Document Detail


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.
MedLine Citation:
PMID:  23030381     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Junhwa Shin; Pochi Shum; Jessica Grey; Shin-ichi Fujiwara; Guarov S Malhotra; Andres González-Bonet; Seok-Hee Hyun; Elaine Moase; Theresa M Allen; David H Thompson
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-03
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  9     ISSN:  1543-8392     ISO Abbreviation:  Mol. Pharm.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-05     Completed Date:  2013-04-30     Revised Date:  2013-11-07    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3266-76     Citation Subset:  IM    
Affiliation:
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-1393, United States.
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MeSH Terms
Descriptor/Qualifier:
Acids / metabolism
Animals
Blood Circulation Time
Diglycerides / pharmacokinetics*
Female
Hydrogen-Ion Concentration
Hydrolysis
Lipids / chemical synthesis*,  pharmacokinetics
Liposomes*
Mice
Mice, Inbred BALB C
Phosphatidylethanolamines / pharmacokinetics*
Polyethylene Glycols / pharmacokinetics*
Tissue Distribution
Vinyl Compounds / pharmacokinetics*
Grant Support
ID/Acronym/Agency:
CA23168/CA/NCI NIH HHS; GM087016/GM/NIGMS NIH HHS; GM55266/GM/NIGMS NIH HHS; R01 GM087016/GM/NIGMS NIH HHS; //Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; 0/Acids; 0/Diglycerides; 0/Lipids; 0/Liposomes; 0/Phosphatidylethanolamines; 0/Polyethylene Glycols; 0/Vinyl Compounds; 2H2T044E11/vinyl ether; 9004-74-4/monomethoxypolyethylene glycol; ADK3G923Z3/diolein
Comments/Corrections

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