Introducing an albumin-binding entity into otherwise short-lived radiopharmaceuticals can be an effective means to improve their pharmacokinetic properties due to enhanced blood residence time. In the current study, DOTA-derivatized albumin binders based on 4-(p-iodophenyl)butanoate (DOTA-ALB-1 and DOTA-ALB-3) and 5-(p-iodophenyl)pentanoate entities (DOTA-ALB-24 and DOTA-ALB-25) without and with a hydrophobic 4-(aminomethyl)benzoic acid (AMBA) linker unit, respectively, were synthesized and labeled with lutetium-177 for in vitro and in vivo comparison. Overall, [177Lu]Lu-DOTA-ALB-1 demonstrated ~3-fold stronger in vitro albumin-binding affinity and a longer blood residence time (T50%IA~8 h) than [177Lu]Lu-DOTA-ALB-24 (T50%IA~0.8 h). Introducing an AMBA linker enhanced the albumin-binding affinity, resulting in a T50%IAof ~24 h for [177Lu]Lu-DOTA-ALB-3 and ~2 h for [177Lu]Lu-DOTA-ALB-25. The same albumin binders without or with the AMBA linker were incorporated into 6R- and 6S-5-methyltetrahydrofolate-based DOTA-conjugates (177Lu-RedFols). Biodistribution studies in mice performed with both diastereoisomers of [177Lu]Lu-RedFol-1 and [177Lu]Lu-RedFol-3, which comprised the 4-(p-iodophenyl)butanoate moiety, demonstrated a slower accumulation in KB tumors than those of [177Lu]Lu-RedFol-24 and [177Lu]Lu-RedFol-25 with the 5-(p-iodophenyl)pentanoate entity. In all cases, the tumor uptake was high (30–45% IA/g) 24 h after injection. Both diastereoisomers of [177Lu]Lu-RedFol-1 and [177Lu]Lu-RedFol-3 demonstrated high blood retention (3.8–8.7% IA/g, 24 h p.i.) and a 2- to 4-fold lower kidney uptake than the corresponding diastereoisomers of [177Lu]Lu-RedFol-24 and [177Lu]Lu-RedFol-25, which were more rapidly cleared from the blood (<0.2% IA/g, 24 h after injection). Kidney retention of the 6S-diastereoisomers of all177Lu-RedFols was consistently higher than that of the respective 6R-diastereoisomers, irrespective of the albumin binder and linker unit used. It was demonstrated that the blood clearance data obtained with177Lu-DOTA-ALBs had predictive value for the blood retention times of the respective folate radioconjugates. The use of these albumin-binding entities without or with an AMBA linker may serve for fine-tuning the blood retention of folate radioconjugates and also other radiopharmaceuticals and, hence, optimize their tissue distribution profiles. Dosimetry estimations based on patient data obtained with one of the most promising folate radioconjugates will be crucial to identify the dose-limiting organ, which will allow for selecting the most suitable folate radioconjugate for therapeutic purposes.
将白蛋白结合基团引入原本半衰期较短的放射性药物中，可通过延长血液滞留时间有效改善其药代动力学特性。本研究合成了基于4-(对碘苯基)丁酸酯（DOTA-ALB-1和DOTA-ALB-3）与5-(对碘苯基)戊酸酯结构单元（DOTA-ALB-24和DOTA-ALB-25）的DOTA衍生化白蛋白结合剂，其中分别未添加及添加了疏水性4-(氨甲基)苯甲酸（AMBA）连接单元，并用镥-177进行标记以进行体外和体内比较。总体而言，[¹⁷⁷Lu]Lu-DOTA-ALB-1显示出比[¹⁷⁷Lu]Lu-DOTA-ALB-24（T50%IA~0.8小时）约强3倍的体外白蛋白结合亲和力及更长的血液滞留时间（T50%IA~8小时）。引入AMBA连接单元可增强白蛋白结合亲和力，使[¹⁷⁷Lu]Lu-DOTA-ALB-3的T50%IA达到约24小时，[¹⁷⁷Lu]Lu-DOTA-ALB-25达到约2小时。将未添加或添加AMBA连接单元的相同白蛋白结合剂整合至基于6R-和6S-5-甲基四氢叶酸的DOTA偶联物（¹⁷⁷Lu-RedFols）中。对含有4-(对碘苯基)丁酸酯结构的[¹⁷⁷Lu]Lu-RedFol-1和[¹⁷⁷Lu]Lu-RedFol-3两种非对映异构体进行的小鼠生物分布研究表明，其在KB肿瘤中的蓄积速度较含有5-(对碘苯基)戊酸酯结构的[¹⁷⁷Lu]Lu-RedFol-24和[¹⁷⁷Lu]Lu-RedFol-25更慢。所有情况下，注射24小时后肿瘤摄取量均较高（30-45% IA/g）。[¹⁷⁷Lu]Lu-RedFol-1和[¹⁷⁷Lu]Lu-RedFol-3的两种非对映异构体均表现出较高的血液滞留（3.8-8.7% IA/g，注射后24小时），肾脏摄取量较相应的[¹⁷⁷Lu]Lu-RedFol-24和[¹⁷⁷Lu]Lu-RedFol-25非对映异构体低2至4倍，后两者从血液中清除更快（<0.2% IA/g，注射后24小时）。所有¹⁷⁷Lu-RedFols的6S-非对映异构体的肾脏滞留量始终高于相应的6R-非对映异构体，与所使用的白蛋白结合剂和连接单元无关。研究表明，通过¹⁷⁷Lu-DOTA-ALBs获得的血液清除数据对相应叶酸放射性偶联物的血液滞留时间具有预测价值。使用这些未添加或添加AMBA连接单元的白蛋白结合基团，可微调叶酸放射性偶联物及其他放射性药物的血液滞留特性，从而优化其组织分布谱。基于最有前景的叶酸放射性偶联物之一的患者数据进行剂量学评估，对于确定剂量限制性器官至关重要，这将有助于选择最适合治疗用途的叶酸放射性偶联物。
肿瘤(癌症)患者之家