| Liposome-dependent drugs (LDD) are a unique class of drug compounds which exhibit improved potency upon encapsulation inside anionic liposomes. These drugs cannot readily pass through the plasma membrane unless they are incorporated into liposomes. Documented LDD include the antitumor agent methotrexate (MTX), and its transport negative derivatives, fluoroorotic acid, and phosphonacetyl-l-aspartic acid (PALA). However, all LDD to date have been polar compounds and anionic in nature.;Lipid toxicity was investigated in several cell lines with and without the presence of an osmotic gradient. Lipid toxicity appeared to be independent of the osmotic gradient, and was observed in CV-1P cells for preparations containing greater than 50% egg PG in PC. This finding agreed with earlier work showing that LDL-induced leakage and cell association were limited to liposomes composed of greater than 50% PG in PC. Elimination of the osmotic gradients in some formulations improved the delivery of liposomal PALA to CV-1P cells. PALA was also tested in pH sensitive liposomes, and was more effective in those liposomes than it was in non pH sensitive liposomes of comparable surface charge density.;The polar cationic compounds S-adenosyl methionine (SAMe) and sinefungin (SF) were identified as being LDD. SF is a demethylated analog of SAMe, which is a ubiquitous metabolite, and is the principal methyl donor in all mammalian cells. SF was effective in cationic liposomes, although most effective in anionic liposomes. SAMe showed in vitro efficacy in anionic but not neutral liposomes. Prior to starting animal experiments, in vitro stability testing was performed with several liposomal SAMe preparations. Two stable liposomal preparations were identified and subsequently used to target SAMe to the liver for the in vivo treatment of a mouse model for acetaminophen (APAP) induced liver toxicity. During dose-response testing, loaded liposomes constructed of DSPG were no more effective for reversing the effects of APAP damage than non-loaded, matched lipid counterparts. Further testing revealed that DSPC was not effective in delivering SAMe, however size was attributed to this formulation's ineffectiveness. |
