title: Preclinical evaluation of a urokinase plasminogen activator receptor-targeted nanoprobe in rhesus monkeys.
abstract: OBJECTIVE
  To translate a recombinant peptide containing the amino-terminal fragment (ATF) of urokinase plasminogen activator receptor-targeted magnetic iron oxide (IO) nanoparticles (uPAR-targeted human ATF-IONPs) into clinical applications, we conducted a pilot study to evaluate the toxicity and pharmacokinetics of this nanoparticle in normal rhesus monkeys.
  
  
  METHODS
  We assessed the changes in the following: magnetic resonance imaging (MRI) signals from pretreatment stage to 14 days posttreatment, serum iron concentrations from 5 minutes posttreatment to 12 weeks posttreatment, routine blood examination and serum chemistry analysis results from pretreatment stage to 12 weeks after administration, and results of staining of the liver with Perls' Prussian Blue and hematoxylin-eosin at 24 hours and 3 months posttreatment in two rhesus monkeys following an intravenous administration of the targeted nanoparticles either with a polyethylene glycol (ATF-PEG-IONP) or without a PEG (ATF-IONP) coating.
  
  
  RESULTS
  The levels of alkaline phosphatase, alanine transaminase, and direct bilirubin in the two monkeys increased immediately after the administration of the IONPs but returned to normal within 20 days and stayed within the normal reference range 3 months after the injection. The creatinine levels of the two monkeys stayed within the normal range during the study. In addition, red blood cells, white blood cells, hemoglobin level, and platelets remained normal during the 3 months of the study.
  
  
  CONCLUSIONS
  All of the results suggest that a transient injury in terms of normal organ functions, but no microscopic necrotic lesions, was observed at a systemic delivery dose of 5 mg/kg of iron equivalent concentration in the acute phase, and that no chronic toxicity was found 3 months after the injection. Therefore, we conclude that uPAR-targeted IONPs have the potential to be used as receptor-targeted MRI contrasts as well as theranostic agents for the detection and treatment of human cancers in future studies.
authors.affiliation: Molecular Imaging Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Yushu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Sichuan Primed Bio-Tech Group Co, Ltd, Chengdu, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Gong
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
authors.affiliation: Molecular Imaging Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Jichun
authors.initials: J
authors.lastname: Liao
authors.affiliation: Molecular Imaging Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Sun
authors.affiliation: Molecular Imaging Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Molecular Imaging Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Molecular Imaging Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Pengjin
authors.initials: P
authors.lastname: Zhu
authors.affiliation: Molecular Imaging Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Ocean NanoTech, LLC, San Diego, CA.
authors.forename: Yongqiang Andrew
authors.initials: YA
authors.lastname: Wang
authors.affiliation: Sichuan Primed Bio-Tech Group Co, Ltd, Chengdu, People's Republic of China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Mao
authors.affiliation: Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Yang
authors.affiliation: Molecular Imaging Center, Department of Radiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Fabao
authors.initials: F
authors.lastname: Gao
mesh_terms: D000818:Animals; D005290:Ferric Compounds; D008099:Liver / Q000378:metabolism; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D013997:Time Factors
chemical_list: D005290:Ferric Compounds; D055293:Receptors, Urokinase Plasminogen Activator; C000499:ferric oxide; D011092:Polyethylene Glycols
keywords: nonhuman primates; self-healing; transient harm; uPAR-IONP