Acid-Labile mPEG鈥揤inyl Ether鈥?,2-Dioleylglycerol Lipids with Tunable pH Sensitivity: Synthesis and Structural Effects on Hydrolysis Rates, DOPE Liposome Release Performance, and Pharmacokinetics

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• 作者：Junhwa Shin ; Pochi Shum ; Jessica Grey ; Shin-ichi Fujiwara ; Guarov S. Malhotra ; Andres Gonz谩lez-Bonet ; Seok-Hee Hyun ; Elaine Moase ; Theresa M. Allen ; David H. Thompson
• 刊名：Molecular Pharmaceutics
• 出版年：2012
• 出版时间：November 5, 2012
• 年：2012
• 卷：9
• 期：11
• 页码：3266-3276
• 全文大小：556K
• 年卷期：v.9,no.11(November 5, 2012)
• ISSN：1543-8392

文摘

A family of 3-methoxypoly(ethylene glycol)鈥搗inyl ether鈥?,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 鈮?0 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 ¹²⁵I-tyraminylinulin as a label. The pharmacokinetic profiles gave a tb>1/2b> 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鈥搇ipid 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.<br>

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d="authors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=mPEG%E2%88%92lipid&qsSearchArea=searchText">mPEG鈭抣ipid; d="authors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=vinyl+ether+hydrolysis&qsSearchArea=searchText">vinyl ether hydrolysis; d="authors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=drug+delivery&qsSearchArea=searchText">drug delivery; d="authors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=dePEGylation&qsSearchArea=searchText">dePEGylation