uPAR-targeted Optical Imaging Contrasts as Theranostic Agents for Tumor Margin Detection

• Type of Material: Article
• Authors: Lily Yang, Emory University; Hari Krishna Sajja, Emory University; Zehong Cao, Emory University; Wei Ping Qian, Emory University; Laura Bender, Emory University; Adam I Marcus, Emory University; Malgorzata Lipowska, Emory University; William C Wood, Emory University; Y. Andrew Wang, Ocean Nanotech, LLC
• Language: English
• Date: 2014
• Publisher: Ivyspring International Publisher
• Publication Version: Final Published Version
• Copyright Statement: © Ivyspring International Publisher
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://www.thno.org/v04p0106.htm
• Title of Journal or Parent Work: Theranostics
• ISSN: 1838-7640
• Volume: 4
• Issue: 1
• Start Page: 106
• End Page: 118
• Grant/Funding Information: This research project was supported by NIH/NCI grants, R01CA133722 (Yang), R01 CA154129A01 (Yang), and U54 CA119338 (Nie), and the Nancy Panoz Endowed Chair Funds (Yang).
• Keywords: image-guided surgery; tumor margin; theranostic nanoparticles; uPAR; optical imaging
• Research Categories: Health Sciences, Radiology; Health Sciences, Oncology

Abstract

Complete removal of tumors by surgery is the most important prognostic factor for cancer patients with the early stage cancers. The ability to identify invasive tumor edges of the primary tumor, locally invaded small tumor lesions, and drug resistant residual tumors following neoadjuvant therapy during surgery should significantly reduce the incidence of local tumor recurrence and improve survival of cancer patients. In this study, we report that urokinase plasminogen activator (uPA) and its receptor (uPAR) are the ligand/cell surface target pair for the development of targeted optical imaging probes for enhancing imaging contrasts in the tumor border. Recombinant peptides of the amino terminal fragment (ATF) of the receptor binding domain of uPA were labeled with near infrared fluorescence (NIR) dye molecules either as peptide-imaging or peptide-conjugated nanoparticle imaging probes. Systemic delivery of the uPAR-targeted imaging probes in mice bearing orthotopic human breast or pancreatic tumor xenografts or mouse mammary tumors led to the accumulation of the probes in the tumor and stromal cells, resulting in strong signals for optical imaging of tumors and identification of tumor margins. Histological analysis showed that a high level of uPAR-targeted nanoparticles was present in the tumor edge or active tumor stroma immediately adjacent to the tumor cells. Furthermore, following targeted therapy using uPAR-targeted theranostic nanoparticles, residual tumors were detectable by optical imaging through the imaging contrasts produced by NIR-dye-labeled theranostic nanoparticles in drug resistant tumor cells. Therefore, results of our study support the potential of the development of uPAR-targeted imaging and theranostic agents for image-guided surgery. Keywords: uPAR, optical imaging, theranostic nanoparticles, tumor margin, and image-guided surgery