作者: Magda Cabaj ; Lieselotte de Smet ; Josbert M. Metselaar ; Marcel H.A.M. Fens ; Gert Storm ; Manuela Banciu ; Maria Coimbra ; Raymond M. Schiffelers

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.

2002-04-01·Journal of Controlled Release1区 · 医学

Inhibition of liver metastasis by targeting of immunomodulators using mannosylated liposome carriers

1区 · 医学

Article

作者: Makiya Nishikawa ; Shigeru Kawakami ; Praneet Opanasopit ; Megumi Sakai ; Mitsuru Hashida ; Fumiyoshi Yamashita

Mannosylated liposomes were prepared by incorporating cholesten-5-yloxy-N-(4-((1-imino-2-beta-D-thiomannosylethyl)amino)butyl)formamide (Man-C4-Chol) into small unilamellar liposomes consisting of cholesterol and distearoyl phosphatidylcholine (DSPC). The biodistribution of liposomes labeled with [3H]cholesteryl hexadecyl ether was examined in mice. The rate and extent of the hepatic uptake of those [3H]liposomes increased proportionally on increasing the mixing ratio of Man-C4-Chol. Their hepatic uptake was reduced by increasing the administered dose due to the limited number of mannose receptors. The liver uptake of [3H]Man-liposomes was preferentially mediated by liver non-parenchymal cells (NPC) and significantly inhibited by co-injection with an excess of Man-BSA, indicating the involvement of a mannose receptor-mediated mechanism in the hepatic uptake of Man-liposomes. Muramyl dipeptide (MDP), an immunomodulator, was also incorporated into the liposomes and its inhibitory effect in an experimental liver metastasis model was examined. In contrast to free MDP treatment, which showed little effect on the inhibition of metastasis, liposomal MDP significantly reduced the number of metastatic colonies in the liver. Active targeting of MDP to liver NPC by Man-liposomes resulted in more effective inhibition than delivery of MDP by liposomes without mannose. Treatment with MDP/Man-liposomes further increased the survival of the tumor-bearing mice. These results suggest that Man-liposomes are effective carriers for targeted delivery of bioactive compounds to liver NPC.

1994-05-01·Journal of Immunotherapy

Secretion Pattern of the Rat Liver Macrophage Population Following Activation with Liposomal Muramyl Dipeptide In Vivo and In Vitro

Article

作者: Daemen, Toos ; Morselt, Henriette W. M. ; Hoedemakers, Rein M. J. ; Scherphof, Gerrit L.

Incubation of rat liver macrophages in vitro with free or liposome-encapsulated muramyl dipeptide (N-acetylmuramyl-L-alanyl-D-isoglutamine; MDP) resulted in a rapid but transient release of tumor necrosis factor-alpha (TNF-alpha), followed by a slow, steady release of nitric oxide (NO) and prostaglandin (PG) E. The secretion pattern induced in situ was determined by isolating the liver macrophages at 2, 12, 24, 48, and 72 h after injection of liposomal MDP and measuring the amounts of products secreted in a 24-h period following isolation. TNF-alpha secretion was detected only in macrophages isolated as early as 2 h after injection of liposomal MDP and not at later time points. Considerable heterogeneity was observed among macrophages of different size: For example, the large-sized cells were far more potent in TNF secretion than the smaller cells. Nitric oxide secretion, on the other hand, was maintained over a full 24-h period following MDP administration and was virtually independent of macrophage size. With regard to PGE release, similar to TNF-alpha secretion, considerable differences in secretory activity between cells of different size were observed. Also in this case the large cells were several times more active than the small cells. In contrast to TNF, however, PGE secretion could be detected up to 24 h after injection of liposomal MDP. These findings support the notion that the development and maintenance of the activated state of liver macrophages, induced by immunomodulators such as liposomal MDP, are under the control of a complex network of regulatory functions and that multiple secretory products play a role in the observed macrophage-mediated cytotoxicity.

100 项与 Liposomal tamoxifen(BTG) 相关的药物交易

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