Therapeutic effect of intravenous delivery of lipoplexes containing the interferon-beta gene and poly I: poly C in a murine lung metastasis model.
We have evaluated and compared the efficacy of systemic administration of lipoplex formulations containing plasmids encoding IFN-beta or IFN-gamma, and a synthetic double-strand RNA poly I:poly C (pI:pC), a type I IFN inducer, in a lung metastasis model in which colon carcinoma CT-26 cells were inoculated intravenously into immunocompatible mice. Injection of lipoplexes containing plasmid DNA, regardless of IFN gene insertion, stimulated a transient increase in the serum concentration of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and IFN-gamma, while injection of lipoplexes containing pI:pC led to a low level of TNF-alpha and undetectable IFN-gamma production. Furthermore, injection of these lipoplexes containing plasmids resulted in the production of a mixture of type I and type II IFNs, partly derived from the inserted IFN genes, in lung tissue cultures. In tumor-prophylactic experiments, intravenous injection of lipoplexes containing plasmid, regardless of IFN gene insertion, showed a significant reduction in lung metastatic nodules probably due to proinflammatory cytokines such as TNF-alpha and IFN-gamma nonspecifically induced by the CpG motifs in the plasmid and the type I IFNs produced. On the other hand, the antimetastatic effect of pI:pC-lipoplex seemed to be due mainly to IFN-beta induced by pI:pC. In established lung metastasis experiments, a single intravenous administration of lipoplexes containing IFN-beta gene or pI:pC, but not other lipoplexes, showed a significant therapeutic effect on the tumor metastasis: reduction in tumor nodules and prolongation of survival time of tumor-burden mice. The therapeutic effects were specifically impaired by anti-IFN-beta antibody treatment, indicating that IFN-beta produced by the lipoplexes played an important role in the suppression of established metastatic lung tumors. Thus, the local IFN-beta in the lung delivered by intravenous administration of lipoplex containing IFN-beta gene or pI:pC may be a convenient and useful method of inhibiting established metastatic lung tumors.
Sakurai
Fuminori
F
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Terada
Takeshi
T
Maruyama
Masato
M
Watanabe
Yoshihiko
Y
Yamashita
Fumiyoshi
F
Takakura
Yoshinobu
Y
Hashida
Mitsuru
M
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015316:Genetic Therapy; D007167:Immunotherapy; D007275:Injections, Intravenous; D016898:Interferon-alpha / Q000097:blood / Q000378:metabolism; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism; D008081:Liposomes / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009368:Neoplasm Transplantation; D011070:Poly I-C / Q000008:administration & dosage* / Q000627:therapeutic use*; D012330:RNA, Double-Stranded / Q000008:administration & dosage / Q000494:pharmacology; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000906:Antibodies; D016898:Interferon-alpha; D008081:Liposomes; D012330:RNA, Double-Stranded; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D007371:Interferon-gamma; D011070:Poly I-C