Preclinical evaluation of a urokinase plasminogen activator receptor-targeted nanoprobe in rhesus monkeys

• Type of Material: Article
• Authors: Yushu Chen, Sichuan University; Li Gong, Sichuan Primed Bio-Tech Group Co, Ltd; Ning Gao, Emory University; Jichun Liao, Sichuan University; Jiayu Sun, Sichuan University; Yuqing Wang, Sichuan University; Lei Wang, Sichuan University; Pengjin Zhu, Sichuan University; Qing Fan, Sichuan University; Yongqiang Andrew Wang, Ocean NanoTech, LLC; Wen Zeng, Sichuan Primed Bio-Tech Group Co, Ltd; Hui Mao, Emory University; Lily Yang, Emory University; Fabao Gao, Sichuan University
• Language: English
• Date: 2015-01-01
• Publisher: Dove Medical Press
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Chen et al.
• License: Creative Commons Attribution-Noncommercial 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.2147/IJN.S90587
• Title of Journal or Parent Work: International Journal of Nanomedicine
• ISSN: 1176-9114
• Volume: 10
• Start Page: 6689
• End Page: 6698
• Grant/Funding Information: The authors are grateful to the National Natural Science Foundation of China (81130027, 81520108014), the National “Twelfth Five-Year” Plan for Science and Technology Support (2012BAI23B08), and the National Basic Research Program of China (973 Program, 2011CB935800).
• Keywords: Science & Technology - Other Topics; self-healing; transient harm; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; POTENTIAL TARGET; ZNO NANOPARTICLES; Nanoscience & Nanotechnology; TOXICITY; THERANOSTIC NANOPARTICLES; nonhuman primates; IRON-OXIDE NANOPARTICLES; BISPHENOL-A PHARMACOKINETICS; uPAR-IONP; CONTRAST AGENTS; IN-VIVO; BREAST-CANCER; CANCER-THERAPY
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology

Abstract

Purpose: 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. Conclusion: 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.