Improved retention of idarubicin after intravenous injection obtained for cholesterol-free liposomes

Abstract

To date there has been a focus on the application of sterically stabilized liposomes, composed of saturated diacylphospholipid, polyethylene glycol (PEG) conjugated lipids (5-10 mole%) and cholesterol (CH) (>30 mole%), for the systemic delivery of drugs. However, we are now exploring the utility of liposome formulations composed of diacylphospholipid conjugated PEG mixtures prepared in the absence of added cholesterol, with the primary objective of developing formulations that retain encapsulated drug better than comparable formulations prepared with cholesterol. In this report the stability of cholesterol-free distearoylphosphatidylcholine (DSPC):distearoylphosphatidylethanolamine (DSPE)-PEG(2000) (95:5 mol/mol) liposomes was characterized in comparison to cholesterol-containing formulations DSPC:CH (55:45 mol/mol) and DSPC:CH:DSPE-PEG(2000) (50:45:5 mol/mol/mol), in vivo. Circulation longevity of these formulations was determined in consideration of variables that included varying phospholipid acyl chain length, PEG content and molecular weight. The application of cholesterol-free liposomes as carriers for the hydrophobic anthracycline antibiotic, idarubicin (IDA), was assessed. IDA was encapsulated using a transmembrane pH gradient driven process. To determine stability in vivo, pharmacokinetic studies were performed using 'empty' and drug-loaded [(3)H]cholesteryl hexadecyl ether radiolabeled liposomes administered intravenously to Balb/c mice. Inclusion of 5 mole% of DSPE-PEG(2000) or 45 mole% cholesterol to DSPC liposomes increased the mean plasma area under the curve (AUC(0-24h)) 19-fold and 10-fold, respectively. Cryo-transmission electron micrographs of IDA loaded liposomes indicated that the drug formed a precipitate within liposomes. The mean AUC(0-4h) for free IDA was 0.030 micromole h/ml as compared to 1.38 micromole h/ml determined for the DSPC:DSPE-PEG(2000) formulation, a 45-fold increase, demonstrating that IDA was retained better in cholesterol-free compared to cholesterol-containing liposomes.

Freeze-Dried Targeted Mannosylated Selenium-Loaded Nanoliposomes: Development and Evaluation

“…An optimized liposomal drug delivery system should be stable under physiological conditions, yet be permeable and capable of drug release to the target site of action. Similar to our results, the incorporation of cholesterol with a liposomal formulation produced retardation in the release of doxorubicin and arabinofuranosyl cytidine (ara-C), whereas, at a higher mole percent, a much larger release rate of idarubicin was observed compared to cholesterol-free liposomes (90)(91)(92). A study by Taira et al showed that liposomes composed of egg phosphatidylcholine and cholesterol were found to be most stable within acidic gastric simulated media (pH 2) (93).…”

The functional roles of poly(ethylene glycol)‐lipid and lysolipid in the drug retention and release from lysolipid‐containing thermosensitive liposomes in vitro and in vivo

“…This observation is anticipated from previous studies with cholesterol-free liposomes where a change in PEG surface density had a minor effect on liposome elimination. 43 Taken together, these data show that the lysolipid component, even in liposomes containing 5-10 mol% PEG on the surface, reduced the circulation longevity of LTSL-doxorubicin. Studies by Mills and Needham 11 suggested that lysolipid is retained during the phase transition from the gel phase to complete liquid crystalline phase upon heating the LTSL through T c .…”

Liposomal Irinotecan

“…However, the results can be compared with other studies using comparable lipid compositions (primarily DSPC and Chol) to encapsulate doxorubicin (51), vincristine (52), mitoxantrone (53), daunorubicin (54), idarubicin (55), topotecan (28), and cisplatin (56). Such a comparison clearly demonstrates that a composition that is useful for one anticancer drug may be not be of any therapeutic value for another.…”