This is a competing renewal proposal in the area of the development of controlled release systems for immunocontraception. There are several reasons why this is a very important area. First, for active immunization with sperm antigens, the ability to release the antigens for long periods of time will enhance it's immunogenicity. Second, for passive immunization with monoclonal antibodies against sperm or zona pellucida protein, the ability to provide long-term release of an active antibody would be very desirable. In the past grant period, we proposed the synthesis of a class of novel degradable polymers involving L-tyrosine peptide derivatives. The major objective was to design devices that would provide controlled release of the antigen for prolonged periods of time. In addition, one of the desirable features of these polymers would be that the products formed from polymer hydrolysis could have an adjuvant effect on the immune response and thereby enhance the level or duration of antibody production. In the last grant period, we successfully synthesized polymers composed of, or containing, a variety of tyrosine and tyrosine dipeptide monomers and fully characterized them with respect to a variety of properties relevant to antigen delivery. We developed micron-sized antigen-loaded spheres (i.e., microspheres) from these polymers and developed approaches to provide prolonged release of model proteins from these systems. A number of papers in very good journals have resulted from these studies.
The specific aims of the current proposal are to further develop this area by utilizing specific antigens (such as PH-20, a peptide from the active site of a fertilin beta, and a recombinant fertilin beta extracellular domain) now available from our collaborators, and to expand potential methods of achieving controlled release immunocontraception, including new routes of administration and approaches for achieving pulsatile release.
The specific aims are as follows: 1) To incorporate antigens from the other Centers into polymer microspheres based on tyrosine derivatives. 2) To pursue the idea of vaccine delivery by using a new approach involving FDA approved lactic/glycolic acid polymers which can provide pulses of vaccine. In addition, we will pursue a novel idea of stabilizing proteins in these polymers systems using an oil-based microencapsulation. 3) To develop delivery systems for mucosal immunization, in particular systems which can be administered by the pulmonary route.
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