Preparing Size-Controlled Liposomes Modified with Polysaccharide Derivatives for pH-Responsive Drug Delivery Applications
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The liposome particle size is an important parameter because it strongly affects content release from liposomes as a result of different bilayer curvatures and lipid packing. Earlier, we developed pH-responsive polysaccharide-derivative-modified liposomes that induced content release from the liposomes under weakly acidic conditions. However, the liposome used in previous studies size was adjusted to 100-200 nm. The liposome size effects on their pH-responsive properties were unclear. For this study, we controlled the polysaccharide-derivative-modified liposome size by extrusion through polycarbonate membranes having different pore sizes. The obtained liposomes exhibited different average diameters, in which the diameters mostly corresponded to the pore sizes of polycarbonate membranes used for extrusion. The amounts of polysaccharide derivatives per lipid were identical irrespective of the liposome size. Introduction of cholesterol within the liposomal lipid components suppressed the size increase in these liposomes for at least three weeks. These liposomes were stable at neutral pH, whereas the content release from liposomes was induced at weakly acidic pH. Smaller liposomes exhibited highly acidic pH-responsive content release compared with those from large liposomes. However, liposomes with 50 mol% cholesterol were not able to induce content release even under acidic conditions. These results suggest that control of the liposome size and cholesterol content is important for preparing stable liposomes at physiological conditions and for preparing highly pH-responsive liposomes for drug delivery applications.Cite
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Bax-α5 and Bcl-xL-α5, which are shorter versions of apoptosis-regulating proteins Bax and Bcl-xL, were simulated with lipid bilayers composed of pure dioleoylglycerophosphocholine (DOPC) lipids or a mixture of DOPCs and cholesterols. Starting with the initial peptide position near the bilayer surface, both Bax-α5 and Bcl-xL-α5 bind to the bilayer because of their charge interactions with lipid head groups. After binding to the bilayer surface, Bax-α5 inserts into the pure DOPC bilayer, but not into the DOPC-cholesterol bilayer, showing the effect of cholesterols on the peptide-bilayer interaction. Despite the similar peptide structure, Bcl-xL-α5 does not insert into the bilayer, in contrast to the interaction of Bax-α5 with the bilayer. Bcl-xL-α5 predominantly has the random-coil structure in both aqueous and membrane environments, while Bax-α5 shows a higher extent of α-helical structure in the bilayer than in water, in quantitative agreement with experiment. In particular, although Bax-α5 and Bcl-xL-α5 have the same extent of the electrostatic interaction with lipid head groups, Bax-α5 has stronger hydrophobic interaction with lipid tails than does Bcl-xL-α5. These indicate that Bax-α5 retains α-helical structure, where hydrophobic residues on one side of the α-helix interact with lipid tails and thus can easily attract the peptide into the lipid-tail region, while Bcl-xL-α5 forms a random coil that tends to spread on the bilayer surface and thus has weaker hydrophobic interaction with lipid tails. Our findings help explain the experimental observation that showed that Bax-α5 disorders lipids and induces pore formation, but Bcl-xL-α5 does not.
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Bcl-xL
Lipid bilayer mechanics
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We present a novel formulation of non-phospholipid liposomes formed from cholesterol and palmitic acid. Despite the fact that these two lipidic species do not form individually fluid bilayers, we show that once mixed together, fluid bilayers can be obtained and, moreover, these can be extruded using classical extrusion processes to form liposomes. The chemical analysis indicates that these liposomes contain 70 mol % cholesterol, a content that is considerably higher that the saturation limit generally reported for phospholipid bilayers. These cholesterol-rich liposomes, formed with molecules that have low toxicity in vivo, display an improved impermeability relative to that of traditional phospholipid liposomes. In addition, because of the presence of palmitic acid, the stability of the liposomes is pH-dependent, and it is possible to trigger the release of encapsulated materials by pH stimuli.
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We present results of molecular dynamics simulations of the interaction of a positively charged antimicrobial peptide, carnobacteriocin B2, with a mixed (anionic−zwitterionic) lipid bilayer carrying a net negative charge. When the peptide is initially immersed in an aqueous medium, it approaches the bilayer surface because of electrostatic attraction. Insertion of the single peptide in the bilayer, however, is not spontaneous. Simulations are also conducted by employing initial configurations where the peptide is partially or completely inserted into the bilayer. When the peptide is partially inserted into the bilayer, it experiences a slight loss of helical structure with the appearance of a hinge region in the C-terminal helix. Complete insertion of the peptide in the bilayer results in a stable straight helix with the N- and C-terminals electrostatically tethered to the opposing headgroups of the bilayer. The charged amino acids of the peptide do not cross the charged headgroups of the bilayer in any of the simulations, nor is any bilayer disruption observed in these studies. These results show that single peptides do not spontaneously penetrate lipid membranes and corroborate deductions from previous experimental studies that alternate mechanisms are necessary for their penetration into lipid bilayers.
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Model lipid bilayer
Lipid bilayer mechanics
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