Efficacy of liposome-encapsulated indomethacin in response against metastatic 3LL and B16F1 tumor cells.
The ability of large liposomes to be taken up by tissue phagocytic cells, e.g., macrophages, has made it possible to increase the efficacy of several drugs as immunomodulating agents. In the present work, we have evaluated the effect of indomethacin, a prostaglandin synthesis inhibitor, both free and encapsulated in liposomes, on the spontaneous metastatic potential of 3LL and B16F1 tumor cells. Liposomes containing either carboxyfluorescein, indomethacin, or carboxyfluorescein plus indomethacin, were made in order to evaluate their in vitro plasma stability and in vivo clearance from the blood. The liposomes showed a high stability after 6 hours of plasma incubation and they were rapidly cleared in vivo. Liposomes encapsulating propidium iodide, a fluorescent DNA binding dye, were mainly taken up in vivo by hepatic and spleen macrophages 1 hour after intravenous injection, but not by lung macrophages. When C57BL/6 mice were intravenously inoculated with 10(5) 3LL or B16F1 tumor cells previously incubated with indomethacin (10(-7) M) for 48 hours, the number of experimental lung metastatic foci was increased with respect to their respective control groups. Also, in 3LL or B16F1 tumor-bearing mice, treatment with indomethacin (0.5 mg/kg weight/day) for 10 days enhanced the number of lung metastases, but not significantly. However, when mice received indomethacin encapsulated in liposomes, the number of metastases was significantly reduced. In addition, encapsulated indomethacin (0.5 mg/kg weight/day) inhibits prostaglandin E2 production by peritoneal and spleen macrophages, whereas no significant inhibitory effect was observed with control-liposomes or equivalent doses of free indomethacin. We conclude that intravenous administration of liposome-encapsulated indomethacin has an antimetastatic effect on tumor-bearing mice. Use of indomethacin in liposomes may avoid the stimulation of metastases observed when the drug is administered alone.
Aliño
S F
SF
Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Spain.
Unda
F J
FJ
Iruarrizaga
A
A
Alfaro
J
J
Hilario
E
E
Pérez-Yarza
G
G
Bobadilla
M
M
Lejarreta
M
M
D000818:Animals; D002277:Carcinoma / Q000188:drug therapy / Q000556:secondary; D002851:Chromatography, High Pressure Liquid; D015232:Dinoprostone / Q000032:analysis; D004337:Drug Carriers; D007213:Indomethacin / Q000008:administration & dosage* / Q000494:pharmacology; D008081:Liposomes; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary*; D008264:Macrophages / Q000187:drug effects; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D014407:Tumor Cells, Cultured
D004337:Drug Carriers; D008081:Liposomes; D015232:Dinoprostone; D007213:Indomethacin