Volková M, Mandíková J, Lázníčková A, Lázníček M, Bárta P, Trejtnar F
Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic.
Department of Biophysics and Physical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic.
Nucl Med Biol. 2015 Jan;42(1):1-7. doi: 10.1016/j.nucmedbio.2014.09.003. Epub 2014 Sep 19.
Radiolabeled receptor-targeting peptides are a useful tool for the diagnostic imaging and radiotherapy of some malignancies. However, the retention of radioactivity in the kidney may result in renal radiotoxic injury. This study seeks to evaluate the role of endocytic receptor megalin, renal SLC influx transporters and fluid phase endocytosis (FPE) in the cellular accumulation of radiolabeled peptides.
In vitro transport cellular studies using megalin ligands (RAP, albumin), fluid phase endocytosis (FPE) inhibitor rottlerin and low temperature were employed to evaluate the transport mechanisms of the peptides. Cells transfected with hOAT1 or hOCT2 were used to analyze the role of these SLC transporters. Somatostatin ((177)Lu-DOTA-[Tyr(3)]octreotate, (177)Lu-DOTA-[1-Nal(3)]octreotide), gastrin ((177)Lu-DOTA-sargastrin) and bombesin ((177)Lu-DOTA-[Pro(1),Tyr(4)]bombesin, (177)Lu-DOTA-[Lys(3)]bombesin, (177)Lu-PCTA-[Lys(3)]bombesin) analogues were involved in the study.
RAP, albumin and low temperature decreased the accumulation of all the studied peptides significantly. With one exception, rottlerin caused the concentration dependent inhibition of the cellular accumulation of the radiopeptides. No significant differences in the uptake of the peptides between the control cells and those transfected with hOAT1 or hOCT2 were observed.
The study showed that active transport mechanisms are decisive for the cellular accumulation in all tested (177)Lu-labeled somatostatin, gastrin and bombesin analogues. Besides receptor-mediated endocytosis by megalin, FPE participates significantly in the uptake. The tested types of renal SLC transporters are not involved in this process.
放射性标记的靶向受体肽是某些恶性肿瘤诊断成像和放射治疗的有用工具。然而，肾脏中放射性的滞留可能导致肾脏放射性毒性损伤。本研究旨在评估内吞受体巨膜蛋白、肾脏溶质载体（SLC）流入转运体和液相内吞作用（FPE）在放射性标记肽细胞摄取中的作用。
使用巨膜蛋白配体（RAP、白蛋白）、液相内吞作用（FPE）抑制剂rottlerin和低温进行体外转运细胞研究，以评估肽的转运机制。使用转染了hOAT1或hOCT2的细胞来分析这些SLC转运体的作用。参与研究的有生长抑素（（177）Lu-DOTA-[Tyr(3)]奥曲肽、（177）Lu-DOTA-[1-Nal(3)]奥曲肽）、胃泌素（（177）Lu-DOTA-促胃液素）和蛙皮素（（177）Lu-DOTA-[Pro(1),Tyr(4)]蛙皮素、（177）Lu-DOTA-[Lys(3)]蛙皮素、（177）Lu-PCTA-[Lys(3)]蛙皮素）类似物。
RAP、白蛋白和低温显著降低了所有研究肽的摄取。除了一个例外，rottlerin导致放射性肽细胞摄取的浓度依赖性抑制。在对照细胞与转染hOAT1或hOCT2的细胞之间，未观察到肽摄取的显著差异。
该研究表明，主动转运机制对于所有测试的（177）Lu标记的生长抑素、胃泌素和蛙皮素类似物的细胞摄取起决定性作用。除了巨膜蛋白介导的受体介导内吞作用外，FPE在摄取中也起重要作用。所测试的肾脏SLC转运体类型不参与此过程。
