STIMULATION OF MACROPHAGE PROTEASE SECRETION VIA LIPOSOMAL DELIVERY OF MURAMYL DIPEPTIDE DERIVATIVES TO INTRACELLULAR SITES

  • 1 January 1984
    • journal article
    • research article
    • Vol. 51  (3) , 517-527
Abstract
Murine macrophages can be activated for enhanced neutral protease secretion by exposing the cells to muramyl dipeptides (MDP). A lipophilic derivative of nor-MDP is more efficacious than the parent hydrophilic nor-MDP. The efficacy and potency of the lipophilic and more prominently the hydrophilic drugs can be increased (10- to 103-fold) by encapsulating them in lipid vesicles (liposomes); however the encapsulation of drug causes a delay in the onset of activation. The enhanced effectiveness of liposomal MDP seems to be due partly to increased uptake, slow release and potentiated action of the drug at intracellular sites as emphasized by studies with [3H]-MDP. Appropriate distribution of the drug to intracellular compartments of the cell also seems to be an important factor in the activation process. The internalization of a relatively large amounts (> 5 ng/106 cells) of nor-MDP results in down regulation, that is reduced protease secretion, as compared to effects produced by internalization of lesser amounts of the drug. The macrophage activating effects of liposomal MDP do not seem to require the processing of liposomes in the lysosomal compartment; thus lysosome-blocking agents, such as chloroquine and dextran sulfate, do not affect the induction of protease secretion.