COMPARISON OF DIFFERENT HYDROPHOBIC ANCHORS CONJUGATED TO POLY(ETHYLENE GLYCOL) - EFFECTS ON THE PHARMACOKINETICS OF LIPOSOMAL VINCRISTINE

Poly(ethylene glycol) (PEG) conjugated lipids have been used to increa se the circulation longevity of liposomal carriers encapsulating thera peutic compounds. PEG is typically conjugated to distearoylphosphatidy lethanolamine (DSPE) via a carbamate linkage that results in a net neg ative charge on the phosphate moiety at physiological pH, It was antic ipated that the presence of this negative charge could have deleteriou s effects on liposome pharmacokinetic characteristics. We describe her e the synthesis of a new class of neutrally charged PEG-lipid conjugat es in which the PEG moiety was linked to ceramide (CER). These PEG-CER conjugates were compared with PEG-DSPE conjugates for their effects o n the pharmacokinetics of liposomal vincristine, PEG-CER (78% palmitic acid, C16) and PEG-DSPE achieved comparable increases in the circulat ion lifetimes of sphingomyelin/cholesterol (SM/chol) liposomes, Howeve r, PEG-DSPE significantly increased the in vitro and in vivo leakage r ates of vincristine from SM/chol-based liposomes compared to vincristi ne leakage observed when PEG-CER was used. The increase in drug leakag e observed in vitro that was due to the presence of PEG-DSPE was likel y due to the presence of a negative surface charge. Analysis of the el ectrophoretic mobilities of these formulations suggested that the nega tive surface charges were shielded by approx. 80% by the PEG layer ext ending from the membrane surface. In contrast, formulations containing PEG-CER had no surface charge and no electrophoretic mobility. A comp arison of the effects of the ceramide acyl chain length (C8 through C2 4) on the pharmacokinetics of SM/chol/PEG-CER formulations of vincrist ine demonstrated that longer acyl chains on the PEG-CER were associate d with longer circulation lifetimes of the liposomal carriers and, con sequently, higher plasma vincristine concentrations, These data sugges t that the short chain PEG-ceramides underwent rapid partitioning from the vesicles after i,v. administration, whereas the longer chain PEG- ceramides had stronger anchoring properties in the liposome bilayers a nd partitioned slowly from the administered vesicles. These data demon strate the utility of ceramide-based steric stabilizing lipids as well as the potential for developing controlled release formulations by ma nipulating the retention of the PEG-ceramide conjugate in liposome bil ayers, (C) 1998 Elsevier Science B,V. All rights reserved.