Efficient peritoneal dissemination treatment obtained by an immunostimulatory phosphorothioate-type CpG DNA/cationic liposome complex in mice.
Peritoneal dissemination remains the most difficult type of metastasis to treat, and current systemic chemotherapy or radiotherapy tends to have little effect; therefore, immunotherapy using immunostimulatory CpG DNA could be a promising new therapeutic approach. Recently, we have reported that intraperitoneal administration of phosphodiester (PO) CpG DNA-lipoplex could efficiently inhibit peritoneal dissemination in mice. In this study, chemically modified phosphorothioate (PS)-CpG DNA and natural PO-CpG DNA were complexed with DOTMA/cholesterol cationic liposomes (PS-CpG DNA-lipoplex and PO-CpG DNA-lipoplex) and their antitumor activity was evaluated in a mouse model of peritoneal dissemination. Intraperitoneal administration of the PS-CpG DNA-lipoplex inhibited the proliferation of tumor cells in the greater omentum and the mesentery more efficiently than PO-CpG DNA-lipoplex. PS-CpG DNA-lipoplex induced higher cytokine production from primary cultured mouse peritoneal macrophages, suggesting that the high antitumor activity of the PS-CpG DNA-lipoplex is mediated by a high rate of cytokine production from immunocompetent cells such as macrophages. The serum transaminase levels of mice receiving intraperitoneal PS-CpG DNA-lipoplex treatment were measured to evaluate systemic toxicity, and these were found to be the same as those of untreated mice. These results suggest that intraperitoneal administration of PS-CpG DNA-lipoplex could be efficient immunotherapy for peritoneal dissemination.
Kuramoto
Yukari
Y
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Kawakami
Shigeru
S
Zhou
Shuwen
S
Fukuda
Kyouichi
K
Yamashita
Fumiyoshi
F
Hashida
Mitsuru
M
D000818:Animals; D002412:Cations / Q000737:chemistry; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000737:chemistry; D016207:Cytokines / Q000276:immunology; D004247:DNA / Q000008:administration & dosage*; D005260:Female; D007167:Immunotherapy / Q000379:methods*; D008081:Liposomes; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000737:chemistry; D010316:Particle Size; D010534:Peritoneal Neoplasms / Q000276:immunology / Q000628:therapy*; D054735:Phosphorothioate Oligonucleotides / Q000008:administration & dosage* / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
C408982:CPG-oligonucleotide; D002412:Cations; D016207:Cytokines; D008081:Liposomes; D009838:Oligodeoxyribonucleotides; D054735:Phosphorothioate Oligonucleotides; D000644:Quaternary Ammonium Compounds; C054005:N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium; D004247:DNA; D002784:Cholesterol