Biomedical subjects

Alexander M Klibanov

Publications and source records attributed to Alexander M Klibanov.

30 records · Page 2Linked to original sources

PubMed2003

Mechanism of bactericidal and fungicidal activities of textiles covalently modified with alkylated polyethylenimine.

Our previous studies have led to a novel "nonrelease" approach to making materials bactericidal by covalently attaching certain moderately hydrophobic polycations to their surfaces. In the present work, this strategy is extended beyond the heretofore-used nonporous materials to include common woven textiles (cotton, wool, nylon, and polyester). Pieces of such cloths derivatized with N-hexylated+methylated high-molecular-weight polyethylenimine (PEI) are strongly bactericidal against several airborne Gram-positive and Gram-negative bacteria. In contrast, the immobilized and N-alkylated PEIs of low molecular weight have only a weak, if any, bactericidal activity. These findings support a mechanism of the antibacterial action whereby high-molecular-weight and hydrophobic polycationic chains penetrate bacterial cell membranes/walls and fatally damage them. The bactericidal textiles prepared herein are lethal not only to pathogenic bacteria but to fungi as well.

Alkylation↗

PubMed2003

Controling the rate of protein release from polyelectrolyte complexes.

Extended protein release from readily prepared, water-insoluble complexes with oppositely charged polyions is explored. Using hen egg-white lysozyme as a model, its sustained release from such complexes with a number of polyanions under physiological conditions has been demonstrated and rationalized. The rate of release varies orders of magnitude and is controlled by the nature of the polyanion (decreasing upon increase in its linear charge density, length, and hydrophobicity) and the complex particle size (the larger the particles, the slower the release).

Alginates↗

PubMed2003

A potential approach for decreasing the burst effect of protein from PLGA microspheres.

A central issue in controlled delivery of therapeutics from biodegradable microspheres is the immediate burst of drug release upon injection. This burst is often observed with microsphere systems made by the double emulsion (w/o/w) technique, and may be prevented by improving the drug distribution throughout the polymer matrix. To this end, protein and polymer (poly-lactide-co-glycolide or PLGA) were dissolved within the same solvent system, and micron-sized microspheres were created from this solution by spontaneous emulsification. Improved protein loading was achieved by ion-pairing the protein with charged surfactants to increase solubility in the single-phase solvent system. Both in vitro and in vivo results showed a much diminished burst: compared to microspheres made by double emulsion, it was reduced over 10-fold.

Animals↗

PubMed2003

Asymmetric enzymatic oxidoreductions in organic solvents.

It is now beyond doubt that enzymes can vigorously work even in neat organic solvents containing little or no water. Switching the enzymatic reaction medium from aqueous to nonaqueous can make previously problematic processes feasible through, for example, increased substrate solubility or diminished side reactions. Moreover, when placed in this highly unnatural milieu, enzymes exhibit new and potentially valuable properties, including greater stability, markedly altered selectivity that can be readily controlled by the solvent, and molecular memory. Consequently, novel synthetic and biotechnological opportunities ensue, as illustrated herein by those based on enzymatic oxidoreductions such as the asymmetric peroxidase-catalyzed sulfoxidation of organic sulfides.

Alcohol Dehydrogenase↗

PubMed2003

Making thin polymeric materials, including fabrics, microbicidal and also water-repellent.

A procedure is developed and validated for making a non-functionalized polyolefin fabric/film highly bactericidal and fungicidal which involves a free-radical grafting of maleic anhydride, followed by an attachment of polyethylenimine (PEI) and its subsequent N-alkylation. Separately, cotton fabric coated with a micron layer of a hydrophobic polymer using hot-filament chemical vapor deposition is rendered markedly hydrophobic; if this coating is preceded by immobilization of N-alkyl-PEI, the fabric becomes both water-repellent and bactericidal.

Bacteria↗

PubMed2003

Asymmetric thiosulfinations catalyzed by bovine serum albumin and horseradish peroxidase.

Bovine serum albumin (BSA) and horseradish peroxidase (HRP) catalyzed the monooxidation of organic disulfides with peroxides to optically active thiosulfinates. With BSA, a hydrophobic disulfide was oxidized in a stereoselective manner, and the nature of the oxidant (H2O2 or tert-butyl hydroperoxide) controlled the absolute configuration of the product. The rates of HRP-catalyzed thiosulfination in methanol were several times faster than in water but the enzyme was less stereoselective.

Animals↗

PubMed2002

Enhancing polyethylenimine's delivery of plasmid DNA into mammalian cells.

The effect of various chemical modifications of nitrogen atoms on the efficiency of polyethylenimines (PEIs) as synthetic vectors for the delivery of plasmid DNA into monkey kidney cells in vitro has been systematically investigated. The resultant structure-activity relationship has both provided mechanistic insights and led to PEI derivatives with markedly enhanced performance. For example, N-acylation of PEI with the molecular mass of 25 kDa (PEI25, one of the most potent polycationic gene delivery vectors) with alanine nearly doubles its transfection efficiency in the presence of serum and also lowers its toxicity. Furthermore, dodecylation of primary amino groups of 2-kDa PEI yields a nontoxic polycation whose transfection efficiency in the presence of serum is 400 times higher than the parent's and which exceeds 5-fold even that of PEI25.

Animals↗

PubMed2002

Polymer surfaces derivatized with poly(vinyl-N-hexylpyridinium) kill airborne and waterborne bacteria.

A facile methodology has been developed for covalently derivatizing the surfaces of common materials with a designed antibacterial polycation, poly(vinyl-N-pyridinium bromide), wherein the first, key step involves surface coating with a nanolayer of silica. Various commercial synthetic polymers derivatized in this manner become bactericidal-they kill up to 99% of deposited, from either an aerosol or an aqueous suspension, Gram-positive and Gram-negative bacteria on contact.

Air Microbiology↗

PubMed2002

Asymmetric sulfoxidations mediated by alpha-chymotrypsin.

The oxidation of aryl alkyl sulfides with H(2)O(2) in aqueous solution is a reasonably facile reaction producing racemic sulfoxides. We show that in the presence of the hydrolytic enzyme alpha-chymotrypsin such a sulfoxidation is accelerated and, more importantly, becomes stereoselective. With phenyl isobutyl sulfide as a model, the chymotrypsin-mediated, highly asymmetric oxidation is shown to occur in the hydrophobic binding pocket of the enzyme active site. The stereoselectivity of the chymotrypsin-mediated sulfoxidations is correctly explained by means of structure-based molecular modeling of the enzyme-sulfide complexes.

Animals↗

PubMed2002

Binding of hydrophobic hydroxamic acids enhances peroxidase's stereoselectivity in nonaqueous sulfoxidations.

Horseradish peroxidase exhibits a meager stereoselectivity (E) in the sulfoxidation of thioanisole (1a) in 99.8% (v/v) methanol. The E value, however, is greatly enhanced when the enzyme forms a complex with benzohydroxamic acid (2a). These findings are rationalized by means of molecular dynamics simulations and energy minimization which correctly explain (i) why the free enzyme is not stereoselective, (ii) why 2a inhibits peroxidase-catalyzed sulfoxidation of 1a but the enzymatic formation of one enantiomer of the sulfoxide product is inhibited much more than that of the other, thereby raising peroxidase's E, and (iii) why in the presence of 2a the enzyme favors production of the S sulfoxide of 1a. The generality of the observed ligand-induced stereoselectivity enhancement is demonstrated with other hydrophobic hydroxamic acids, as well as with additional thioether substrates.

Binding Sites↗

PubMedDate not supplied

Bactericidal properties of flat surfaces and nanoparticles derivatized with alkylated polyethylenimines.

We previously discovered that covalently coating glass and plastic slides with certain long poly(vinyl-N-alkylpyridinium) chains enables the resultant surfaces to kill a variety of airborne and waterborne bacteria on contact. In the present study, these findings have been extended to an unrelated polymer class, polyethylenimines (PEIs). Alkylated PEIs attached to flat macroscopic surfaces and to those of nanoparticles make these materials highly bactericidal toward both Gram-positive and Gram-negative pathogenic bacteria. Systematic chemical modifications of the immobilized PEI conducted herein shed light on the relationship between the structure of the polymer and the antibacterial efficiency of the resultant coating.

Coated Materials, Biocompatible↗

PubMedDate not supplied

One-step, painting-like coating procedures to make surfaces highly and permanently bactericidal.

Previously we found that covalent attachment of long-chained, moderately hydrophobic polycations to surfaces of solid objects renders the latter permanently bactericidal. Herein we replaced such surface-specific, multistep immobilization techniques with a single-step, general procedure akin to common painting. Glass or polyethylene slides were briefly dipped into organic solutions of certain optimally hydrophobic N-alkyl-PEI (where PEI stands for branched 750-kDa polyethylenimine) polycations, followed by solvent evaporation. The resultant polycation-coated slides were able to kill on contact all of the encountered bacterial cells, whether the Gram-positive human pathogen Staphylococcus aureus or its Gram-negative brethren Escherichia coli. This biocidal effect was found not to be caused by N-alkyl-PEI molecules leached from the surface. Further examination of the mechanism of this bactericidal action suggested that the surface-deposited N-alkyl-PEI kills bacteria by rupturing their cellular membranes. This conclusion was further supported by studies in which the molecular weight of PEI and the hydrophobicity of the alkyl moiety were varied.

Escherichia coli↗