Liposomes can very efficiently deliver
immunomodulators to macrophages so as to induce
tumor cytotoxicity.
Liposomes most widely used for that purpose contain negatively charged
lipids, in particular
phosphatidylserine (PS), to enhance
liposome uptake by the macrophages. We investigated the effect of three negatively charged liposomal
lipids on the in vitro activation of liver macrophages to
tumor cytotoxicity by
muramyl dipeptide (MDP) and
lipopolysaccharide (LPS). Both MDP- and LPS-induced
tumor cytotoxicity towards murine
colon adenocarcinoma cells were strongly inhibited by PS-containing
liposomes. Under comparable conditions
phosphatidylglycerol (
DPPG)-containing or
dicetyl phosphate (DCP)-containing
liposomes did not inhibit or only marginally inhibited the induction of
tumor cytotoxicity. We did not observe PS-mediated inhibition of
tumor cell toxicity when the exposure of the macrophages to PS-
liposomes was limited to the 4-h activation period prior to addition of the
tumor target cells, suggesting that the inhibitory effect is accomplished at the level of the later stages of the activation process. Previously, we showed that macrophages which are activated to
tumor cytotoxicity during a 24-h incubation with MDP become refractory to a second activation with MDP. Now we observed that simultaneous incubation with PS-containing
liposomes partially prevents this refractoriness, which is also compatible with an interfering action of PS at a relatively late stage in the activation process. We conclude that PS, despite its reported stimulatory effect on
liposome uptake by macrophages, can seriously antagonize the effectiveness of
immunomodulating agents acting on macrophages. This bears relevance to the use of PS-containing
liposomes as a vehicle for such agents. The results are discussed in perspective of earlier reported pharmacological effects of PS and its metabolites.