Novel Cationic Lipid That Delivers siRNA and Enhances Therapeutic Effect in Lung Cancer Cells

Abstract

We have developed lipid-polycation-DNA (LPD) nanoparticles containing DOTAP and targeted with polyethylene glycol (PEG) tethered with anisamide (AA) to specifically deliver siRNA to H460 human lung carcinoma cells which express the sigma receptor. A novel non-glycerol based cationic lipid which contains both a guanidinium and a lysine residue as the cationic headgroup, i.e. DSGLA, downregulated pERK more efficiently in H460 cells than DOTAP. As demonstrated by using fluorescently labeled siRNA, LPD-PEG-AA prepared with DSGLA efficiently delivered siRNA to the cytoplasm of the H460 cells. Although the siRNA delivered by LPD-PEG-AA containing either DOTAP or DSGLA could effectively silence EGFR expression, a synergistic cell killing effect in promoting cellular apoptosis was only observed with DSGLA. The fluorescently labeled siRNA was efficiently delivered into the cytoplasm of H460 xenograft tumor by the LPD-PEG-AA containing either DOTAP or DSGLA 4 h after intravenous injection. Three daily injections (0.6 mg/kg) of siRNA formulated in the LPD-PEG-AA containing either DOTAP or DSGLA could effectively silence the epidermal growth factor receptor (EGFR) in the tumor, but the formulation containing DSGLA could induce more cellular apoptosis. A significant improvement in tumor growth inhibition was observed after dosing with LPD-PEG-AA containing DSGLA. Thus, DSGLA served as both a formulation component as well as a therapeutic agent which synergistically enhanced the activity of siRNA.

Multifunctional Nanoparticles Delivering Small Interfering RNA and Doxorubicin Overcome Drug Resistance in Cancer

“…Major problems of siRNA delivery include poor cellular uptake, low stability, and rapid clearance from the systemic circulation. We have developed a cationic lipid containing both a guanidinium and a lysine residue as a cationic head group that can down-regulate mitogenactivated protein kinase (MAPK) signaling, form cationic liposome-polycation-DNA (LPD) to intravenously deliver siRNA to the solid tumor in high efficiency, and achieve a synergistic therapeutic effect with siRNA on a human lung cancer model (6). In this study, we further explored the biological activity of the guanidinium-containing cationic lipid, i.e.…”

Therapeutic targeting in the silent era: advances in non-viral siRNA delivery

“…Banerief et al [77] first demonstrated the use of the selective sigma ligand namely anisamide to mediate efficient targeting of liposomal drugs to sigma receptor-expressing prostate cancer cells in vitro and in vivo. Since then there have been several articles reporting the application of anisamide targeting nanoparticles for the cell specific delivery of therapeutic siRNA [78][79][80] .…”

“…As these ABCD formulations are nearly neutral or even negative in charge, the remarkable gene silencing data when administered systemically must be a result of active cell-specific targeting. Li and colleagues developed a nanoparticle formulation for successfully systemic delivery of siRNA into xenograft [122,80] and metastatic tumours [78,79] which produced anti-cancer effects. In this system, the nucleic acids (siRNAs and carrier DNA), a polycationic peptide (protamine) and a cationic liposome, were initially prepared in a condensed core.…”

“…In this system, the nucleic acids (siRNAs and carrier DNA), a polycationic peptide (protamine) and a cationic liposome, were initially prepared in a condensed core. The resulting core was then modified by PEG-lipid containing the tumour targeting ligand, anisamide (see above) [78][79][80] . The resulting targeted nanoparticles silenced the epidermal growth factor receptor (EGFR) in the tumour and induced ~15% tumour cell apoptosis without any indication of immunotoxicity [122] .…”

Cationic Liposomes in Different Structural Levels for Gene Delivery

“…They found LPD vectors to be more efficient and less cytotoxic compared to conventional cationic liposomal vectors. Later, they modified LPDs through different cationic liposomes wherein LPDs were used to deliver antisense oligodeoxynucleotide and siRNA (Li & Huang, 2006;Chen et al, 2009;Gao & Huang, 2009). As a cationic polymer, PEI is commonly used for the delivery of genes.…”