Triggering Stealth Liposomes by pH-Sensitive Conformational Switch of Lipid Tails

Purpose. To characterize the ability of a novel pH-sensitive lipid to trigger the release of PEG-grafted liposomes as potential drug delivery systems. Methods. A number of liposomes were constructed by freeze-thawing and extrusion. The liposomes comprised PEG-lipid conjugates, phospholipids, and the pH-sensitive lipid carrying a trans-2-aminocyclohexanol headgroup as a pH-sensitive conformational switch of lipid tails. The liposomes also contained the fluorescent dyes ANT/DPX so that liposome permeation can be monitored by the release of the dyes, which de-quenches their fluorescence. The liposomes were incubated in buffers of different pHs at 37 C and the change of the fluorescence of the samples were monitored on a QuataMaster Fluorometer. The data were then converted into the Rich Text format and processed by Microsoft Excel to give the percentage of liposome leakage over time. Results. At pH 7.4, most of the constructed liposomes carried homogenous size and near-zero Zeta potential. The liposomes can be stored at pH 7.4, 4 C for months. Upon exposure to pH 5.5, the liposomes released their encapsulated dyes. The extend of liposome contents release at the lowered pH depended on the percentage of the pH-sensitive lipid and the nature of the phospholipids. Conclusion. Conformational switch of the lipid tails has been validated as a versatile approach to render PEG-grafted liposomes pHsensitive. Such pH-sensitive and yet stealth liposomes may be used as more effective anticancer drug delivery systems compared to traditional stealth liposomes

NMR investigation of phospholipid/PEG-ceramide-liposomes

Liposomes are macromolecular structures in which an aqueous core is surrounded by a double-layered lipid membrane. Surface modifications in liposomes serve the purpose of enhanced water-solubility, immuno-compatibility, and targeted delivery of liposome “cargo”, e.g. drugs or DNA/RNA. Liposomal drug delivery systems are frequently composed of phospho-lipids and ceramides amongst others. We investigated pH-sensitive liposomes. Complete NMR structure assignment and quantification of all components provided quality control. During liposome extrusion/preparation/loading and cleanup, little to no variation in composition was observed

Triggering Stealth Liposomes by pH-Sensitive Conformational Switch of Lipid Tails

Purpose. To characterize the ability of a novel pH-sensitive lipid to trigger the release of PEG-grafted liposomes as potential drug delivery systems. Methods. A number of liposomes were constructed by freeze-thawing and extrusion. The liposomes comprised PEG-lipid conjugates, phospholipids, and the pH-sensitive lipid carrying a trans-2-aminocyclohexanol headgroup as a pH-sensitive conformational switch of lipid tails. The liposomes also contained the fluorescent dyes ANT/DPX so that liposome permeation can be monitored by the release of the dyes, which de-quenches their fluorescence. The liposomes were incubated in buffers of different pHs at 37 C and the change of the fluorescence of the samples were monitored on a QuataMaster Fluorometer. The data were then converted into the Rich Text format and processed by Microsoft Excel to give the percentage of liposome leakage over time. Results. At pH 7.4, most of the constructed liposomes carried homogenous size and near-zero Zeta potential. The liposomes can be stored at pH 7.4, 4 C for months. Upon exposure to pH 5.5, the liposomes released their encapsulated dyes. The extend of liposome contents release at the lowered pH depended on the percentage of the pH-sensitive lipid and the nature of the phospholipids. Conclusion. Conformational switch of the lipid tails has been validated as a versatile approach to render PEG-grafted liposomes pHsensitive. Such pH-sensitive and yet stealth liposomes may be used as more effective anticancer drug delivery systems compared to traditional stealth liposomes

NMR investigation of phospholipid/PEG-ceramide-liposomes

Liposomes are macromolecular structures in which an aqueous core is surrounded by a double-layered lipid membrane. Surface modifications in liposomes serve the purpose of enhanced water-solubility, immuno-compatibility, and targeted delivery of liposome “cargo”, e.g. drugs or DNA/RNA. Liposomal drug delivery systems are frequently composed of phospho-lipids and ceramides amongst others. We investigated pH-sensitive liposomes. Complete NMR structure assignment and quantification of all components provided quality control. During liposome extrusion/preparation/loading and cleanup, little to no variation in composition was observed

pH-Triggered conformational switches based on trans-2-aminocyclohexanol moiety

Properly designed trans-2-aminocyclohexanols possess a negative allosteric cooperativity and can serve as powerful conformational pH-triggers. Their protonation leads to a conformational flip due to a strong intramolecular hydrogen bond. This \u27impulse\u27 is mechanically transmitted by the cycle to induce a conformational change of a remote site, thus altering its properties. Variation of NR2 groups allows a tuning of the conformational equilibrium, which was studied by NMR. These triggers were used in pH-sensitive lipid vesicles for drug and gene delivery

pH-Triggered conformational switches based on trans-2-aminocyclohexanol moiety

Properly designed trans-2-aminocyclohexanols possess a negative allosteric cooperativity and can serve as powerful conformational pH-triggers. Their protonation leads to a conformational flip due to a strong intramolecular hydrogen bond. This \u27impulse\u27 is mechanically transmitted by the cycle to induce a conformational change of a remote site, thus altering its properties. Variation of NR2 groups allows a tuning of the conformational equilibrium, which was studied by NMR. These triggers were used in pH-sensitive lipid vesicles for drug and gene delivery

Exploration of trans-2-(1,2,3-triazolyl)-cyclohexanols as potential inhibitors for fungal glycosidases

A series of carbasugars based on trans-2-(1,2,3-triazolyl)-cyclohexanol moiety was synthesized for the first time by a “click reaction” of the corresponding azides and alkynes, and tested for the inhibitory activity towards fungal glycosidases from Aspergillus and Penicillium sp