title: Pharmaco attributes of dioleoylphosphatidylethanolamine/cholesterylhemisuccinate liposomes containing different types of cleavable lipopolymers.
abstract: Various amounts of one of three different types of cleavable methoxy polyethylene glycol (mPEG)-phospholipids or of a non-cleavable counterpart (mPEG-DSPE) were included into pH-sensitive liposome formulations containing dioleoylphosphatidylethanolamine (DOPE) and cholesterylhemisuccinate (CHEMS) at a 6:4 molar ratio, and the effect on plasma clearance and contents release rates was determined. The cleavable lipopolymers were all based on a distearoylphosphatidyl lipid anchor, which was linked to mPEG via dithiodipropionateaminoethanol (mPEG-DTP-DSPE), dithio-3-hexanol (mPEG-DTH-DSPA), or Gly-Phe-Leu-Gly-aminoethanol (mPEG-GFLG-DSPE) linkers. In contrast to the first-generation thiolytically cleavable lipopolymer, mPEG-DTP-DSPE, the second generation conjugates contained a hindered disulfide or enzymatically cleavable tetrapeptide, respectively, as the points of scission. In the absence of mPEG-lipid, DOPE/CHEMS liposomes had rapid clearance half-lives. As the mol% of mPEG-lipid in the liposomes increased, the rate of clearance of DOPE/CHEMS liposomes in mice decreased. Zeta-potential measurements showed that decreased clearance was correlated with a decrease in the apparent surface charge of the liposomes, which approached neutrality as the content of mPEG-lipids increased to above 15 mol%. At these levels, liposomes containing mPEG-DTP-DSPE were cleared from blood circulation faster than liposomes containing other, less vulnerable lipopolymers. Liposomes with the peptide-linked lipopolymer exhibited the slowest clearance. The presence of either cleavable or non-cleavable mPEG-lipids at concentrations of 5 mol% or higher in the DOPE/CHEMS liposomes inhibited the release of doxorubicin from these liposomes in response to acid pH.
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, AB, Canada T6G 2H7.
authors.forename: Janny X
authors.initials: JX
authors.lastname: Zhang
authors.forename: Samuel
authors.initials: S
authors.lastname: Zalipsky
authors.forename: Nasreen
authors.initials: N
authors.lastname: Mullah
authors.forename: Michal
authors.initials: M
authors.lastname: Pechar
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Allen
mesh_terms: D000818:Animals; D002788:Cholesterol Esters / Q000737:chemistry; D004317:Doxorubicin / Q000032:analysis; D004337:Drug Carriers; D005260:Female; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D013997:Time Factors
chemical_list: D002788:Cholesterol Esters; D004337:Drug Carriers; D008081:Liposomes; D010714:Phosphatidylethanolamines; C107570:polyethylene glycol-distearoylphosphatidylethanolamine; C094877:dioleoyl phosphatidylethanolamine; D011092:Polyethylene Glycols; D004317:Doxorubicin; C028210:monomethoxypolyethylene glycol; C013440:cholesteryl succinate