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.
Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Isao
I
Ito
Tomoyuki
T
Saeki
Imran
I
Mohuiddin
Yuji
Y
Saito
Cynthia D
CD
Branch
Ara
A
Vaporciyan
Jack A
JA
Roth
Rajagopal
R
Ramesh
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