Targeted Drug Delivery and Image-Guided Therapy of Heterogeneous Ovarian Cancer Using HER2-Targeted Theranostic Nanoparticles

• Type of Material: Article
• Authors: Minati Satpathy, Emory University; Liya Wang, Emory University; Rafal J. Zielinski, University of Texas MD Anderson Cancer Center; Wei Ping Qian, Emory University; Y. Andrew Wang, Ocean NanoTech LLC; Aaron M. Mohs, Emory University; Brad A. Kairdolf, Emory University; Xin Ji, Ocean NanoTech LLC; Jacek Capala, National Cancer Institute; Malgorzata Lipowska, Emory University; Shuming Nie, Emory University; Hui Mao, Emory University; Lily Yang, Emory University
• Language: English
• Date: 2019-01-01
• Publisher: Ivyspring International Publisher
• Publication Version: Final Published Version
• Copyright Statement: © Ivyspring International Publisher.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.7150/thno.29964
• Title of Journal or Parent Work: Theranostics
• ISSN: 1838-7640
• Volume: 9
• Issue: 3
• Start Page: 778
• End Page: 795
• Grant/Funding Information: This work was supported by the following NIH/NCI awards: R01CA133722-01, R01CA154846-01, R01 CA202846-01, R01CA163256-01, and NCI Cancer Nanotechnology partnership Platform (NIH, U01 CA151810), NIH K99/R00153916, and the Nancy Panoz Endowed Chair to Dr. Lily Yang.
• Keywords: HER2 GENE AMPLIFICATION; resistant mechanism; MR image-guided cancer therapy; targeted drug delivery; Medicine, Research & Experimental; CISPLATIN; IRON-OXIDE NANOPARTICLES; Science & Technology; IN-VIVO; TRASTUZUMAB; INTRATUMORAL HETEROGENEITY; ANTIBODY; theranostic nanoparticles; spectroscopic imaging; BREAST-CANCER; Research & Experimental Medicine; MAGNETIC-RESONANCE; Life Sciences & Biomedicine; RECEPTOR
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics; Health Sciences, Oncology

Abstract

Cancer heterogeneity and drug resistance limit the efficacy of cancer therapy. To address this issue, we have developed an integrated treatment protocol for effective treatment of heterogeneous ovarian cancer. Methods: An amphiphilic polymer coated magnetic iron oxide nanoparticle was conjugated with near infrared dye labeled HER2 affibody and chemotherapy drug cisplatin. The effects of the theranostic nanoparticle on targeted drug delivery, therapeutic efficacy, non-invasive magnetic resonance image (MRI)-guided therapy, and optical imaging detection of therapy resistant tumors were examined in an orthotopic human ovarian cancer xenograft model with highly heterogeneous levels of HER2 expression. Results: We found that systemic delivery of HER2-targeted magnetic iron oxide nanoparticles carrying cisplatin significantly inhibited the growth of primary tumor and peritoneal and lung metastases in the ovarian cancer xenograft model in nude mice. Differential delivery of theranostic nanoparticles into individual tumors with heterogeneous levels of HER2 expression and various responses to therapy were detectable by MRI. We further found a stronger therapeutic response in metastatic tumors compared to primary tumors, likely due to a higher level of HER2 expression and a larger number of proliferating cells in metastatic tumor cells. Relatively long-time retention of iron oxide nanoparticles in tumor tissues allowed interrogating the relationship between nanoparticle drug delivery and the presence of resistant residual tumors by in vivo molecular imaging and histological analysis of the tumor tissues. Following therapy, most of the remaining tumors were small, primary tumors that had low levels of HER2 expression and nanoparticle drug accumulation, thereby explaining their lack of therapeutic response. However, a few residual tumors had HER2-expressing tumor cells and detectable nanoparticle drug delivery but failed to respond, suggesting additional intrinsic resistant mechanisms. Nanoparticle retention in the small residual tumors, nevertheless, produced optical signals for detection by spectroscopic imaging. Conclusion: The inability to completely excise peritoneal metastatic tumors by debulking surgery as well as resistance to chemotherapy are the major clinical challenges for ovarian cancer treatment. This targeted cancer therapy has the potential for the development of effective treatment for metastatic ovarian cancer.