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Induction of Colony-stimulating Activity in Mice by Injection of Liposomes Containing Lipophilic Muramyl Peptide Derivatives

Laboratoire de Biologie des Régulations Immunitaires, Immunology Department, Institut Pasteur, 25 rue du Docteur Roux, 75015 Paris, France [A. G., B. C.]; Montreal General Hospital Research Institute, Quebec H3G 1A4, Canada [N. C. P.]; and Department of Pharmacology and Therapeutics, H. Lee Moffitt Cancer Center and Research Institute at USF, Tampa, Florida [L. C.]

Colony-stimulating factor (CSF) activity induction by lipophilic derivatives of three muramyl peptides, glyceryl dipalmitate-MDP derivatives, was studied in vivo and in vitro and compared to the activity of the same compounds incorporated within freeze-dried liposomes. Two lipophilic derivatives (MDP-GDP and MDPGBe-GDP) were able to induce CSF activity in vivo and in vitro. The incorporation of these compounds within appropriately designed liposomes composed of distearoylphosphatidylcholine and phosphatidylserine (DSPC/PS) increased their ability to induce CSF activity in vivo but completely abrogated their ability to induce CSF activity in vitro. Furthermore, the phospholipid composition of liposomes influenced the efficacy of glycopeptide liposomal incorporation. Thus, the serum CSF-inducing effect of MDP-GDP was considerably enhanced by incorporation of this compound within liposomes composed of DSPC/PS at a molar ratio 7:0.3 but was not modified if the DSPC/PS molar ratio was 7:3. The lipophilic derivative of MDP (D-D), MDP (D-D)-GDP, was unable to induce CSF activity in vivo or in vitro but surprisingly became active in vivo after entrapment within DSPC/PS liposomes (molar ratio 7:0.3). Our results show that appropriate liposomes may be suitable carriers to deliver CSF activity-inducing agents to macrophages in vivo.

Received 5/10/88. Revised 11/ 1/88. Accepted 11/ 3/88.