Browsing by Subject "Colloids in medicine"
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Item Molecular design of advanced oral protein delivery systems using complexation hydrogels(2006) Wood, Kristy Marie; Peppas, Nicholas A., 1948-A novel class of pH sensitive complexation hydrogels composed of methacrylic acid and functionalized poly(ethylene glycol) tethers, referred to as P(MAA-g-EG) WGA, was investigated as an oral protein delivery system. The PEG tethers were functionalized with wheat germ agglutinin (WGA), a lectin that can bind to carbohydrates in the intestinal mucosa, to improve residence time of the carrier and absorption of the drug at the delivery site. P(MAA-g-EG) WGA created a specific mucoadhesive interaction between mucin and WGA in in vitro experiments. In addition, it improved the overall adhesion of the carrier by 17% to a cellular monolayer, as compared to P(MAA-g-EG). Administration of P(MAA-g-EG) WGA to a rat small intestine demonstrated that 99% of the microparticles still remained in the rat small intestine after 1 hour. These results confirmed that functionalizing P(MAA-g-EG) with WGA improved the mucoadhesive properties of the carrier. Insulin was effectively entrapped within the polymer network with a loading efficiency of 74%. Release studies with insulin-loaded P(MAA-g-EG) WGA showed that the carrier released less than 10% of the insulin at pH 3.2 after 60 minutes and 70% of the insulin at pH 7.0 after 60 minutes. These studies confirmed that P(MAA-g-EG) WGA can protect insulin in the low pH of the stomach and that the pH change between the stomach and the small intestine can be used as a physiologic trigger to quickly release insulin. The ability of P(MAA-g-EG) WGA to improve insulin absorption was investigated in two different intestinal epithelial models and an animal model. In the Caco-2 cells, P(MAA-g-EG) WGA improved insulin permeability by 9-fold as compared to an insulin only solution. P(MAA-g-EG) WGA was also evaluated in a mucussecreting culture that contained Caco-2 and HT29-MTX cells. Insulin permeability was increased by 5-fold in the presence of P(MAA-g-EG) WGA. The final study determined bioavailability of insulin-loaded P(MAA-g-EG) WGA when administered to a rat small intestine. Bioavailability of insulin was 11.9% for insulin-loaded P(MAA-g-EG) WGA, which is a vast improvement over the 0.5% bioavailability of an insulin only solution. Overall, it is clear that P(MAA-gEG) WGA holds great promise as an oral insulin delivery system.Item Novel pH-responsive microgels and nanogels as intelligent polymer therapeutics(2008-08) Fisher, Omar Zaire, 1979-; Peppas, Nicholas A., 1948-Disease processes that are currently among the leading causes of death now require much more than just a stethoscope for diagnosis and a pill for treatment. The next generation of therapeutics needs to possess a degree of intelligence; the ability to sense and respond to their environment. Biomedical hydrogels have the ability to sense and respond to external stimulus and with the advent of nanotechnology; these polymers can be fabricated on the same size scale as cellular and sub-cellular processes. Throughout the body gradients in pH are used at the cellular level to regulate processes such nutrient transport and to fight infection. Sites of damage or disease within the body are associated with both a change in pH and abnormal nanoporous vasculature. pH-Responsive microgels and nanogels are small enough to access these locations within the body, sense the change in environment, and locally release a therapeutic agent In this work heterogeneous, photoinitiated free radical polymerizations were developed to synthesize novel pH-responsive microgels and nanogels that could be loaded with macromolecular therapeutics and could respond to either a basic or acidic change in pH. A novel photo-dispersion polymerization scheme was developed to synthesize poly(ethylene glycol) grafted poly(methacrylic acid) (P(MAA-g-PEG)) polycomplexation gels for oral protein delivery. These ranged in size from 100- 300 nm in diameter and could swell up to a 17-fold increase in volume, in response to a rise in pH. This property allowed them to protect insulin at low pH and release the protein at neutral pH. In this way the carriers could be used to transport proteins through the stomach to the small intestine for absorption. A novel photo-emulsion polymerization scheme was developed to synthesize poly(ethylene glycol) grafted poly[2-(diethylamino)ethyl methacrylate] nanogels, between 70-150 nm in diameter. These could swell up to a 22-fold increase in volume, in response to a drop in pH. These nanostructures were able to successfully target clathrin-dependent endocytosis and deliver macromolecules to the cytosol.Item Synthesis & characterization of temperature- and pH- responsive nanostructures derived from block copolymers containing statistical copolymers of HEMA and DMAEMA(2008-05) Guice, Kyle B., 1982-; Loo, Yueh-Lin, 1974-; Sanchez, Isaac C.Hydrogels containing of 2-dimethylaminoethyl methacrylate, DMAEMA, exhibit changes in their swelling properties in response to both pH and temperature. Accordingly, these materials are useful for a variety of applications, such as tissue scaffolds, responsive lenses, separations and drug delivery. The response of DMAEMAcontaining hydrogels can be tuned by copolymerization with other monomers, such as 2-hydroxyethyl methacrylate, HEMA. We have developed methodologies for the controlled synthesis of poly(HEMAco-DMAEMA), PHD, statistical copolymers with uniform composition distributions, controlled molecular weights, and narrow molecular weight distributions using controlled free-radical polymerization techniques, such as atom transfer radical polymerization and radical addition-fragmentation chain transfer polymerization. We have also investigated the controlled synthesis and characterization of amphiphilic block copolymers containing PHD statistical copolymers. These block copolymers microphase separate to form periodic nanostructures such as alternating lamellae, cylinders on a hexagonal lattice, or spheres on a body-centered cubic lattice, depending on the volume fraction of each block, the interblock segregation strength, and the choice of casting solvent. When swollen with water, these microphase-separated PHD-containing block copolymers form model hydrogels with uniform composition distributions. Model block copolymer hydrogels containing PHD statistical copolymers are responsive to changes in pH or temperature. The response of these model block copolymer hydrogels can be tuned by adjusting of the DMAEMA content within the PHD block. Moreover, the response can be tuned by changing the hydrophobic block. Specifically, the use of a glassy hydrophobic block, such as polystyrene or poly(tert-butyl acrylate) at temperatures below its glass transition temperature, resulted in the preservation of the original block copolymer morphology during swelling. In contrast, the use of a hydrophobic block that is rubbery during swelling, such as poly(methyl acrylate), enabled reversible morphological transformations.