Antibiotic-conjugated polyacrylate nanoparticles: New opportunities for development of anti-MRSA agents
Bioorganic & Medicinal Chemistry Letters 17 (2007) 53–56
ABSTRACT: This report describes the preparation of polyacrylate nanoparticles in which an N-thiolated b-lactam antibiotic is covalently conjugated onto the polymer framework. These nanoparticles are formed in water by emulsion polymerization of an acrylated antibiotic pre-dissolved in a liquid acrylate monomer (or mixture of co-monomers) in the presence of sodium dodecyl sulfate as a surfactant and potassium persulfate as a radical initiator. Dynamic light scattering analysis and electron microscopy images of these emulsions show that the nanoparticles are approximately 40 nm in diameter. The emulsions have potent in vitro antibacterial properties against methicillin-resistant Staphylococcus aureus and have improved bioactivity relative to the non-polymerized form of the antibiotic. A unique feature of this methodology is the ability to incorporate water-insoluble drugs directly into the nanoparticle framework without the need for post-synthetic modification. Additionally, the antibiotic properties of the nanoparticles can be modulated by changing the length or location of the acrylate linker on the drug monomer. 2006 Elsevier Ltd. All rights reserved. Read More
ABSTRACT: This report describes the preparation of polyacrylate nanoparticles in which an N-thiolated b-lactam antibiotic is covalently conjugated onto the polymer framework. These nanoparticles are formed in water by emulsion polymerization of an acrylated antibiotic pre-dissolved in a liquid acrylate monomer (or mixture of co-monomers) in the presence of sodium dodecyl sulfate as a surfactant and potassium persulfate as a radical initiator. Dynamic light scattering analysis and electron microscopy images of these emulsions show that the nanoparticles are approximately 40 nm in diameter. The emulsions have potent in vitro antibacterial properties against methicillin-resistant Staphylococcus aureus and have improved bioactivity relative to the non-polymerized form of the antibiotic. A unique feature of this methodology is the ability to incorporate water-insoluble drugs directly into the nanoparticle framework without the need for post-synthetic modification. Additionally, the antibiotic properties of the nanoparticles can be modulated by changing the length or location of the acrylate linker on the drug monomer. 2006 Elsevier Ltd. All rights reserved. Read More
Glycosylated polyacrylate nanoparticles by emulsion polymerization
Carbohydrate Polymers 70 (2007) 32–37
ABSTRACT: A selection of glycosylated polyacrylate nanoparticles has been prepared by radical-initiated emulsion polymerization in aqueous media. Using ethyl acrylate as a co-monomer, carbohydrate acrylates were incorporated into the poly(ethyl acrylate) framework to give stable emulsions of glyconanoparticles with an average particle size of around 40 nm. Using this technique a variety of glyconanoparticles were prepared from 3-O-acryloyl-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose, 1-O-acryloyl-2,3:5,6-di-O-isopropylidene-a-Dmannofuranose, 6-O-acryloyl-1,2:3,4-di-O-isopropylidene-a-D-galactopyranose, 2-N-acryloyl-1,3,4,6-tetra-O-acetyl-b-D-glucosamine, 5-O-acryloyl-2,3-isopropylidene-1-methoxy-b-D-ribofuranose and 4-N-acetyl-50-O-acryloyl-20,30-O-isopropylidene cytidine. Scanning electron microscopy, dynamic light scattering and proton NMR analysis of the emulsions indicated essentially 100% incorporation of the carbohydrate acrylate monomer into the polymer with the exception of O-benzyl- and O-benzoyl-protected carbohydrate acrylates, which gave incomplete incorporation. Formation of larger glyconanoparticles of 80 nm with (unprotected) 3-O-acryloyl-D-glucose and 5-O-acryloyl-1-methoxy-b-D-ribofuranose revealed the influence of free hydroxyl groups in the monomer on the particle size during polymerization, a feature which is also apparently dependent on the amount of carbohydrate in the matrix. This methodology allows for a new, simple route to the synthesis of polymeric glyconanoparticles with potential applications in targeted drug delivery and materials development. 2007 Elsevier Ltd. All rights reserved. Read More
ABSTRACT: A selection of glycosylated polyacrylate nanoparticles has been prepared by radical-initiated emulsion polymerization in aqueous media. Using ethyl acrylate as a co-monomer, carbohydrate acrylates were incorporated into the poly(ethyl acrylate) framework to give stable emulsions of glyconanoparticles with an average particle size of around 40 nm. Using this technique a variety of glyconanoparticles were prepared from 3-O-acryloyl-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose, 1-O-acryloyl-2,3:5,6-di-O-isopropylidene-a-Dmannofuranose, 6-O-acryloyl-1,2:3,4-di-O-isopropylidene-a-D-galactopyranose, 2-N-acryloyl-1,3,4,6-tetra-O-acetyl-b-D-glucosamine, 5-O-acryloyl-2,3-isopropylidene-1-methoxy-b-D-ribofuranose and 4-N-acetyl-50-O-acryloyl-20,30-O-isopropylidene cytidine. Scanning electron microscopy, dynamic light scattering and proton NMR analysis of the emulsions indicated essentially 100% incorporation of the carbohydrate acrylate monomer into the polymer with the exception of O-benzyl- and O-benzoyl-protected carbohydrate acrylates, which gave incomplete incorporation. Formation of larger glyconanoparticles of 80 nm with (unprotected) 3-O-acryloyl-D-glucose and 5-O-acryloyl-1-methoxy-b-D-ribofuranose revealed the influence of free hydroxyl groups in the monomer on the particle size during polymerization, a feature which is also apparently dependent on the amount of carbohydrate in the matrix. This methodology allows for a new, simple route to the synthesis of polymeric glyconanoparticles with potential applications in targeted drug delivery and materials development. 2007 Elsevier Ltd. All rights reserved. Read More
Glyconanobiotics: Novel carbohydrated nanoparticle antibiotics for MRSA and Bacillus anthracis
Bioorganic & Medicinal Chemistry 16 (2008) 2412–2418
ABSTRACT: This report describes the synthesis and evaluation of glycosylated polyacrylate nanoparticles that have covalently-bound antibiotics within their framework. The requisite glycosylated drug monomers were prepared from one of three known antibiotics, an N-sec-butylthio b-lactam, ciprofloxacin, and a penicillin, by acylation with 3-O-acryloyl-1,2-O-isopropylidene-5,6 bis((chlorosuccinyl)oxy)-D-glucofuranose (7) or 6-O-acetyl-3-O-acryloyl-1,2-O-isopropylidene-5-(chlorosuccinyl)oxy-a-D-glucofuranose (10). These acrylated monomers were subjected to emulsion polymerization in a 7:3 (w:w) mixture of butyl acrylate–styrene in the presence of sodium dodecyl sulfate as surfactant (3 weight %) and potassium persulfate as a radical initiator (1 weight %). The resulting nanoparticle emulsions were characterized by dynamic light scattering and found to have similar diameters (40 nm) and size distributions to those of our previously studied systems. Microbiological testing showed that the N-sec-butylthio b-lactam and ciprofloxacin nanoparticles both have powerful in vitro activities against methicillin-resistant Staphylococcus aureus and Bacillus anthracis, while the penicillin-bound nanoparticles have no antimicrobial activity. This indicates the need for matching a suitable antibiotic with the nanoparticle carrier. Overall, the study shows that even relatively large, polar acrylate monomers (MW > 1000 amu) can be efficiently incorporated into the nanoparticle matrix by emulsion polymerization, providing opportunities
for further advances in nanomedicine. 2007 Elsevier Ltd. All rights reserved. Read More
ABSTRACT: This report describes the synthesis and evaluation of glycosylated polyacrylate nanoparticles that have covalently-bound antibiotics within their framework. The requisite glycosylated drug monomers were prepared from one of three known antibiotics, an N-sec-butylthio b-lactam, ciprofloxacin, and a penicillin, by acylation with 3-O-acryloyl-1,2-O-isopropylidene-5,6 bis((chlorosuccinyl)oxy)-D-glucofuranose (7) or 6-O-acetyl-3-O-acryloyl-1,2-O-isopropylidene-5-(chlorosuccinyl)oxy-a-D-glucofuranose (10). These acrylated monomers were subjected to emulsion polymerization in a 7:3 (w:w) mixture of butyl acrylate–styrene in the presence of sodium dodecyl sulfate as surfactant (3 weight %) and potassium persulfate as a radical initiator (1 weight %). The resulting nanoparticle emulsions were characterized by dynamic light scattering and found to have similar diameters (40 nm) and size distributions to those of our previously studied systems. Microbiological testing showed that the N-sec-butylthio b-lactam and ciprofloxacin nanoparticles both have powerful in vitro activities against methicillin-resistant Staphylococcus aureus and Bacillus anthracis, while the penicillin-bound nanoparticles have no antimicrobial activity. This indicates the need for matching a suitable antibiotic with the nanoparticle carrier. Overall, the study shows that even relatively large, polar acrylate monomers (MW > 1000 amu) can be efficiently incorporated into the nanoparticle matrix by emulsion polymerization, providing opportunities
for further advances in nanomedicine. 2007 Elsevier Ltd. All rights reserved. Read More
Methods for purifying and detoxifying sodium dodecyl sulfate–stabilized polyacrylate nanoparticles
Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) 98–105
ABSTRACT: Recent research in our laboratory has centered on studies of polyacrylate and polyacrylamide nanoparticle emulsions for use in antibiotic delivery. Our goal is to develop these nanoparticle emulsions for treatment of life-threatening bacterial infections such as those caused by methicillinresistant Staphylococcus aureus. For this intended application it is necessary to ensure that the biological activity of the emulsion is due only to the drug attached to the polymeric chain and not to any extraneous components. To investigate this we evaluated cytotoxicity and microbiological activity of the nanoparticle emulsions before and after purification by centrifugation, dialysis, and gel filtration. Depending on the amount of surfactant used, all or most of the microbial and cellular toxicity can be removed by a simple purification procedure. © 2008 Elsevier Inc. All rights reserved. Read More
ABSTRACT: Recent research in our laboratory has centered on studies of polyacrylate and polyacrylamide nanoparticle emulsions for use in antibiotic delivery. Our goal is to develop these nanoparticle emulsions for treatment of life-threatening bacterial infections such as those caused by methicillinresistant Staphylococcus aureus. For this intended application it is necessary to ensure that the biological activity of the emulsion is due only to the drug attached to the polymeric chain and not to any extraneous components. To investigate this we evaluated cytotoxicity and microbiological activity of the nanoparticle emulsions before and after purification by centrifugation, dialysis, and gel filtration. Depending on the amount of surfactant used, all or most of the microbial and cellular toxicity can be removed by a simple purification procedure. © 2008 Elsevier Inc. All rights reserved. Read More
Antibiotic-conjugated polyacrylate nanoparticles: New opportunities for development of anti-MRSA agents
Bioorganic & Medicinal Chemistry Letters 17 (2007) 53–56
ABSTRACT: This report describes the preparation of polyacrylate nanoparticles in which an N-thiolated b-lactam antibiotic is covalently conjugated onto the polymer framework. These nanoparticles are formed in water by emulsion polymerization of an acrylated antibiotic pre-dissolved in a liquid acrylate monomer (or mixture of co-monomers) in the presence of sodium dodecyl sulfate as a surfactant and potassium persulfate as a radical initiator. Dynamic light scattering analysis and electron microscopy images of these emulsions show that the nanoparticles are approximately 40 nm in diameter. The emulsions have potent in vitro antibacterial properties against methicillin-resistant Staphylococcus aureus and have improved bioactivity relative to the non-polymerized form of the antibiotic. A unique feature of this methodology is the ability to incorporate water-insoluble drugs directly into the nanoparticle framework without the need for post-synthetic modification. Additionally, the antibiotic properties of the nanoparticles can be modulated by changing the length or location of the acrylate linker on the drug monomer. 2006 Elsevier Ltd. All rights reserved. Read More
ABSTRACT: This report describes the preparation of polyacrylate nanoparticles in which an N-thiolated b-lactam antibiotic is covalently conjugated onto the polymer framework. These nanoparticles are formed in water by emulsion polymerization of an acrylated antibiotic pre-dissolved in a liquid acrylate monomer (or mixture of co-monomers) in the presence of sodium dodecyl sulfate as a surfactant and potassium persulfate as a radical initiator. Dynamic light scattering analysis and electron microscopy images of these emulsions show that the nanoparticles are approximately 40 nm in diameter. The emulsions have potent in vitro antibacterial properties against methicillin-resistant Staphylococcus aureus and have improved bioactivity relative to the non-polymerized form of the antibiotic. A unique feature of this methodology is the ability to incorporate water-insoluble drugs directly into the nanoparticle framework without the need for post-synthetic modification. Additionally, the antibiotic properties of the nanoparticles can be modulated by changing the length or location of the acrylate linker on the drug monomer. 2006 Elsevier Ltd. All rights reserved. Read More
Penicillin-bound polyacrylate nanoparticles: Restoring the activity of b-lactam antibiotics against MRSA
Bioorganic & Medicinal Chemistry Letters 17 (2007) 3468–3472
ABSTRACT: This report describes the preparation of antibacterially active emulsified polyacrylate nanoparticles in which a penicillin antibiotic is covalently conjugated onto the polymeric framework. These nanoparticles were prepared in water by emulsion polymerization of an acrylated penicillin analogue pre-dissolved in a 7:3 (w:w) mixture of butyl acrylate and styrene in the presence of sodium dodecyl sulfate (surfactant) and potassium persulfate (radical initiator). Dynamic light scattering analysis and atomic force microscopy images show that the emulsions contain nanoparticles of approximately 40 nm in diameter. The nanoparticles have equipotent in vitro antibacterial properties against methicillin-susceptible and methicillin-resistant forms of Staphylococcus aureus and indefinite stability toward b-lactamase. 2007 Elsevier Ltd. All rights reserved. Read More
ABSTRACT: This report describes the preparation of antibacterially active emulsified polyacrylate nanoparticles in which a penicillin antibiotic is covalently conjugated onto the polymeric framework. These nanoparticles were prepared in water by emulsion polymerization of an acrylated penicillin analogue pre-dissolved in a 7:3 (w:w) mixture of butyl acrylate and styrene in the presence of sodium dodecyl sulfate (surfactant) and potassium persulfate (radical initiator). Dynamic light scattering analysis and atomic force microscopy images show that the emulsions contain nanoparticles of approximately 40 nm in diameter. The nanoparticles have equipotent in vitro antibacterial properties against methicillin-susceptible and methicillin-resistant forms of Staphylococcus aureus and indefinite stability toward b-lactamase. 2007 Elsevier Ltd. All rights reserved. Read More