Degradable controlled release systems useful for protein delivery.
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Biocompatible Materials↗
Biomedical subjects
R Maskiewicz
Publications and source records attributed to R Maskiewicz.
Sterile filtration of a parenteral emulsion.
The Syntex adjuvant formulation (SAF) containing [thr1]-muramyldipeptide in an oil-in-water emulsion has proven to be an effective adjuvant eliciting both cell-mediated and humoral immune response. As a parenteral emulsion, sterility of the final product was a concern, and various methods of achieving sterility were considered. For emulsions, most conventional sterilization methods are not viable, requiring the more cumbersome technique of sterilizing individual components and assembling/manufacturing under sterile conditions. Emulsion vehicles were manufactured with various models in the Microfluidizer M110 series. All equipment examined was capable of reducing the average dispersed oil droplet size to approximately 160 nm, with varying size ranges. Operating at an internal equipment pressure of greater than 16,000 psi, with at least five cycles through the interaction chamber, the resulting emulsion had a narrow droplet size range distribution, with the largest droplets being small enough to enable sterile filtration. Under specific-manufacturing conditions, the adjuvant emulsion becomes easily filtered through a 0.22-micron cartridge filter, thus yielding a sterile end product. This is the first published example of emulsion sterilization being achieved by terminal filtration.
Chemistry, Pharmaceutical↗
Interaction of positively-charged liposomes with blood: implications for their application in vivo.
Liposomes with positively-charged lipid components have previously demonstrated efficacy in animal models for human diseases, and are currently being evaluated in human clinical studies. Cationic lipids can improve entrapment efficiency of drugs and other substances which are negatively charged, and facilitate penetration of biological membranes in vitro, e.g. in transfection. However, toxic effects have also been reported for positively-charged liposomes containing stearylamine. In this report we have examined gross interactions between plasma components or erythrocytes with cholesterol-rich SUV composed of PC or DPPC and having 0-50 mol% of phospholipid replaced with positively-charged stearylamine, DOTMA, or BisHOP. Plasma interactions observed included increased turbidity of the usually clear stroma and/or formation of a clot-like mass. At plasma concentrations of 0.25 mumol/ml or more, the extent of plasma interactions depended upon the concentration of positive charge, the charge density of cationic lipid initially present in the liposomes, and to a lesser degree, the nature of the lipid providing the positive charge. At liposomal positive charge concentrations of greater than 0.5 mumol/ml plasma, stearylamine provoked a strong increase in plasma turbidity, whereas liposomes incorporating DOTMA or BisHOP provoked a strong clotting response. Some hemolysis of erythrocytes in vitro occurred on interaction with cationic liposomes where positive charge was contributed by DOTMA or stearylamine, but not BisHOP. Implications for the clinical use of liposomes containing cationic lipids, is discussed.
1,2-Dipalmitoylphosphatidylcholine↗
Analysis of polyethylene glycol modified superoxide dismutase by chromatographic, electrophoretic, light scattering, chemical and enzymatic methods.
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Animals↗
Use of high-performance size-exclusion, ion-exchange, and hydrophobic interaction chromatography for the measurement of protein conformational change and stability.
Size-exclusion, ion-exchange, and hydrophobic interaction chromatographic techniques able to detect conformational changes induced by urea were developed for three globular proteins: bovine serum albumin, lysozyme, and trypsin. Alterations in tertiary structure were manifest chromatographically by highly reproducible changes in peak height, retention, and appearance of multiple peaks. Denaturation equilibria and kinetics obtained by classical physical methods, such as fluorescence intensity measurements for bovine serum albumin and enzyme activity for trypsin, could be correlated to particular changes in chromatographic behavior. The chromatographic methods utilized were selective toward specific structural changes and monitored independent denaturation steps via multiphasic kinetics. The correlation of chromatographic behavior to both independent measures of conformational changes and to assays which measure loss in biological activity, in the case of select proteins indicates that non-denaturing high-performance liquid chromatography can be a useful tool to detect and quantitate perturbations of protein three dimensional structure which result in a loss in biological activity.
Animals↗
Kinetic study of the dissolution of Fe4S4(2-)-cluster core ions of ferredoxins and high potential iron protein.
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Bacillus↗
Dependence of the rates of dissolution of the Fe4S4 clusters of Chromatium vinosum high-potential iron protein and ferredoxin on cluster oxidation state.
The influence of oxidation state on the pH dependence of the dissolution of the Fe(4)S(4) clusters of Chromatium vinosum ferredoxin and high-potential iron protein (HIPIP) has been studied. The first-order rate constants (k(obs)) for dissolution of both the Fe(4)S(4)(S-Cys)(4) (2-) and Fe(4)S(4)(S-Cys)(4) (3-) clusters of the ferredoxin follow the same overall kinetic equation but with differing specific rate and equilibrium constants. The dependence of rate and equilibrium constants upon oxidation state may be rationalized on the basis of the accompanying change in electrostatic affinity of a cluster toward H(+) and HO(-). A more drastic change in the pH dependence of the kinetics of dissolution of the Fe(4)S(4) cluster of the HIPIP accompanies its change in oxidation state. Whereas the values of k(obs) for dissolution of HIPIP containing the Fe(4)S(4)(S-Cys)(4) (2-) cluster are strictly second order to [H(+)] and [HO(-)], the pH dependence for dissolution of the HIPIP Fe(4)S(4)(S-Cys)(4) (1-) cluster indicates a first-order dependence upon [H(+)], a second-order dependence upon [HO(-)], and a spontaneous or water rate. These reactivity differences may be related to changes in cluster charge density. Mechanisms of dissolution involve preequilibrium protonation at acidic pH and preequilibrium ligand exchange at basic pH.
Chromatium↗
The acid-base properties and kinetics of dissolution of the Fe4S4 cores of Chromatin ferredoxin and high potential iron protein.
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Bacterial Proteins↗
The Acid-Base Properties, Hydrolytic Mechanism, and Susceptibility to O(2) Oxidation of Fe(4)S(4)(SR)(4) Clusters.
The iron-sulfur cluster compounds Fe(4)S(4)(SR)(4) (-2) [where -SR = -SCH(3), -S-C(CH(3))(3), and -S- CH(2)-CH(CH(3))(2)] have been found to represent the base species of weak acids of pK(a) comparable to that of carboxylic acids. The acid species Fe(4)S(4)(SR)(4)H(-) is most subject to reaction with O(2) and to acid-catalyzed solvolysis, while the base species Fe(4)S(4)(SR)(4) (-2) most readily undergoes ligand exchange. The kinetics for hydrolysis of the isobutyl mercaptide cluster salt has been investigated in detail and a mechanism involving the stepwise process [Formula: see text] has been proposed. The importance of the acid-base equilibria in determining the reactivity of the iron-sulfur clusters and its possible importance as a factor in the determination of the potentials of ferredoxins and high potential iron protein are discussed.
Journal Article↗