title: Improved safety and efficacy of213Bi-DOTATATE-targeted alpha therapy of somatostatin receptor-expressing neuroendocrine tumors in mice pre-treated with L-lysine.
abstract: BACKGROUND
  Targeted alpha therapy (TAT) offers advantages over current β-emitting conjugates for peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors. PRRT with177Lu-DOTATATE or90Y-DOTATOC has shown dose-limiting nephrotoxicity due to radiopeptide retention in the proximal tubules. Pharmacological protection can reduce renal uptake of radiopeptides, e.g., positively charged amino acids, to saturate in the proximal tubules, thereby enabling higher radioactivity to be safely administered. The aim of this preclinical study was to evaluate the therapeutic effect of213Bi-DOTATATE with and without renal protection using L-lysine in mice. Tumor uptake and kinetics as a function of injected mass of peptide (range 0.03-3 nmol) were investigated using111In-DOTATATE. These results allowed estimation of the mean radiation absorbed tumor dose for213Bi-DOTATATE. Pharmacokinetics and dosimetry of213Bi-DOTATATE was determined in mice, in combination with renal protection. A dose escalation study with213Bi-DOTATATE was performed to determine the maximum tolerated dose (MTD) with and without pre-administration of L-lysine as for renal protection. Neutrophil gelatinase-associated lipocalin (NGAL) served as renal biomarker to determine kidney injury.
  
  
  RESULTS
  The maximum mean radiation absorbed tumor dose occurred at 0.03 nmol and the minimum at 3 nmol. Similar mean radiation absorbed tumor doses were determined for 0.1 and 0.3 nmol with a mean radiation absorbed dose of approximately 0.5 Gy/MBq213Bi-DOTATATE. The optimal mass of injected peptide was found to be 0.3 nmol. Tumor uptake was similar for111In-DOTATATE and213Bi-DOTATATE at 0.3 nmol peptide. Lysine reduced the renal uptake of213Bi-DOTATATE by 50% with no effect on the tumor uptake. The MTD was <13.0 ± 1.6 MBq in absence of L-lysine and 21.7 ± 1.9 MBq with L-lysine renal protection, both imparting an LD50mean renal radiation absorbed dose of 20 Gy. A correlation was found between the amount of injected radioactivity and NGAL levels.
  
  
  CONCLUSIONS
  The therapeutic potential of213Bi-DOTATATE was illustrated by significantly decreased tumor burden and improved overall survival. Renal protection with L-lysine immediately prior to TAT with213Bi-DOTATATE prolonged survival providing substantial evidence for pharmacological nephron blockade to mitigate nephrotoxicity.
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. h.s.chan1982@gmail.com.
authors.forename: Ho Sze
authors.initials: HS
authors.lastname: Chan
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Konijnenberg
authors.affiliation: Radiopharmaceutical Sciences Program, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Daniels
authors.affiliation: Radiopharmaceutical Sciences Program, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Monique
authors.initials: M
authors.lastname: Nysus
authors.affiliation: Radiopharmaceutical Sciences Program, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Mehran
authors.initials: M
authors.lastname: Makvandi
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: de Blois
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: Wouter A
authors.initials: WA
authors.lastname: Breeman
authors.affiliation: Radiopharmaceutical Sciences Program, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.|Los Alamos National Laboratory, Los Alamos, NM, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Atcher
authors.affiliation: Department of Radiology and Nuclear Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
authors.affiliation: Radiopharmaceutical Sciences Program, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Norenberg
keywords: 213Bi-DOTATATE; L-lysine; Maximum tolerated dose; Nephrotoxicity; Targeted alpha therapy