The chronic inflammatory environment of
tumors is a target for novel antitumor therapeutic strategies. Besides
cholesterol lowering effects,
statins have been studied for their anti-inflammatory and immunomodulatory properties. These pleiotropic effects result mainly from the altered post-translational modification of
GTP-binding proteins which regulate many intracellular pathways involved in cell growth and survival. Although pre-clinical studies suggest that
statins may be effective
anticancer agents required doses that are 100 to 500 fold higher than those needed to lower
cholesterol levels. Furthermore, in view of their wide-ranging effects on cellular metabolism, target site-specific delivery is preferred. In this study, we investigated
tumor-specific delivery of
pravastatin using small long-circulating
liposomes. In vitro studies on the effects of (liposomal)
pravastatin on viability and proliferation of
tumor cells, endothelial cells and macrophages revealed that the latter were the most sensitive cell type towards (liposomal)
pravastatin treatment. In vivo,
liposome-encapsulated
pravastatin (5mg/kg) inhibited murine B16F10-melanoma growth over 70% as compared to free
pravastatin, which was ineffective. As expected, treatments did not influence serum
cholesterol levels within the time frame of the study. At 48 h post-injection, 3 μg of
pravastatin could still be recovered from the
tumors of liposomal
pravastatin treated mice, whereas
pravastatin could not be detected in
tumors of the free drug treated mice (i.e. < 20 ng). In contrast to the free drug, liposomal
pravastatin treatment effectively inhibited the production of several pro-inflammatory/pro-angiogenic mediators involved in
inflammation and angiogenesis, out of a range of a panel of 24
proteins studied. Furthermore, liposomal
pravastatin treatment increased MHC class I
protein expression in the
tumor tissue whereas free drug showed no effect. Taken together, targeted delivery of
statins can improve their
tumor growth inhibiting activity by increasing local drug concentration and direct modulation of macrophage function. The antitumor activity seems to result primarily from a local inhibition of
tumor inflammation and stimulation of antitumor immune response.