title: Pharmacokinetics and toxicity of (213)Bi-labeled PAI2 in preclinical targeted alpha therapy for cancer.
abstract: OBJECTIVE
  The plasminogen activator inhibitor type 2 (PAI2) when labelled with (213)Bi forms the (213)Bi-PAI2 alpha conjugate (AC). This AC has been shown to be efficacious in preclinical studies with breast, ovarian, prostate and pancreatic cancers. The objectives of this study were to investigate the pharmacokinetics and in vivo stability of (213)Bi-PAI2 in mice, its toxicity in mice and rabbits; and to determine whether a prior injection of a metal chelator (Ca-DTPA) or lysine can reduce toxicity by decreasing renal uptake.
  
  
  METHODS
  Two chelators (CHX-A"-DTPA and cDTPA) were used for preparation of the (213)Bi-PAI2 conjugate, for intraperitoneal administration in mice and ear vein injection in rabbits. The mice were sacrificed at different time points for pharmacokinetic studies. Blood and organs were collected for toxicity studies for all groups.
  
  
  RESULTS
  Both chelators were found to have similar %ID/g in the kidneys over four hours. Mice and rabbits did not show any short term toxicity over 13 weeks at 1420 MBq/kg and 120 MBq/kg (213)Bi-PAI2 respectively. Kidney uptake was decreased three fold by lysine. Radiation nephropathy was observed at 20-30 weeks in mice, leading to severe weight loss, whereas severe and widespread renal tubular necrosis was observed at 13 weeks in rabbits.
  
  
  CONCLUSIONS
  Radiation nephropathy is the dose limiting toxicity observed in mice and rabbits. Lysine can reduce kidney uptake by three fold. Based on long-term monitoring, the maximum tolerance doses (MTD) are 350 and 120 MBq/kg for mice and rabbits respectively.
authors.affiliation: Centre for Experimental Radiation Oncology, Cancer Care Centre, St. George Hospital, Kogarah, Australia.
authors.forename: Emma Y
authors.initials: EY
authors.lastname: Song
authors.forename: Syed M
authors.initials: SM
authors.lastname: Abbas Rizvi
authors.forename: Chang F
authors.initials: CF
authors.lastname: Qu
authors.forename: Chand
authors.initials: C
authors.lastname: Raja
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.forename: Christos
authors.initials: C
authors.lastname: Apostolidis
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Allen
mesh_terms: D000512:Alpha Particles; D000818:Animals; D001729:Bismuth / Q000493:pharmacokinetics* / Q000633:toxicity*; D002614:Chelating Agents / Q000494:pharmacology; D005260:Female; D007668:Kidney / Q000473:pathology; D008495:Medical Oncology / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D017396:Plasminogen Activator Inhibitor 2 / Q000493:pharmacokinetics* / Q000633:toxicity*; D011817:Rabbits; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000737:chemistry / Q000633:toxicity*; D013997:Time Factors
chemical_list: D002614:Chelating Agents; D017396:Plasminogen Activator Inhibitor 2; D011868:Radioisotopes; D001729:Bismuth