title: The involvement of selected membrane transport mechanisms in the cellular uptake of (177)Lu-labeled bombesin, somatostatin and gastrin analogues.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Volková
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Mandíková
authors.affiliation: Department of Biophysics and Physical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic.
authors.forename: A
authors.initials: A
authors.lastname: Lázníčková
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Lázníček
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Bárta
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. Electronic address: trejtnarf@faf.cuni.cz.
authors.forename: F
authors.initials: F
authors.lastname: Trejtnar
mesh_terms: D000818:Animals; D001692:Biological Transport; D001839:Bombesin / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D004705:Endocytosis; D005755:Gastrins / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007553:Isotope Labeling; D008187:Lutetium; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D036361:Peptide Hormones / Q000737:chemistry* / Q000378:metabolism*; D013004:Somatostatin / Q000737:chemistry / Q000378:metabolism; D013552:Swine
chemical_list: D005755:Gastrins; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D036361:Peptide Hormones; C490280:SLC22A7 protein, human; D013004:Somatostatin; D008187:Lutetium; D001839:Bombesin
keywords: Fluid phase endocytosis; Megalin; Nephrotoxicity; Organic anion transporter; Organic cation transporter; Peptides