Indication for different mechanisms of kidney uptake of radiolabeled peptides
Indication for different mechanisms of kidney uptake of radiolabeled peptides
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DOI：
10.2967/jnumed.106.036020
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发表时间：
2007-04-01
影响因子：
9.3
通讯作者：
Boerman, Otto
中科院分区：
文献类型：
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作者：
Gotthardt, Martin;van Eerd-Vismale, Julliette;Boerman, Otto
由于放射性标记肽的肾重吸收引起的肾毒性限制了肽受体放射治疗（PRRT）中的肿瘤剂量。因此，我们评估了几种药物抑制不同放射性肽在肾脏蓄积的能力。研究方法：雄性Wistar大鼠（每组4只）静脉注射1 MBq In-111标记的奥曲肽（OCT）、小胃泌素（MG）、蛙皮素（BOM）或毒蜥外泌肽（EX），以及潜在的肾摄取抑制剂（赖氨酸[Lys]、聚谷氨酸[PGA]和Gelofusine [GF]，一种明胶基血浆扩张剂）或磷酸盐缓冲盐水作为对照。注射后20小时的器官摄取测定为每克注射活性的百分比（%IA/g）。还将Lys、PGA和GF组合以确定是否可以获得累加效应。使用磷光成像仪通过放射自显影研究肽在肾脏中的定位。结果：赖氨酸和GF可抑制OCT在肾脏的蓄积（40.7%~ 45.1%），而PGA对OCT无明显抑制作用. PGA和GF对BOM、MG和EX的肾摄取有抑制作用（15.4%~ 85.4%），而Lys则无抑制作用。GF与Lys合用对OCT摄取的抑制作用呈相加效应，而PGA与GF合用对EX摄取的抑制作用呈相加效应。肾脏摄取的量与带电荷氨基酸的数量相关。放射自显影显示，所有放射性肽均位于肾皮质。结论：赖氨酸或PGA均可抑制检测放射性肽的肾脏蓄积，但不能同时抑制，这表明存在2种不同的摄取机制。放射性肽在肾脏蓄积的差异可能与分子的电荷数有关。GF是唯一抑制所有检测放射性肽肾蓄积的化合物。需要额外的实验来进一步阐明这些发现，并优化放射性肽的肾脏蓄积抑制，以减少PRRT中的肾脏剂量。
Nephrotoxicity due to renal reabsorption of radiolabeled peptides limits the tumor dose in peptide receptor radiotherapy (PRRT). Therefore, we evaluated the ability of several agents to inhibit the renal accumulation of different radiopeptides. Methods: Male Wistar rats (4 per group) were injected intravenously with 1 MBq of In-111-labeled octreotide (OCT), minigastrin (MG), bombesin (BOM), or exendin (EX), together with a potential inhibitor of renal uptake (lysine [Lys], poly-glutamic acid [PGA], and Gelofusine [GF], a gelatin-based plasma expander) or phosphate-buffered saline as a control. Organ uptake at 20 h after injection was determined as the percentage of injected activity per gram (%IA/g). Lys, PGA, and GF were also combined to determine whether an additive effect could be obtained. The localization of the peptides in the kidneys was investigated by autoradiography using a phosphor imager. Results: OCT accumulation in the kidney was inhibited by Lys and GF (40.7%-45.1 %), whereas PGA was ineffective. On the other hand, renal uptake of BOM, MG, and EX was inhibited by PGA and GF (15.4%-85.4%), whereas Lys was ineffective. The combination of GF and Lys showed additive eff ects in inhibiting OCT uptake, whereas PGA and GF had additive effects for the inhibition of EX uptake. The amount of kidney uptake correlated with the number of charged amino acids. All radiopeptides were localized in the renal cortex, as indicated by autoradiography. Conclusion: Inhibition of renal accumulation of the radiopeptides tested could be achieved by either Lys or PGA but not by both at the same time, suggesting 2 different uptake mechanisms. The differences in renal accumulation of radiopeptides may be related to the number of charges of a mol ecule. GF is the only compound that inhibited renal accumulation of all radiopeptides tested. Additional experiments are needed to further elucidate these findings and to optimize inhibition of renal accumulation of radiopeptides to reduce the kidney dose in PRRT.