Reducing renal uptake of radiolabeled peptides using albumin fragments
Reducing renal uptake of radiolabeled peptides using albumin fragments
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DOI：
10.2967/jnumed.108.053249
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发表时间：
2008-09-01
影响因子：
9.3
通讯作者：
Boerman, Otto C.
中科院分区：
文献类型：
--
作者：
Vegt, Erik;van Eerd, Julliette E. M.;Boerman, Otto C.
在大多数类型的肽受体放射性核素疗法中，可以施用的最大活性剂量受到放射性标记的肽的高且持久的肾保留的限制，其至少部分地由巨蛋白受体介导。已经鉴定了几种干扰放射性标记肽的肾重吸收的试剂（例如，赖氨酸、精氨酸、琥珀酰明胶溶液），但这些都不能完全抑制肾重吸收。白蛋白，一种天然丰富的巨蛋白配体，可能是一种安全有效的替代品。本研究分析了白蛋白和白蛋白片段（FRALB）对In-111-二乙烯三胺五乙酸（DTPA）-D-Phe（1）-奥曲肽肾重吸收的影响（In-111-奥曲肽）、[Lys（40）[氨基己酸-DTPA-In-111] NH 2]-exendin-4（In-111-毒蜥外泌肽）和In-111- 1，4，7，10-四氮杂环十二烷-N，N '，N“，N”"-四乙酸（DOTA）-Glu（1）-小胃泌素（In-111-小胃泌素）。研究方法：使用大鼠卵黄囊上皮（BN 16）细胞在体外评估白蛋白和FRALB对In-111-奥曲肽、In-111-exendin和In-111-minigastrin的巨蛋白相关结合的影响。在体内，In-111-白蛋白和In-111-FRALB在Wistar大鼠肾脏中的摄取和定位被确定，以及赖氨酸、琥珀酰明胶溶液、白蛋白和FRALB对In-111-奥曲肽、In-111-毒蜥外泌肽和In-111-小胃泌素的肾脏摄取的影响。结果：FRALB显着降低BN 16细胞的In-111-奥曲肽，In-111-exendin和In-111-minigastrin的结合和摄取。大鼠肾摄取In-111标记的FRALB显著高于In-111标记的完整白蛋白（P < 0.001）。FRALB给药有效地降低了In-111-奥曲肽、In-111-毒蜥外泌肽和In-111-小胃泌素的肾摄取。给予1-2 mg FRALB与给予80 mg赖氨酸一样有效地降低In-111-奥曲肽的肾摄取。总结：给予白蛋白片段可有效降低大鼠肾脏对In-111-奥曲肽和其他放射性标记肽的摄取。有必要进行额外的研究，以确定负责抑制肾肽摄取的白蛋白片段。
In most types of peptide receptor radionuclide therapy, the maximum activity dose that can be administered is limited by high and persistent renal retention of the radiolabeled peptides, which is, at least partly, mediated by the megalin receptor. Several agents that interfere with renal reabsorption of radiolabeled peptides have been identified (e.g., lysine, arginine, succinylated gelatin solution), but none of these inhibit renal reabsorption completely. Albumin, a naturally abundant megalin ligand, might be a safe and potent alternative. In this study, we analyzed the effects of albumin and fragments of albumin (FRALB) on the renal reabsorption of In-111-diethylenetriaminepentaacetic acid (DTPA)-D-Phe(1)-octreotide (In-111-octreotide), [Lys(40)(aminohexoic acid-DTPA-In-111)NH2]-exendin-4 (In-111-exendin), and In-111-1,4,7,10-tetraazacyclododecane-N,N',N '',N'''-tetraacetic acid (DOTA)-Glu(1)-minigastrin (In-111-minigastrin). Methods: The effects of albumin and FRALB on megalin-associated binding of In-111-octreotide, In-111-exendin, and In-111-minigastrin were assessed in vitro using rat yolk sac epithelial (BN16) cells. In vivo, uptake and localization of In-111-albumin and In-111-FRALB in the kidneys of Wistar rats were determined, as well as the effect of lysine, succinylated gelatin solution, albumin, and FRALB on the kidney uptake of In-111-octreotide, In-111-exendin, and In-111-minigastrin. Results: FRALB significantly reduced binding and uptake of In-111-octreotide, In-111-exendin, and In-111-minigastrin by BN16 cells. In rats, renal uptake of In-111-labeled FRALB was significantly higher than that of In-111-labeled intact albumin (P < 0.001). FRALB administration effectively reduced renal uptake of In-111-octreotide, In-111-exendin, and In-111-minigastrin. Administration of 1-2 mg of FRALB reduced renal uptake of In-111-octreotide as efficiently as 80 mg of lysine. Conclusion: Renal uptake of In-111-octreotide and other radiolabeled peptides in rats can be effectively reduced by administration of albumin fragments. Additional studies to identify the albumin fragments responsible for inhibition of renal peptide uptake are warranted.