Increased uptake of liposomal-DNA complexes by lung metastases following intravenous administration.
We have investigated the effects of an improved liposomal formulation (extruded DOTAP:cholesterol (DOTAP:Chol)-DNA complex) on transgene expression in tumor cells and normal cells of murine and human origin both in vitro and in vivo. In vitro, transgene expression was significantly increased (P = 0.01) in human tumor cells compared to normal human cells. The increased transgene expression was due to increased uptake of the liposome-DNA complex by tumor cell phagocytosis. Furthermore, immunohistochemical analysis demonstrated a greater transgene expression in lung tumors than in surrounding normal tissues. Increased transgene expression due to enhanced uptake of the liposome-DNA complexes by tumor cells in vivo was also demonstrated using fluorescently labeled DOTAP:Chol liposomes. Finally, evaluation of lung tissue explants obtained from patients undergoing pulmonary resection demonstrated significantly higher (P = 0.001) transgene expression in tumor cells than in normal cells. Thus, we demonstrated that intravenous injection of DOTAP:Chol-DNA complex results in increased transgene expression in tumor and is due to increased phagocytosis of the complexes by tumor cells.
Ito
Isao
I
Department of Thoracic and Cardiovascular Surgery, 77030, Houston, Texas, USA
Began
Gopalan
G
Mohiuddin
Imran
I
Saeki
Tomoyuki
T
Saito
Yuji
Y
Branch
Cynthia D
CD
Vaporciyan
Ara
A
Stephens
L Clifton
LC
Yen
Nancy
N
Roth
Jack A
JA
Ramesh
Rajagopal
R
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000556:secondary / Q000628:therapy; D002470:Cell Survival; D002784:Cholesterol / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D015316:Genetic Therapy; D006801:Humans; D007124:Immunoenzyme Techniques; D007275:Injections, Intravenous; D008081:Liposomes; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary / Q000628:therapy; D051379:Mice; D008809:Mice, Inbred C3H; D010587:Phagocytosis; D010873:Pinocytosis; D000644:Quaternary Ammonium Compounds / Q000378:metabolism*; D019076:Transgenes; D014407:Tumor Cells, Cultured
D005229:Fatty Acids, Monounsaturated; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; D004247:DNA; D002784:Cholesterol; D008156:Luciferases; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane