| 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. | |
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MedLine Citation:
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PMID: 23030381 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2012-10-3 |
Journal Detail:
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Title: Molecular pharmaceutics Volume: - ISSN: 1543-8392 ISO Abbreviation: Mol. Pharm. Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-3 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101197791 Medline TA: Mol Pharm Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-1393, United States. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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