title: Folate receptor-targeted radionuclide therapy: preclinical investigation of anti-tumor effects and potential radionephropathy.
abstract: BACKGROUND
  Application of therapeutic folate radioconjugates is a promising option for the treatment of folate receptor (FR)-positive tumors, although high uptake of radiofolates in the kidneys remains a critical issue. Recently, it was shown that enhancing the blood circulation of radiofolates results in increased tumor uptake and reduced retention of radioactivity in the kidneys. In this study, we investigated and compared the anti-tumor effects and potential long-term damage to the kidneys after application of an albumin-binding ((177)Lu-cm09), and a conventional ((177)Lu-EC0800) folate radioconjugate.
  
  
  METHODS
  In vivo studies were performed with KB tumor-bearing nude mice. (177)Lu-EC0800 and (177)Lu-cm09 were applied at variable quantities (10-30 MBq/mouse), and the tumor growth was monitored over time. Mice without tumors were injected with the same radiofolates and investigated over eight months by determination of creatinine and blood urea nitrogen plasma levels and by measuring renal uptake of (99m)Tc-DMSA using SPECT. At the study end, the morphological changes were examined on renal tissue sections using variable staining methods.
  
  
  RESULTS
  Compared to untreated controls, dose-dependent tumor growth inhibition and prolonged survival was observed in all treated mice. In line with the resulting absorbed dose, the treatment was more effective with (177)Lu-cm09 than with (177)Lu-EC0800, enabling complete tumor remission after application of ≥20MBq (≥28Gy). Application of radiofolates with an absorbed renal dose ≥23 Gy showed increased levels of renal plasma parameters and reduced renal uptake of (99m)Tc-DSMA. Morphological changes observed on tissue sections confirmed radionephropathy of variable stages.
  
  
  CONCLUSIONS
  (177)Lu-cm09 showed more favorable anti-tumor effects and significantly less damage to the kidneys compared to (177)Lu-EC0800 as was expected based on improved tumor-to-kidney ratios. It was demonstrated that enhancing the blood circulation time of radiofolates was favorable regarding the risk-benefit profile of a therapeutic application. These results hold promise for future translation of the albumin-binder concept to the clinics, potentially enabling FR-targeted radionuclide therapy in patients.
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Haller
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland.
authors.forename: Josefine
authors.initials: J
authors.lastname: Reber
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Brandt
authors.affiliation: Department of Radiation Physics, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska Universitetssjukhuset, 41345 Gothenburg, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Bernhardt
authors.affiliation: Merck and Cie, Laternenacker 5, 8200 Schaffhausen, Switzerland.
authors.forename: Viola
authors.initials: V
authors.lastname: Groehn
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland; Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland. Electronic address: cristina.mueller@psi.ch.
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000528:radiation effects; D001835:Body Weight / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D056831:Coordination Complexes / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005492:Folic Acid / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D058972:Folic Acid Transporters / Q000378:metabolism*; D006801:Humans; D007624:KB Cells; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D007674:Kidney Diseases / Q000209:etiology*; D007962:Leukocytes / Q000166:cytology / Q000528:radiation effects; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000097:blood / Q000378:metabolism / Q000532:radiotherapy*; D011832:Radiation Injuries / Q000209:etiology*; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016019:Survival Analysis; D019783:Technetium Tc 99m Dimercaptosuccinic Acid / Q000378:metabolism
chemical_list: C000589258:177Lu-EC0800; C000592412:177Lu-cm09; D056831:Coordination Complexes; D058972:Folic Acid Transporters; D019275:Radiopharmaceuticals; D019783:Technetium Tc 99m Dimercaptosuccinic Acid; D005492:Folic Acid
keywords: (177)Lu; Albumin-binder; Kidney damage; Radiofolates; Radionephropathy; Radionuclide therapy