title: Intravenous delivery of siRNA targeting CD47 effectively inhibits melanoma tumor growth and lung metastasis.
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 protein α (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.
authors.affiliation: Division 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.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Xu
authors.forename: Shutao
authors.initials: S
authors.lastname: Guo
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Arati
authors.initials: A
authors.lastname: Sharma
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Robertson
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D051928:CD47 Antigen / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D008264:Macrophages / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology* / Q000556:secondary; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage; D010587:Phagocytosis; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D014408:Biomarkers, Tumor; D051928:CD47 Antigen; D008081:Liposomes; D034741:RNA, Small Interfering