title: Long-circulating, pH-sensitive liposomes sterically stabilized by copolymers bearing short blocks of lipid-mimetic units.
abstract: A major hurdle towards in vivo utilization of pH-sensitive liposomes is their prompt sequestration by reticuloendothelial system and hence short circulation time. Prolonged circulation of liposomes is usually achieved by incorporation of pegylated lipids, which have been frequently reported to deteriorate the acid-triggered release. In this study we evaluate the ability of four novel nonionic copolymers, bearing short blocks of lipid-mimetic units to provide steric stabilization of DOPE:CHEMs liposomes. The vesicles were prepared using the lipid film hydration method and extrusion, yielding liposomes of 120-160 nm in size. Their pH-sensitivity was monitored via the release of encapsulated calcein. The incorporation of the block copolymers at concentration up to 10 mol% did not deteriorate the pH-sensitivity of the liposomes. A selected formulation was tested for stability in presence of 25% human plasma and proved to significantly outclass the plain DOPE:CHEMs liposomes. The ability of calcein-loaded liposomes to deliver their cargo inside EJ cells was investigated using fluorescent microscopy and the results show that the surface-modified vesicles are as effective to ensure intracellular delivery as plain liposomes. The pharmacokinetics and organ distribution of a selected formulation, containing a copolymer bearing four lipid anchors was investigated in comparison to plain liposomes and PEG (2000)-DSPE stabilized liposomes. The juxtaposition of the blood clearance curves and the calculated pharmacokinetic parameters show that the block copolymer confers superior longevity in vivo. The block copolymers utilized in this study can be consider as promising sterically stabilizing agents for pH-sensitive liposomes.
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Medical University-Sofia, 2 Dunav Street, 1000 Sofia, Bulgaria. dmomekova@yahoo.com
authors.forename: Denitsa
authors.initials: D
authors.lastname: Momekova
authors.forename: Stanislav
authors.initials: S
authors.lastname: Rangelov
authors.forename: Stanislav
authors.initials: S
authors.lastname: Yanev
authors.forename: Elena
authors.initials: E
authors.lastname: Nikolova
authors.forename: Spiro
authors.initials: S
authors.lastname: Konstantinov
authors.forename: Birgit
authors.initials: B
authors.lastname: Romberg
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.forename: Nikolay
authors.initials: N
authors.lastname: Lambov
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002788:Cholesterol Esters / Q000737:chemistry* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D005452:Fluoresceins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008027:Light; D008081:Liposomes; D008297:Male; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D010714:Phosphatidylethanolamines / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012542:Scattering, Radiation; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013997:Time Factors; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D002788:Cholesterol Esters; D005452:Fluoresceins; D008081:Liposomes; D010714:Phosphatidylethanolamines; C013440:cholesteryl succinate; C007740:fluorexon