Mucus epithelia in the intestine, lung, mouth, eye, and vagina provide an effective and essential barrier against the entry of pathogens and toxins. Since these epithelia are readily accessible from outside the body, they also represent valuable sites for drug delivery. Here, we propose to continue our bioengineering studies of the ability of molecules and cells to function in and penetrate the mucus layer that protects these tissues. In previous work, we demonstrated that the controlled delivery of antibodies (Ab) could provide passive immune protection and that the controlled delivery of Vaccinogens (Vg) could provide active immune protection at the mucosal surface. DNA-based Vg proved to be particularly effective at stimulating mucosal immunity when used with our delivery systems. Therefore, our present goal is to evaluate the relationship between local DNA release, diffusional DNA transport, cellular DNA expression, and immune stimulation at mucosal sites. Specifically, biocompatible polymeric controlled release devices will be designed to continuously deliver macromolecules to mucus layers over an extended period. The present studies will focus on 1) improving the performance of controlled delivery systems by ligand-targeting in the intestine and controlled release of nanoparticulates in the vagina and 2) probing the relationship between movement of macromolecules, movement of cells, and stimulation of the immune system. Because these delivery systems provide reliable and controlled application of complex molecules to the mucosal surface, they will permit us to study quantitatively the relationship between delivery of molecular Vg and development of an immune response. Mathematical methods will be used to correlate our results, and to enhance the value of in vitro methods for optimizing devices for use in vivo. All of the information collected from these basic studies will be used to design improved controlled release polymers for the localized and sustained delivery of Vg, particularly DNA-based Vg, to the mucus secretions of mice and monkeys. Our work will focus on the application of this technology in the production of safe, reliable, and effective immunocontraceptives.
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