title: A biodistribution and toxicity study of cobalt dichloride-N-acetyl cysteine in an implantable MRI marker for prostate cancer treatment.
abstract: OBJECTIVE
  C4, a cobalt dichloride-N-acetyl cysteine complex, is being developed as a positive-signal magnetic resonance imaging (MRI) marker to localize implanted radioactive seeds in prostate brachytherapy. We evaluated the toxicity and biodistribution of C4 in rats with the goal of simulating the systemic effects of potential leakage from C4 MRI markers within the prostate.
  
  
  METHODS
  9-μL doses (equivalent to leakage from 120 markers in a human) of control solution (0.9% sodium chloride), 1% (proposed for clinical use), and 10% C4 solution were injected into the prostates of male Sprague-Dawley rats via laparotomy. Organ toxicity and cobalt disposition in plasma, tissues, feces, and urine were evaluated.
  
  
  RESULTS
  No C4-related morbidity or mortality was observed in the biodistribution arm (60 rats). Biodistribution was measurable after 10% C4 injection: cobalt was cleared rapidly from periprostatic tissue; mean concentrations in prostate were 163 μg/g and 268 μg/g at 5 and 30 minutes but were undetectable by 60 minutes. Expected dual renal-hepatic elimination was observed, with percentages of injected dose recovered in tissues of 39.0 ± 5.6% (liver), >11.8 ± 6.5% (prostate), and >5.3 ± 0.9% (kidney), with low plasma concentrations detected up to 1 hour (1.40 μg/mL at 5-60 minutes). Excretion in urine was 13.1 ± 4.6%, with 3.1 ± 0.54% recovered in feces by 24 hours. In the toxicity arm, 3 animals died in the control group and 1 each in the 1% and 10% groups from surgical or anesthesia-related complications; all others survived to scheduled termination at 14 days. No C4-related adverse clinical signs or organ toxicity were observed.
  
  
  CONCLUSIONS
  C4-related toxicity was not observed at exposures at least 10-fold the exposure proposed for use in humans. These data demonstrating lack of systemic toxicity with dual routes of elimination in the event of in situ rupture suggest that C4 warrants further investigation as an MRI marker for prostate brachytherapy.
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, TX 77030, USA. sjfrank@mdanderson.org
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Frank
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Johansen
authors.forename: Karen S
authors.initials: KS
authors.lastname: Martirosyan
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.forename: Carolyn S
authors.initials: CS
authors.lastname: Van Pelt
authors.forename: Agatha
authors.initials: A
authors.lastname: Borne
authors.forename: Yudith
authors.initials: Y
authors.lastname: Carmazzi
authors.forename: Timothy
authors.initials: T
authors.lastname: Madden
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D001918:Brachytherapy / Q000379:methods; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000532:radiotherapy; D051381:Rats; D014018:Tissue Distribution
chemical_list: D000111:Acetylcysteine