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

被引:78
作者
Chen, Yunching [1 ]
Sen, Joyeeta [1 ]
Bathula, Surendar Reddy [1 ]
Yang, Qi [1 ]
Fittipaldi, Raffaella [1 ]
Huang, Leaf [1 ]
机构
[1] Univ N Carolina, Div Mol Pharmaceut, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA
关键词
Gene delivery; cationic lipid; siRNA; apoptosis; nanoparticles; sigma receptor; APOPTOSIS-INDUCING FACTOR; GENE-TRANSFER; FACTOR AIF; TRANSFECTION; LIPOSOMES; MECHANISM; CHEMOTHERAPY; EGFR; NANOPARTICLE; SUPPRESSION;
D O I
10.1021/mp800136v
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:696 / 705
页数:10
相关论文
共 54 条
  • [1] Gene transfection efficacies of novel cationic gemini lipids possessing aromatic backbone and oxyethylene spacers
    Bajaj, Avinash
    Kondaiah, Paturu
    Bhattacharya, Santanu
    [J]. BIOMACROMOLECULES, 2008, 9 (03) : 991 - 999
  • [2] Synthesis and gene transfer activities of novel serum compatible cholesterol-based gemini lipilds possessing oxyethylene-type spacers
    Bajaj, Avinash
    Kondaiah, Paturu
    Bhattacharya, Santanu
    [J]. BIOCONJUGATE CHEMISTRY, 2007, 18 (05) : 1537 - 1546
  • [3] Anisamide-targeted stealth liposomes: A potent carrier for targeting doxorubicin to human prostate cancer cells
    Banerjee, R
    Tyagi, P
    Li, S
    Huang, L
    [J]. INTERNATIONAL JOURNAL OF CANCER, 2004, 112 (04) : 693 - 700
  • [4] New cationic liposomes as vehicles of m-tetrahydroxyphenylchlorin in photodynamic therapy of infectious diseases
    Bombelli, Cecilia
    Bordi, Federico
    Ferro, Stefania
    Giansanti, Luisa
    Jori, Giulio
    Mancini, Giovanna
    Mazzuca, Claudia
    Monti, Donato
    Ricchelli, Fernanda
    Sennato, Simona
    Venanzi, Mariano
    [J]. MOLECULAR PHARMACEUTICS, 2008, 5 (04) : 672 - 679
  • [5] Recent developments in delivery of nucleic acid-based antiviral agents
    Christopher, M. E.
    Wong, J. P.
    [J]. CURRENT PHARMACEUTICAL DESIGN, 2006, 12 (16) : 1995 - 2006
  • [6] Immunostimulation mechanism of LPD nanoparticle as a vaccine carrier
    Cui, Zhengrong
    Han, Su-Ji
    Vangasseri, Dileep Padinjarae
    Huang, Leaf
    [J]. MOLECULAR PHARMACEUTICS, 2005, 2 (01) : 22 - 28
  • [7] Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis
    Daugas, E
    Susin, SA
    Zamzami, N
    Ferri, KF
    Irinopoulou, T
    Larochette, N
    Prévost, MC
    Leber, B
    Andrews, D
    Penninger, J
    Kroemer, G
    [J]. FASEB JOURNAL, 2000, 14 (05) : 729 - 739
  • [8] The PEA-15/PED protein protects glioblastoma cells from glucose deprivation-induced apoptosis via the ERK/MAP kinase pathway
    Eckert, A.
    Boeck, B. C.
    Tagscherer, K. E.
    Haas, T. L.
    Grund, K.
    Sykora, J.
    Herold-Mende, C.
    Ehemann, V.
    Hollstein, M.
    Chneiweiss, H.
    Wiestler, O. D.
    Walczak, H.
    Roth, W.
    [J]. ONCOGENE, 2008, 27 (08) : 1155 - 1166
  • [9] Bisphenol A diglycidyl ether-induced apoptosis involves Bax/Bid-dependent mitochondrial release of apoptosis-inducing factor (AIF), cytochrome c and Smac/DIABLO
    Fehlberg, S
    Gregel, CM
    Göke, A
    Göke, R
    [J]. BRITISH JOURNAL OF PHARMACOLOGY, 2003, 139 (03) : 495 - 500
  • [10] Mitochondrial reactive oxygen species in cell death signaling
    Fleury, C
    Mignotte, B
    Vayssière, JL
    [J]. BIOCHIMIE, 2002, 84 (2-3) : 131 - 141