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Abstract：
OBJECTIVE: A probe for targeted alpha therapy (TAT) using the RGD peptide (Ga-DOTA-K([211At]APBA)-c(RGDfK) ([211At]1)) with albumin-binding moiety (ABM) was recently developed. [211At]1 highly accumulated in tumors and significantly inhibited tumor growth in U-87 MG tumor-bearing mice. However, high [211At]1 retention in blood may cause critical adverse events, such as hematotoxicity. Therefore, we attempted to accelerate the blood clearance of [211At]1 by competitively inhibiting the binding of [211At]1 to albumin to modulate the pharmacokinetics of the former.
METHODS: 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 [211At]1. The biodistribution of [211At]1, SPECT/CT imaging of [67Ga]Ga-DOTA-K(IPBA)-c(RGDfK) ([67Ga]2), and the therapeutic effects of [211At]1 were compared with or without IPBA administration in U-87 MG tumor-bearing mice.
RESULTS: Blood radioactivity of [211At]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 [211At]1 were decreased by IPBA. Meanwhile, tumor [211At]1 accumulation was not changed at 3-h postinjection of IPBA. In SPECT/CT imaging of [67Ga]2, IPBA administration dramatically decreased radioactivity in nontarget tissues, and only tumor tissue was visualized. In therapeutic experiments, [211At]1 with IPBA injected-group significantly inhibited tumor growth compared to the control group.
CONCLUSIONS: IPBA administration (as an albumin-binding inhibitor) could modulate the pharmacokinetics and enhance the therapeutic effects of [211At]1.
METHODS: 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 [211At]1. The biodistribution of [211At]1, SPECT/CT imaging of [67Ga]Ga-DOTA-K(IPBA)-c(RGDfK) ([67Ga]2), and the therapeutic effects of [211At]1 were compared with or without IPBA administration in U-87 MG tumor-bearing mice.
RESULTS: Blood radioactivity of [211At]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 [211At]1 were decreased by IPBA. Meanwhile, tumor [211At]1 accumulation was not changed at 3-h postinjection of IPBA. In SPECT/CT imaging of [67Ga]2, IPBA administration dramatically decreased radioactivity in nontarget tissues, and only tumor tissue was visualized. In therapeutic experiments, [211At]1 with IPBA injected-group significantly inhibited tumor growth compared to the control group.
CONCLUSIONS: IPBA administration (as an albumin-binding inhibitor) could modulate the pharmacokinetics and enhance the therapeutic effects of [211At]1.
摘要：
目的:最近开发了使用具有白蛋白结合部分(ABM)的RGD肽(Ga-DOTA-K([211At]APBA)-c(RGDfK)([211At]1))的靶向α治疗(TAT)的探针。[211At]1在U-87MG荷瘤小鼠中在肿瘤中高度积累并显著抑制肿瘤生长。然而,血液中的高[211At]1滞留可能导致严重的不良事件，如血液毒性。因此,我们试图通过竞争性抑制[211At]1与白蛋白的结合来调节前者的药代动力学，从而加速[211At]1的血液清除。
方法：为了评估白蛋白结合抑制剂对正常小鼠的影响，在注射[211At]1后1小时，给予2、5或10摩尔当量的血液白蛋白4-（4-碘苯基）丁酸钠。[211At]1的生物分布，[67Ga]Ga-DOTA-K（IPBA）-c（RGDfK）（[67Ga]2）的SPECT/CT成像，在U-87MG荷瘤小鼠中，比较了[211At]1的治疗效果。
结果：在正常小鼠中，[211At]1的血液放射性以剂量依赖性方式降低。在U-87MG荷瘤小鼠中，IPBA降低了[211At]1的血液放射性和非靶组织中的积累。同时,在注射IPBA后3小时，肿瘤[211At]1的积累没有改变。在[67Ga]2的SPECT/CT成像中，IPBA给药显著降低了非靶组织的放射性，只有肿瘤组织可见。在治疗实验中,与对照组相比,注射IPBA的[211At]1显著抑制肿瘤生长。
结论：IPBA给药（作为白蛋白结合抑制剂）可以调节[211At]1的药代动力学并增强治疗效果。
方法：为了评估白蛋白结合抑制剂对正常小鼠的影响，在注射[211At]1后1小时，给予2、5或10摩尔当量的血液白蛋白4-（4-碘苯基）丁酸钠。[211At]1的生物分布，[67Ga]Ga-DOTA-K（IPBA）-c（RGDfK）（[67Ga]2）的SPECT/CT成像，在U-87MG荷瘤小鼠中，比较了[211At]1的治疗效果。
结果：在正常小鼠中，[211At]1的血液放射性以剂量依赖性方式降低。在U-87MG荷瘤小鼠中，IPBA降低了[211At]1的血液放射性和非靶组织中的积累。同时,在注射IPBA后3小时，肿瘤[211At]1的积累没有改变。在[67Ga]2的SPECT/CT成像中，IPBA给药显著降低了非靶组织的放射性，只有肿瘤组织可见。在治疗实验中,与对照组相比,注射IPBA的[211At]1显著抑制肿瘤生长。
结论：IPBA给药（作为白蛋白结合抑制剂）可以调节[211At]1的药代动力学并增强治疗效果。
