title: Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies.
abstract: Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for identifying drug targets and for RNAi-based therapy for leukocyte diseases. However, both normal and malignant leukocytes are among the most difficult targets for siRNA delivery as they are resistant to conventional transfection reagents and are dispersed in the body. We used mantle cell lymphoma (MCL) as a prototypic blood cancer for validating a novel siRNA delivery strategy. MCL is an aggressive B-cell lymphoma that overexpresses cyclin D1 with relatively poor prognosis. Down-regulation of cyclin D1 using RNA interference (RNAi) is a potential therapeutic approach to this malignancy. Here, we designed lipid-based nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that are specifically taken up by human MCL cells in the bone marrow of xenografted mice. When loaded with siRNAs against cyclin D1, CD38-targeted LNPs induced gene silencing in MCL cells and prolonged survival of tumor-bearing mice with no observed adverse effects. These results highlight the therapeutic potential of cyclin D1 therapy in MCL and present a novel RNAi delivery system that opens new therapeutic opportunities for treating MCL and other B-cell malignancies.
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel; Department of Materials Science and Engineering, the Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv 6997801, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 6997801, Israel;
authors.forename: Shiri
authors.initials: S
authors.lastname: Weinstein
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel; Department of Materials Science and Engineering, the Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv 6997801, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 6997801, Israel;
authors.forename: Itai A
authors.initials: IA
authors.lastname: Toker
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel; Department of Materials Science and Engineering, the Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv 6997801, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 6997801, Israel;
authors.forename: Rafi
authors.initials: R
authors.lastname: Emmanuel
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel; Department of Materials Science and Engineering, the Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv 6997801, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 6997801, Israel;
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ramishetti
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel; Department of Materials Science and Engineering, the Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv 6997801, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 6997801, Israel;
authors.forename: Inbal
authors.initials: I
authors.lastname: Hazan-Halevy
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel; Department of Materials Science and Engineering, the Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv 6997801, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 6997801, Israel;
authors.forename: Daniel
authors.initials: D
authors.lastname: Rosenblum
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel; Department of Materials Science and Engineering, the Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv 6997801, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 6997801, Israel;
authors.forename: Meir
authors.initials: M
authors.lastname: Goldsmith
authors.affiliation: Division of Hematology and Oncology, Sheba Medical Center, Tel Hashomer 5262100, Israel;
authors.forename: Avigdor
authors.initials: A
authors.lastname: Abraham
authors.affiliation: Division of Hematology and Oncology, Sheba Medical Center, Tel Hashomer 5262100, Israel;
authors.forename: Ohad
authors.initials: O
authors.lastname: Benjamini
authors.affiliation: Institute of Hematology, Rabin Medical Center, Petah Tikva 4941492, Israel;
authors.forename: Osnat
authors.initials: O
authors.lastname: Bairey
authors.affiliation: Institute of Hematology, Rabin Medical Center, Petah Tikva 4941492, Israel;
authors.forename: Pia
authors.initials: P
authors.lastname: Raanani
authors.affiliation: Division of Hematology and Oncology, Sheba Medical Center, Tel Hashomer 5262100, Israel;
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel; Department of Materials Science and Engineering, the Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv 6997801, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 6997801, Israel; peer@tauex.tau.ac.il.
authors.forename: Dan
authors.identifier: http://orcid.org/0000-0001-8238-0673
authors.initials: D
authors.lastname: Peer
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics; D015536:Down-Regulation; D020868:Gene Silencing; D006801:Humans; D008055:Lipids; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D020522:Lymphoma, Mantle-Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D008055:Lipids; D034741:RNA, Small Interfering; D019938:Cyclin D1; D051997:ADP-ribosyl Cyclase 1
keywords: CD38; cyclin D1; mantle cell lymphoma; nanomedicine; siRNA