PubMed · 8681650
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S Romero, A Candela, J M Arriero. 1996. Keep testing the waters.. https://doi.org/10.1378/chest.110.1.299
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KEEP EXPLORING
We describe an early prototype of a pulsatile delivery system for drug containing vesicles. Nonionic surfactant vesicles (niosomes) of average diameter 4-30 microm are extruded from glass capillaries (exit diameter, 5-10 microm), using air pressures of 0.5-5 p.s.i. The formulation of the vesicles is vital. Extrusions were affected by the size, shape, and membrane composition of the niosomes used. Spherical or polyhedral niosomes, formed by polyoxyethylene alkyl ethers with and without cholesterol, respectively, with diameters larger than the exit diameter of the capillary do not retain their membrane integrity on extrusion and were sheared to form new ultrastructures. The expulsion of single or groups of intact polystyrene microspheres or tetradecyl-beta-D-maltoside niosomes with sizes smaller than the exit diameter can be achieved readily. The stepwise release profile of luteinizing hormone releasing hormone (LHRH) obtained after pulsatile expulsion of groups of niosomes entrapping LHRH indicates the feasibility of this system for pulsatile delivery of vesicles, although it requires miniaturization.
Cholesterol oxidase from Pseudomonas sp. strain ST-200 oxidized cholesterol and cholestanol to 6beta-hydroperoxycholest-4-en-3-one and 5alpha-cholestan-3-one respectively. The former was converted spontaneously to several oxysteroids such as 6-hydroxycholest-4-en-3-one and cholest-4-ene-3,6-dione, with the consumption of 2 mol of O(2) and the formation of 1 mol of H(2)O(2) for each mole of cholesterol oxidized. An oxidized form of the cholesterol oxidase dehydrogenates cholesterol, probably to the 5-en-3-one derivative. A reduced form of the enzyme, yielded from the cholesterol dehydrogenation reaction, dioxygenated cholest-5-en-3-one to 6beta-hydroperoxycholest-4-en-3-one.
To clarify the molecular mechanism by which an amphipathic negatively charged peptide consisting of 11 residues (WAE) induces fusion, and the relevance of these features for fusion, its mode of insertion and orientation into target bilayers were investigated. Using attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) in combination with techniques based on tryptophan fluorescence, the peptide was found to form an alpha-helix, shallowly inserted into the membrane to which it is anchored. Interestingly, in the presence of target membranes, WAE inserts into the target bilayer as an alpha-helix oriented almost parallel to the lipid acyl chains. The accessibility of the peptide to either acrylamide (as an aqueous quencher of Trp fluorescence) or deuterium oxide (on the course of an FTIR deuteration kinetics) was lower in the presence than in the absence of target membranes, confirming that under those conditions, the peptide was shielded from the aqueous environment. Since fusion experiments have shown a temperature dependence, the effect of this later parameter on the structure and mode of insertion of the peptide was also analyzed. In the presence of target membrane, but not in their absence, the amount of alpha-helical structure increased with temperature, reflecting a similar temperature-dependent increase in the rate and extent of WAE-induced fusion. Also, the extent of penetration of the helix into the target membrane was greater at 37 degrees C than at lower temperatures. This temperature-dependent distinction was revealed by a decreased accessibility of the peptide to deuterium oxide and acrylamide at 37 degrees C as compared to that at lower temperatures. These data underscore the role of peptide structure, peptide penetration, and orientation in the mechanism of protein-induced membrane fusion.