Persistent transgene expression following intravenous administration of a liposomal complex: role of interleukin-10-mediated immune suppression.
Studies conducted in non-tumor-bearing, immunocompetent mice have shown that intravenous administration of liposome-DNA complex elicits an inflammatory response that results in a failure to sustain adequate transgene expression. In the present study, however, we investigated the effects of a cationic liposomal DOTAP:cholesterol (DOTAP:Chol)-DNA complex on cytokine production and transgene expression in both experimental lung tumor-bearing (TB) mice and non-tumor-bearing (NTB) syngeneic mice and nude mice. Intravenous injection of DOTAP:Chol-luciferase (luc) DNA complex resulted in tumor necrosis factor-alpha levels that were 50% lower and interleukin-10 levels that were 50-60% higher in TB mice than in NTB mice. Furthermore, a significant increase in luc expression (P = 0.001) that persisted for 7 days was observed in TB mice. In contrast, luc expression decreased significantly from day 1 to day 2 in NTB mice. Also, luc expression was two- to threefold higher in TB mice that were given multiple injections of DOTAP:Chol-luc complex than in mice who received a single injection. In contrast, luc expression was significantly suppressed following multiple injections in NTB mice (P = 0.01). Further analysis revealed IL-10 protein expression by the tumor cells in TB mice. Injection of anti-IL-10 antibody in TB mice resulted in a significant decrease in luc expression (P = 0.01) compared with that in mice injected with a control antibody. Based on these findings, we conclude that transgene expression persists in TB mice and is partly mediated by IL-10. Additionally, multiple injections of liposome-DNA complex can increase transgene expression in TB mice. These findings have clinical applications in the treatment of cancer.
Ito
Isao
I
Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Saeki
Tomoyuki
T
Mohuiddin
Imran
I
Saito
Yuji
Y
Branch
Cynthia D
CD
Vaporciyan
Ara
A
Roth
Jack A
JA
Ramesh
Rajagopal
R
D000818:Animals; D002784:Cholesterol / Q000737:chemistry; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D005354:Fibrosarcoma / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D007249:Inflammation; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D013997:Time Factors; D019076:Transgenes
D016207:Cytokines; D005229:Fatty Acids, Monounsaturated; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; D016753:Interleukin-10; D004247:DNA; D002784:Cholesterol; D008156:Luciferases; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane