TY - JOUR
T1 - Hyaluronan grafted lipid-based nanoparticles as RNAi carriers for cancer cells
AU - Landesman-Milo, Dalit
AU - Goldsmith, Meir
AU - Leviatan Ben-Arye, Shani
AU - Witenberg, Bruria
AU - Brown, Emily
AU - Leibovitch, Sigalit
AU - Azriel, Shalhevet
AU - Tabak, Sarit
AU - Morad, Vered
AU - Peer, Dan
N1 - Funding Information: This work was supported in part by Grants from the Israeli Centers of Research Excellence ( I-CORE ), Gene Regulation in Complex Human Disease, Center No. 41/11, by the MAGNET program Rimonim, and by the FTA: Nanomedicine for Personalized Theranostics awarded to D.P. [CrossRef], [CAS][CrossRef], [CAS].
PY - 2013/7/1
Y1 - 2013/7/1
N2 - 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.
AB - 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.
KW - Cancer cells
KW - Hyaluronan
KW - Immune response
KW - Lipid-based nanoparticles
KW - RNAi
UR - http://www.scopus.com/inward/record.url?scp=84878263116&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.canlet.2012.08.024
DO - https://doi.org/10.1016/j.canlet.2012.08.024
M3 - مقالة
SN - 0304-3835
VL - 334
SP - 221
EP - 227
JO - Cancer Letters
JF - Cancer Letters
IS - 2
ER -