Original Article
Subject Category: Oligonucleotide Therapy
Molecular Therapy advance online publication 18 June 2013; doi: 10.1038/mt.2013.135
Intravenous Delivery of siRNA Targeting CD47 Effectively Inhibits Melanoma Tumor Growth and Lung Metastasis
Yuhua Wang1, Zhenghong Xu1, Shutao Guo1, Lu Zhang1, Arati Sharma2,3,4,5, Gavin P Robertson2,3,4,5 and Leaf Huang1
- 1Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- 2Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, USA
- 3Department of Pathology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, USA
- 4Department of Dermatology, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, USA
- 5Department of Surgery, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, USA
Correspondence: Yuhua Wang, Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, 1319 Kerr Hall, Chapel Hill, North Carolina 27599, USA. E-mail: alwang@email.unc.edu
The first two authors contributed equally to this work.
Received 3 December 2012; Accepted 21 May 2013
Advance online publication 18 June 2013
Top of page Abstract
CD47 is a “self marker” that is usually overexpressed on the surface of cancer cells to enable them to escape immunosurveillance. Recognition of CD47 by its receptor, signal regulatory proteinα (SIRPα), which is expressed in the macrophages, inhibits phagocytic destruction of cancer cells by the macrophages. In this study, we have first shown that clinical isolates of human melanoma significantly upregulate CD47, possibly as a mechanism to defend themselves against the macrophages. We then exploited RNA interference (RNAi) technology to test the hypothesis that knocking down CD47 in the tumor cells will render them targets for macrophage destruction; hence, creating a novel anti-cancer therapy. Anti-CD47 siRNA was encapsulated in a liposome-protamine-hyaluronic acid (LPH) nanoparticle (NP) formulation to address the challenge of targeted delivery of siRNA-based therapeutics in vivo. Efficient silencing of CD47 in tumor tissues with systemic administration of LPH(CD47) also significantly inhibited the growth of melanoma tumors. In a lung metastasis model, LPH(CD47) efficiently inhibited lung metastasis to about 27% of the untreated control. Moreover, no hematopoietic toxicity was observed in the animals that received multiple doses of LPH(CD47). Our findings indicate CD47 as a potential prognostic marker for melanoma development as well as a target for therapeutic intervention with RNAi-based nanomedicines.