Novel hydrogels of poly(methacrylic acid) (PMAA) grafted with poly(ethylene glycol) (PEG) will be synthesized by free radical, UV-initiated, and thermally initiated polymerizations. These gels exhibit reversible, pH-dependent swelling behavior due to the formation or dissociation of interpolymer complexes between the acidic pendant groups and the ether groups of the grafted chains. Previous experimental studies in our laboratory have shown that these gels are promising carriers for oral delivery of protein drugs, including insulin. These delivery characteristics are due to large changes in the network mesh over a relatively narrow range of pH values due to the formation of the interpolymer complexes. Additionally, these gels can be used as carriers of drugs including oxprenolol, proxyphilline, diltiazem and bleomycin, drugs that present a range of ionization characteristics and solubility parameters, The formation of the interpolymer complexes serves to protect the drugs from binding with the polymeric carrier. The hypothesis of this proposal is that these PEG-grafted hydrogels can promote protein delivery due to protein protection by the poly(ethylene glycol) chains and due to the enzyme inhibition exhibited by the PMAA component of the structure, as recently shown by Lehr. An additional hypothesis is that these carriers exhibit prolonged adhesion on the intestinal mucosa. Therefore, the goals of this work include optimization of the PEG-grafted hydrogel structure, study of the diffusion of protein drugs in these complexation networks, and analysis of the interactions between the hydrogel carrier and the drugs to gain a fundamental understanding of the ability of the polymeric carriers to serve as protein delivery systems. Complexation mechanisms in the gels and interactions between polymers and proteins will be investigated using NMR spectroscopy. In vitro diffusion and release experiments of proteins and drugs will be conducted. The mucoadhesive behavior of these systems will be studied in order to analyze the anchoring of free poly(ethylene glycol) chains to the mucosa. The transcellular and paracellular mechanisms of protein transport will be investigated using monolayer Caco-2 cell lines. Finally, the insulin delivery efficacy of these novel devices will be tested using in vivo experiments.
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