Hyaluronan grafted lipid-based nanoparticles as RNAi carriers for cancer cells

Dalit Landesman-Milo, Meir Goldsmith, Shani Leviatan Ben-Arye, Bruria Witenberg, Emily Brown, Sigalit Leibovitch, Shalhevet Azriel, Sarit Tabak, Vered Morad, Dan Peer

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

RNA interference (RNAi), a natural cellular mechanism for RNA-guided regulation of gene expression could in fact become new therapeutic modality if an appropriate efficient delivery strategy that is also reproducible and safe will be developed. Numerous efforts have been made for the past eight years to address this challenge with only mild success. The majority of these strategies are based on cationic formulations that condense the RNAi payload and deliver it into the cell cytoplasm. However, most of these formulations also evoke adverse effects such as mitochondrial damage, interfering with blood coagulation cascade, induce interferon response, promote cytokine induction and activate the complement. Herein, we present a strategy that is devised from neutral phospholipids and cholesterol that self-assembled into lipid-based nanoparticles (LNPs). These LNPs were then coated with the glycosaminoglycan, hyaluronan (HA). HA-LNPs bound and internalized specifically into cancer cells compared with control, non-coated particles. Next, loaded with siRNAs against the multidrug resistance extrusion pump, p-glycoprotein (P-gp), HA-LNPs efficiently and specifically reduced mRNA and P-gp protein levels compared with control particles and with HA-LNPs loaded with control, non-targeted siRNAs. In addition, no cellular toxicity or cytokine induction was observed when these particles were cultured with human Peripheral Blood Mononuclear Cells (PBMCs). The HA-LNPs may offer an alternative approach to cationic lipid-based formulations for RNAi delivery into cancer cells in an efficient and safe manner.

Original languageEnglish (US)
Pages (from-to)221-227
Number of pages7
JournalCancer Letters
Volume334
Issue number2
DOIs
StatePublished - Jul 1 2013

Keywords

  • Cancer cells
  • Hyaluronan
  • Immune response
  • Lipid-based nanoparticles
  • RNAi

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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