects of albumin-binding inhibitors in normal mice, sodium 4-(4-iodophenyl)butanoate at 2, 5, or 10 molar equivalents of blood albumin was administered at 1-h postinjection of [At]1. The biodistribution of [At]1, SPECT/CT imaging of [Ga]Ga-DOTA-K(IPBA)-c(RGDfK) ([Ga]2), and the therapeutic effects of [At]1 were compared with or without IPBA administration in U-87 MG tumor-bearing mice.
Blood radioactivity of [At]1 was decreased in a dose-dependent manner with IPBA in normal mice. In U-87 MG tumor-bearing mice, the blood radioactivity and accumulation in nontarget tissues of [At]1 were decreased by IPBA. Meanwhile, tumor [At]1 accumulation was not changed at 3-h postinjection of IPBA. In SPECT/CT imaging of [Ga]2, IPBA administration dramatically decreased radioactivity in nontarget tissues, and only tumor tissue was visualized. In therapeutic experiments, [At]1 with IPBA injected-group significantly inhibited tumor growth compared to the control group.
IPBA administration (as an albumin-binding inhibitor) could modulate the pharmacokinetics and enhance the therapeutic effects of [At]1.
最近开发了一种使用带有白蛋白结合部分（ABM）的 RGD 肽（Ga-DOTA-K([At]APBA)-c(RGDfK) ([At]1)）的靶向 alpha 治疗（TAT）探针。[At]1 在肿瘤中高度积聚，并显著抑制 U-87 MG 荷瘤小鼠的肿瘤生长。然而，[At]1 在血液中的高保留可能导致严重的不良反应，如血液毒性。因此，我们试图通过竞争性抑制[At]1 与白蛋白的结合来加速[At]1 的血液清除，从而调节前者的药代动力学。
为了评估白蛋白结合抑制剂在正常小鼠中的作用，在注射[At]1 后 1 小时给予 2、5 或 10 摩尔当量的血白蛋白的 4-（4-碘苯基）丁酸钠。比较了[At]1 在有无 IPBA 给药时的生物分布、[Ga]Ga-DOTA-K(IPBA)-c(RGDfK) ([Ga]2)的 SPECT/CT 成像以及[At]1 的治疗效果。
在正常小鼠中，[At]1 的血液放射性随 IPBA 的剂量呈剂量依赖性降低。在 U-87 MG 荷瘤小鼠中，IPBA 降低了[At]1 的血液放射性和非靶组织的积累。同时，在注射 IPBA 后 3 小时，肿瘤[At]1 的积累没有变化。在[Ga]2 的 SPECT/CT 成像中，IPBA 给药显著降低了非靶组织的放射性，仅显示肿瘤组织。在治疗实验中，与对照组相比，注射 IPBA 的[At]1 组显著抑制了肿瘤生长。
IPBA 给药（作为白蛋白结合抑制剂）可以调节[At]1 的药代动力学并增强其治疗效果。
