Graduation Year

2007

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Chemistry

Major Professor

Edward Turos, Ph.D.

Committee Member

Julie P. Harmon, PhD.

Committee Member

Kirpal S. Bisht, PhD.

Committee Member

Roman Manetsch, PhD.

Keywords

Emulsion polymerization, Glyconanoparticle, Drug delivery, Antibiotic, Glycotargeting

Abstract

Carbohydrates on the cell surface conjugates to proteins and lipids and participates in biological processes as glycoconjugates. Carbohydrate functionalized nanoparticles (glyconanoparticles) constitute a good bio-mimetic model of carbohydrate presentation at the cell surface and are currently centered on many glycobiological and biomedical applications. The most of the applications have been reported using gold glyconanoparticles. A brief review of gold glyconanoparticles and some of their applications will be discussed in Chapter I. Although metallic, semiconductor and magnetic glyconanoparticles have been reported, no polyacrylate glyconanoparticles have yet to be described.

Chapter II describes the first preparation of carbohydrate functionalized polymer nanoparticles by microemulsion polymerization and their characterization using scanning electron microscopy, dynamic light scattering and 1H NMR spectroscopy. This methodology can generate a large number of furanose and pyranose nanoparticle derivatives with an average particle size of around 40 nm with the protected carbohydrate hydroxyl functionality as acetyl or dimethylacetal groups. Formation of larger glyconanoparticles of around 80 nm with 3-O-acryloyl-D-glucose and 5-O-acryloyl-1-methoxy-beta-D-ribofuranose reveals 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.

Preparation of glyconanoparticle antibiotics, or glyconanobiotics, by microemulsion of antibiotic-conjugated carbohydrate monomers demonstrates for the first time the use of glyconanoparticles as drug delivery vehicles in Chapter III. The conjugation of an acrylated hydrophobic carbohydrate moiety to the lipophilic antibiotic makes it even more lipophilic and suitable as a co-monomer in microemulsion polymerization with styrene/butyl acrylate. Novel carbohydrate-based acrylated acyl chlorides synthesized from glucose afford antibiotic monomers with enhanced lipophilicity in a one step procedure. These drug monomers and the corresponding glyconanobiotics prepared by conjugating antibiotics such as N-thiolated-beta-lactam, ciprofloxacin, and penicillin shows biological activity against S. aureus, MRSA and B. anthracis microbes.

Glyconanoparticles prepared by microemulsion polymerization of 3-O-acryloyl-D-glucose and styrene/butyl acrylate may be potentially used as recognition units in carbohydrate ligand mediated targeted drug delivery. The binding capability of the surface-exposed carbohydrates on the nanoparticle can be detected by fluorescence spectroscopy utilizing pyranine and 4,4'-N,N-bis(benzyl-2-boronic acid)-bipyridinium dibromide as described in Chapter IV.

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