Simultaneous delivery of doxorubicin and immunostimulatory CpG motif to tumors using a plasmid DNA/doxorubicin complex in mice.
To achieve delivery of doxorubicin (DXR), a very commonly used anticancer agent, to tumor tissues, it was intercalated to plasmid DNA to obtain a plasmid DNA/DXR complex. The cytotoxic effects of DXR, DNA and their complex were examined in colon26/Luc cells, a murine adenocarcinoma clone stably expressing firefly luciferase, co-cultured with RAW264.7 murine macrophage-like cells. Both CpG motif-containing plasmid DNA (CpG plasmid DNA) and DXR significantly inhibited the proliferation of colon26/Luc cells, but their complex was the most effective among those examined. Non-CpG plasmid DNA was less effective than the CpG plasmid DNA. When injected into mice bearing hepatic metastases of colon26/Luc cells, the CpG plasmid DNA/DXR complex produced a significant level of IL-12 in the serum and liver. The amount of DXR delivered to tumor tissues in the liver was greater when DXR was injected as a CpG plasmid DNA/DXR complex than as free DXR. The CpG plasmid DNA/DXR complex effectively inhibited the proliferation of colon26/Luc cells in the liver compared with free DXR, CpG plasmid DNA, or non-CpG plasmid DNA/DXR complex. These results indicate that CpG plasmid DNA is an effective polymer that inhibits tumor growth by delivering both a proinflammatory signal and anticancer agent to tumor tissues.
Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Yumiko
Y
Mizuno
Tomoyuki
T
Naoi
Makiya
M
Nishikawa
Sakulrat
S
Rattanakiat
Nobuko
N
Hamaguchi
Mitsuru
M
Hashida
Yoshinobu
Y
Takakura
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000556:secondary; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018899:CpG Islands / Q000276:immunology; D004317:Doxorubicin / Q000008:administration & dosage*; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology; D018014:Gene Transfer Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D007275:Injections, Intravenous; D018664:Interleukin-12 / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000556:secondary; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000008:administration & dosage* / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000903:Antibiotics, Antineoplastic; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D004317:Doxorubicin