Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies

Shiri Weinstein, Itai A. Toker, Rafi Emmanuel, Srinivas Ramishetti, Inbal Hazan-Halevy, Daniel Rosenblum, Meir Goldsmith, Avigdor Abraham, Ohad Benjamini, Osnat Bairey, Pia Raanani, Arnon Nagler, Judy Lieberman, Dan Peer

Research output: Contribution to journalArticle

47 Scopus citations

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. Downregulation of cyclin D1 using RNA interference (RNAi) is a potential therapeutic approach to this malignancy. Here, we designed lipidbased 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.

Original languageEnglish (US)
Pages (from-to)E16-E22
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number1
DOIs
StatePublished - Jan 5 2016

Keywords

  • CD38
  • Cyclin D1
  • Mantle cell lymphoma
  • Nanomedicine
  • SiRNA

ASJC Scopus subject areas

  • General

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