Gotthardt Martin, van Eerd-Vismale Julliëtte, Oyen Wim J G, de Jong Marion, Zhang Hanwen, Rolleman Edgar, Maecke Helmut R, Béhé Martin, Boerman Otto
Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
J Nucl Med. 2007 Apr;48(4):596-601. doi: 10.2967/jnumed.106.036020.
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.
Male Wistar rats (4 per group) were injected intravenously with 1 MBq of (111)In-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.
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 effects 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.
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 molecule. 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.
放射性标记肽的肾脏重吸收所致肾毒性限制了肽受体放射性核素治疗（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。
将雄性Wistar大鼠（每组4只）静脉注射1 MBq的（111）铟标记的奥曲肽（OCT）、胃泌素（MG）、蛙皮素（BOM）或艾塞那肽（EX），同时给予一种潜在的肾脏摄取抑制剂（赖氨酸[Lys]、聚谷氨酸[PGA]和明胶血浆代用品贺斯[GF]）或磷酸盐缓冲盐水作为对照。注射后20小时的器官摄取量以每克注射活性的百分比（%IA/g）来确定。还将Lys、PGA和GF联合使用，以确定是否能获得相加效应。使用磷成像仪通过放射自显影研究肽在肾脏中的定位。
Lys和GF抑制了OCT在肾脏中的蓄积（40.7%-45.1%），而PGA无效。另一方面，PGA和GF抑制了BOM、MG和EX的肾脏摄取（15.4%-85.4%），而Lys无效。GF和Lys联合使用在抑制OCT摄取方面显示出相加效应，而PGA和GF在抑制EX摄取方面具有相加效应。肾脏摄取量与带电荷氨基酸的数量相关。放射自显影显示，所有放射性肽均定位于肾皮质。
Lys或PGA均可抑制所测试放射性肽在肾脏中的蓄积，但不能同时使用两者，这提示存在两种不同的摄取机制。放射性肽在肾脏蓄积的差异可能与分子的电荷数有关。GF是唯一能抑制所有所测试放射性肽在肾脏蓄积的化合物。需要进一步的实验来进一步阐明这些发现，并优化对放射性肽肾脏蓄积的抑制，以降低PRRT中的肾脏剂量。
