Intravenous injection of siRNA directed against hypoxia-inducible factors prolongs survival in a Lewis lung carcinoma cancer model.
Different routes for the in vivo administration of synthetic siRNA complexes targeting lung tumors were compared, and siRNA complexes were administered for the inhibition of hypoxia-inducible factor (HIF-1alpha and HIF-2alpha). Intravenous jugular vein injection of siRNA proved to be the most effective means of targeting lung tumor tissue in the Lewis lung carcinoma (LLC1) model. In comparison, intraperitoneal injection of siRNA was not suitable for targeting of lung tumor and intratracheal administration of siRNA exclusively targeted macrophages. Inhibition of HIF-1alpha and HIF-2alpha by siRNA injected intravenously was validated by immunohistofluorescent analysis for glucose-transporter-1 (GLUT-1), a well-established HIF target protein. The GLUT-1 signal was strongly attenuated in the lung tumors of mice treated with siRNA-targeting HIF-1alpha and HIF-2alpha, compared with mice treated with control siRNA. Interestingly, injection of siRNA directed against HIF-1alpha and HIF-2alpha into LLC1 lung tumor-bearing mice resulted in prolonged survival. Immunohistological analysis of the lung tumors from mice treated with siRNA directed against HIF-1alpha and HIF-2alpha displayed reduced proliferation, angiogenesis and apoptosis, cellular responses, which are known to be affected by HIF. In conclusion, intravenous jugular vein injection of siRNA strongly targets the lung tumor and is effective in gene inhibition as demonstrated for HIF-1alpha and HIF-2alpha.
Kamlah
F
F
Department of Internal Medicine II/V, Justus Liebig University, Giessen, Germany.
Eul
B G
BG
Li
S
S
Lang
N
N
Marsh
L M
LM
Seeger
W
W
Grimminger
F
F
Rose
F
F
Hänze
J
J
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015536:Down-Regulation; D015316:Genetic Therapy / Q000379:methods*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D007097:Imines / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007601:Jugular Veins; D008055:Lipids / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000628:therapy; D011095:Polyethylenes / Q000008:administration & dosage; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D040521:Subcutaneous Tissue; D014132:Trachea; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007097:Imines; D008055:Lipids; D009363:Neoplasm Proteins; D011095:Polyethylenes; D034741:RNA, Small Interfering; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C086724:Lipofectamine; C505405:poly(ethylene imine)