We have investigated the ability of
liposomes containing a lipophilic
muramyl dipeptide,
N-acetylmuramyl-L-alanyl-D-isoglutamine glycerol dipalmitate (
MDP-GDP) to activate Kupffer cell tumoricidal activity in situ and to inhibit the growth of experimental hepatic
micrometastases of tumor cell line H-59, a liver-homing variant of the
Lewis lung carcinoma.
Liposomes prepared from
distearoylphosphatidylcholine/
dimyristoylphosphatidylglycerol (DSPC/
DMPG) and containing
MDP-GDP (1 mumol and 2 micrograms, respectively) were efficiently taken up by the liver after i.v. administration. A single i.v. injection of DSPC/
DMPG liposomes containing
MDP-GDP was capable of inducing Kupffer cell tumoricidal activity against H-59
tumor cells as measured in vitro. Control
liposomes or 100 micrograms free MDP were ineffective in inducing Kupffer cell tumoricidal activity in situ. Two treatment regimens were evaluated in vivo: firstly, C57BL/6 mice were injected with tumor cell line H-59 and subsequently treated with multiple
injections of liposomal
MDP-GDP. Secondly, treatment with liposomal
MDP-GDP was initiated prior to
tumor cell injection and continued after
tumor cell injection. The ability of
liposomes containing
MDP-GDP to reduce the number of hepatic
micrometastases using the first protocol was related to the
tumor cell inoculum, significant inhibition being observed at lower liver
tumor burdens (less than 25
tumor nodules). Pretreatment of the mice prior to
tumor cell challenge followed by treatment afterwards greatly enhanced the efficacy of liposomal
MDP-GDP and brought about a highly significant inhibition of the growth of experimental
metastases even at high liver
tumor burdens (greater than 50 nodules).