title: Hyaluronan grafted lipid-based nanoparticles as RNAi carriers for cancer cells.
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.
authors.affiliation: Laboratory of Nanomedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Dalit
authors.initials: D
authors.lastname: Landesman-Milo
authors.forename: Meir
authors.initials: M
authors.lastname: Goldsmith
authors.forename: Shani
authors.initials: S
authors.lastname: Leviatan Ben-Arye
authors.forename: Bruria
authors.initials: B
authors.lastname: Witenberg
authors.forename: Emily
authors.initials: E
authors.lastname: Brown
authors.forename: Sigalit
authors.initials: S
authors.lastname: Leibovitch
authors.forename: Shalhevet
authors.initials: S
authors.lastname: Azriel
authors.forename: Sarit
authors.initials: S
authors.lastname: Tabak
authors.forename: Vered
authors.initials: V
authors.lastname: Morad
authors.forename: Dan
authors.initials: D
authors.lastname: Peer
mesh_terms: D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000737:chemistry; D008055:Lipids / Q000008:administration & dosage* / Q000737:chemistry; D053758:Nanoparticles; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D014162:Transfection / Q000379:methods*
chemical_list: D008055:Lipids; D034741:RNA, Small Interfering; D006820:Hyaluronic Acid