Incorporation of N-(omega-carboxy)acylamido-phosphatidylethanolamines (-PEs) into large unilamellar vesicles (LUVs) of L-alpha-distearoylphosphatidylcholine (DSPC) was found to dramatically increase the in vivo liposomal circulation lifetime in rats, reaching a maximal effect at 10 mol.% of the total phospholipid. Neither pure DSPC liposomes nor those with the longest circulating derivative, N-glutaryl-dipalmitoylphosphatidylethanolamine (-DPPE), were found to significantly bind complement from serum. Therefore, the relatively short circulation time of pure DSPC liposomes did not appear to be related to greater complement opsonization leading to uptake by the reticuloendothelial system. However, N-(omega-carboxy)acylamido-PEs were particularly efficient inhibitors of a limited aggregation detected for pure DSPC liposomes. The aggregation tendency of DSPC liposomes incorporating various structural analogs of N-glutaryl-DPPE correlated inversely with the circulation lifetimes. Therefore, it is concluded that such PE derivatives enhance the circulation time by preventing liposomal aggregation and avoiding a poorly understood mechanism of clearance that is dependent on size but is independent of complement opsonization. At high concentrations of N-glutaryl-DPPE (above 10 mol.%), the liposomes exhibited strong complement opsonization and were cleared from circulation rapidly, as were other highly negatively charged liposomes. These data demonstrate that both the lack of opsonization and the lack of a tendency to aggregate are required for long circulation. Liposomal disaggregation via N-(omega-carboxy)acylamido-PEs yields a new class of large unilamellar DSPC liposomes with circulation lifetimes that are comparable to those of sterically stabilized liposomes.
Amphotericin B lipid complex for injection (ABLC) is a suspension of amphotericin B complexed with the lipidsl-α-dimyristoylphosphatidylcholine (DMPC) andl-α-dimyristoylphosphatidylglycerol. ABLC is less toxic than amphotericin B deoxycholate (AmB-d), while it maintains the antifungal activity of AmB-d. Active amphotericin B can be released from ABLC by exogenously added (snake venom, bacteria, orCandida-derived) phospholipases or by phospholipases derived from activated mammalian vascular tissue (rat arteries). Such extracellular phospholipases are capable of hydrolyzing the major lipid in ABLC. Mutants of C. albicans that were resistant to ABLC but not AmB-d in vitro were deficient in extracellular phospholipase activity, as measured on egg yolk agar or as measured by their ability to hydrolyze DMPC in ABLC. ABLC was nevertheless effective in the treatment of experimental murine infections produced by these mutants. Isolates of Aspergillus species, apparently resistant to ABLC in vitro (but susceptible to AmB-d), were also susceptible to ABLC in vivo. We suggest that routine in vitro susceptibility tests with ABLC itself as the test material may not accurately predict the in vivo activity of ABLC and that the enhanced therapeutic index of ABLC relative to that of AmB-d in vivo may be due, in part, to the selective release of active amphotericin B from the complex at sites of fungal infection through the action of fungal or host cell-derived phospholipases.
TLC ELL-12 is a liposomal formulation of the novel antineoplastic compound 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (L-ET-18-OCH(3)). The purpose of these studies was to evaluate the activity and tissue distribution of L-ET-18-OCH(3) when administered i.v. as TLC ELL-12 to rats bearing solid tumors. Growth-inhibitory activity of L-ET-18-OCH(3) and TLC ELL-12 against methylnitrosourea (MNU)-induced tumors grown in vitro was evaluated. Female Buffalo rats were injected s.c. with transplantable MNU-induced tumor cells. Four days later, animals were treated i.v. with L-ET-18-OCH(3) administered as TLC ELL-12 once daily for 5 consecutive days. Another group of MNU-tumor bearing rats was given a single 12.5 mg/kg dose of TLC ELL-12 containing [14C]L-ET-18-OCH(3) by i.v. injection into a tail vein. The 50% growth inhibitory concentration for TLC ELL-12 against MNU tumor cells in vitro was 63 microM (about 30 microg/ml). Tumor growth was significantly inhibited in ELL-12-treated rats versus controls. After a single dose, whole blood L-ET-18-OCH(3) concentrations declined in a multiphasic fashion with C(max) and terminal half-life values of approximately 91.1 microg L-ET-18-OCH(3)/ml and 13.1 h, respectively. Tumor L-ET-18-OCH(3) levels increased through the first 16-24 h post-dosing to about 23 microg/g and remained elevated at the terminal time point with little evidence of metabolism. Concentration-time profiles for selected tissues indicate rapid distribution of L-ET-18-OCH(3) from the circulation into tissues with highest concentrations in spleen, liver, lungs, kidneys and gastrointestinal tract. L-ET-18-OCH(3) as TLC ELL-12 shows both in vitro and in vivo activity against the MNU tumor line. When i.v. administered, L-ET-18-OCH(3) from ELL-12 is well distributed and slowly eliminated by metabolism in tissues.
TLC ELL-12 is a liposomal formulation of the antineoplastic L-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine [L-ET-18-OCH3 (EL)]. The purpose of these studies was to characterize the toxicity and disposition of [N-methyl-14C] L-ET-18-OCH3 administered as TLC ELL-12. Rats received TLC ELL-12 by i.v. infusion into a tail vein as a single 12.5 or 62.5 mg/kg dose or as five daily doses at 12.5 mg/kg (cumulative dose of 62.5 mg/kg). Whole blood and tissue samples were collected over 24 h, and assayed for total and EL-specific radioactivity. The amounts of radioactivity in urine, bile, injection site and carcass were determined for up to 48 h. TLC ELL-12 was well tolerated in male and female rats in single doses up to 37.5 mg/kg. The minimum lethal dose was 112.5 mg/kg. Doses of 12.5 mg/kg (no observed adverse effects) and 62.5 mg/kg (approximate maximum tolerated dose) were chosen for further study. The pharmacokinetics of EL given as TLC ELL-12 were non-linear with a disproportionate increase in AUC at the higher dose. Daily dosing at 12.5 mg/kg did not result in accumulation in the blood. The highest concentrations of EL at 24 h after dosing were in the spleen and liver. Virtually no radioactivity was recovered in the urine or bile of rats, most remaining in the carcass and injection site (tail). After a 12.5 mg/kg dose of TLC ELL-12, the levels of EL in the blood and most tissues examined were well above the levels that inhibit tumor growth and may therefore be therapeutically active.
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