Tumor Penetrating Theranostic Nanoparticles for Enhancement of Targeted and Image-guided Drug Delivery into Peritoneal Tumors following Intraperitoneal Delivery

• Type of Material: Article
• Authors: Ning Gao, Emory University; Erica N. Bozeman, Emory University; Wei Qian, Emory University; Liya Wang, Emory University; Hongyu Chen, Ocean Nanotech LLC; Malgorzata Lipowska, Emory University; Charles Staley, Emory University; Lily Yang, Emory University; Hui Mao, Emory University
• Language: English
• Date: 2017-01-01
• Publisher: Ivyspring International Publisher
• Publication Version: Final Published Version
• Copyright Statement: © Ivyspring International Publisher.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.7150/thno.18125
• Title of Journal or Parent Work: Theranostics
• ISSN: 1838-7640
• Volume: 7
• Issue: 6
• Start Page: 1689
• End Page: 1704
• Grant/Funding Information: We also thank research funding supports from NIH/NCI, including U01CA151810 (Yang and Mao) and R01CA202846-01(Yang, Mao and Wang), SBIR Phase II Contract NO. HHSN261201200029C (Wang, Yang and Mao), and F32CA189633 (Bozeman), and the Nancy Panoz Endowed Chair Funds (Yang).
• Keywords: CYTOREDUCTIVE SURGERY; CHEMOTHERAPY; image-guided therapy; GYNECOLOGIC-ONCOLOGY-GROUP; Science & Technology; tumor penetration; PHASE-I TRIAL; Medicine, Research & Experimental; THERAPY; Life Sciences & Biomedicine; OVARIAN-CANCER; EXPRESSION; intraperitoneal drug delivery; PANCREATIC-CANCER; Research & Experimental Medicine; CARCINOMATOSIS; PLASMINOGEN-ACTIVATOR RECEPTOR; pancreatic cancer; Targeted theranostic nanoparticles
• Research Categories: Health Sciences, Radiology; Health Sciences, Medicine and Surgery

Abstract

The major obstacles in intraperitoneal (i.p.) chemotherapy of peritoneal tumors are fast absorption of drugs into the blood circulation, local and systemic toxicities, inadequate drug penetration into large tumors, and drug resistance. Targeted theranostic nanoparticles offer an opportunity to enhance the efficacy of i.p. therapy by increasing intratumoral drug delivery to overcome resistance, mediating image-guided drug delivery, and reducing systemic toxicity. Herein we report that i.p. delivery of urokinase plasminogen activator receptor (uPAR) targeted magnetic iron oxide nanoparticles (IONPs) led to intratumoral accumulation of 17% of total injected nanoparticles in an orthotopic mouse pancreatic cancer model, which was three-fold higher compared with intravenous delivery. Targeted delivery of near infrared dye labeled IONPs into orthotopic tumors could be detected by non-invasive optical and magnetic resonance imaging. Histological analysis revealed that a high level of uPAR targeted, PEGylated IONPs efficiently penetrated into both the peripheral and central tumor areas in the primary tumor as well as peritoneal metastatic tumor. Improved theranostic IONP delivery into the tumor center was not mediated by nonspecific macrophage uptake and was independent from tumor blood vessel locations. Importantly, i.p. delivery of uPAR targeted theranostic IONPs carrying chemotherapeutics, cisplatin or doxorubicin, significantly inhibited the growth of pancreatic tumors without apparent systemic toxicity. The levels of proliferating tumor cells and tumor vessels in tumors treated with the above theranostic IONPs were also markedly decreased. The detection of strong optical signals in residual tumors following i.p. therapy suggested the feasibility of image-guided surgery to remove drug-resistant tumors. Therefore, our results support the translational development of i.p. delivery of uPAR-targeted theranostic IONPs for image-guided treatment of peritoneal tumors.