An acid-cleavable PEG lipid, 1′-(4′-cholesteryloxy-3′-butenyl)-ω-methoxy-polyethylene [112] glycolate (CVEP), has been developed that produces stable liposomes when dispersed as a minor component (0.5-5 mol%) in 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Cleavage of CVEP at mildly acidic pH's results in dePEGylation of the latently fusogenic DOPE liposomes, thereby triggering the onset of contents release. This paper describes the synthesis of CVEP via a six step sequence starting from the readily available precursors 1,4-butanediol, cholesterol, and mPEG acid. The hydrolysis rates and release kinetics from CVEP:DOPE liposome dispersions as a function of CVEP loading, as well as the cryogenic transmission electron microscopy and pH-dependent monolayer properties of 9:91 CVEP:DOPE mixtures, also are reported. When folate-receptor positive KB cells were exposed to calcein-loaded 5:95 CVEP:DOPE liposomes containing 0.1 mol% folatemodified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-polyethylene[76] glycolamide (folate-PEG-DSPE), efficient delivery of the calcein cargo to the cytoplasm of the cells was observed as determined by fluorescence microscopy and flow cytometry. Fluorescence resonance energy transfer analysis of lipid mixing in these cells was consistent with membrane-membrane fusion between the liposome and endosomal membranes.
An Efficient New Route to Plasmenyl-Type Lipids: Synthesis and Cytotoxicity of a Plasmenylcholine Analogue of the Antitumor Ether Lipid ET-18-OMe.-Key step in the synthesis of the novel plasmenylcholine analogue (IX) is the Z-selective lithiation-alkylation of vinyldioxane (V) under Barbier-type reaction conditions to give enol (VII). Plasmenylcholine analogue (IX) possesses cytotoxic activity comparable to ET-18-OMe and ET-16-OMe. Interestingly, the Tbs analogue (X) of vinyldioxane (V) provides the enols (XII)/(XIII) with E-selectivity during Barbier-type lithiation-alkylation. -(SHIN, JUNHWA; QUALLS, MARQUITA M.; BOOMER, JEREMY A.; ROBARGE, JASON; THOMPSON, DAVID H.; J.
This work describes the synthesis of a hexadecyl‐modified anthracene‐based photoacid generator for use as alight‐activated trigger, which will induce contents release from phospholipid1,2‐dioleoyl‐sn‐glycero‐3‐phosphoethanolamine (DOPE):lysoplasmenylcholine liposomes. The liposomes containing photosensitizers such as bacteriochlorophylla or aluminum phthalocyaninetetrasulfonate are also described. Finally, biodistribution of aluminum phthalocyaninetetrasulfonate loaded liposomes in a murine tumor xenograft model is discussed.
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