title: Acid-labile mPEG-vinyl ether-1,2-dioleylglycerol lipids with tunable pH sensitivity: synthesis and structural effects on hydrolysis rates, DOPE liposome release performance, and pharmacokinetics.
abstract: A family of 3-methoxypoly(ethylene glycol)-vinyl ether-1,2-dioleylglycerol (mPEG-VE-DOG) lipopolymer conjugates, designed on the basis of DFT calculations to possess a wide range of proton affinities, was synthesized and tested for their hydrolysis kinetics in neutral and acidic buffers. Extruded ∼100 nm liposomes containing these constructs in ≥90 mol % 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) produced dispersions that retained their calcein cargo for more than 2 days at pH 7.5, but released the encapsulated contents over a wide range of time scales as a function of the electronic properties of the vinyl ether linkage, the solution pH, and the mPEG-VE-DOG composition in the membrane. The in vivo performance of two different 90:10 DOPE:mPEG-VE-DOG compositions was also evaluated for blood circulation time and biodistribution in mice, using (125)I-tyraminylinulin as a label. The pharmacokinetic profiles gave a t(1/2) of 7 and 3 h for 90:10 DOPE:ST302 and 90:10 DOPE:ST502, respectively, with the liposomes being cleared predominantly by liver and spleen uptake. The behavior of these DOPE:mPEG-VE-DOG formulations is consistent with their relative rates of vinyl ether hydrolysis, i.e., the more acid-sensitive mPEG-VE-DOG derivatives produced faster leakage rates from DOPE:mPEG-VE-DOG liposomes, but decreased the blood circulation times in mice. These findings suggest that the vinyl ether-based PEG-lipid derivatives are promising agents for stabilizing acid-sensitive DOPE liposomes to produce formulations with a priori control over their pH responsiveness in vitro. Our data also suggest, however, that the same factors that contribute to enhanced acid sensitivity of the DOPE:mPEG-VE-DOG dispersions are also likely responsible for their reduced pharmacokinetic profiles.
authors.affiliation: Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-1393, United States.
authors.forename: Junhwa
authors.initials: J
authors.lastname: Shin
authors.forename: Pochi
authors.initials: P
authors.lastname: Shum
authors.forename: Jessica
authors.initials: J
authors.lastname: Grey
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Fujiwara
authors.forename: Guarov S
authors.initials: GS
authors.lastname: Malhotra
authors.forename: Andres
authors.initials: A
authors.lastname: González-Bonet
authors.forename: Seok-Hee
authors.initials: SH
authors.lastname: Hyun
authors.forename: Elaine
authors.initials: E
authors.lastname: Moase
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Allen
authors.forename: David H
authors.initials: DH
authors.lastname: Thompson
mesh_terms: D000143:Acids / Q000378:metabolism; D000818:Animals; D001776:Blood Circulation Time; D004075:Diglycerides / Q000493:pharmacokinetics*; D005260:Female; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008055:Lipids / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D010714:Phosphatidylethanolamines / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014753:Vinyl Compounds / Q000493:pharmacokinetics*
chemical_list: C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D000143:Acids; D004075:Diglycerides; D008055:Lipids; D008081:Liposomes; D010714:Phosphatidylethanolamines; D014753:Vinyl Compounds; C100195:vinyl ether; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; C013965:diolein