Controlled release combination therapy, in a local delivery environment, could potentially provide greater efficacy and less toxicity than single drug therapy. The judicious selection of combination protocols, based on a solid understanding of each drug's specific mechanism(s) of action, co-durg interactions, and release would assist in identifying potentially synergistic regimens. We will use polymer and copolymer systems based on rational assessment of drug-polymer, durg-drug, and paired-associated interactions to optimize the co-release of selected drugs. The polyanhydrides, polyphosphoesters, as well as copolymers and blends of these polymers, have been extensively studied and used as biodegradable matrices in the release of bioactive agents. With the possibility of drug-polymer interactions, the use of different polymers allows the freedom to apply different polymer structures for design and formulation leeway. We will initially focus on polyanhydrides, as discussed below, but if there is a problem for any reason, having other polymers available will be helpful. The goal of a second set of studies will be to obtain protein stabilizing formulations and controlled long-term delivery of immune-responsive agents (i.e., cytokines and radiolabeled antibodies) for therapeutic intervention. Protein delivery has been problematic due to adverse processes that effect the protein's activity during formulation and storage. Mechanisms of protein inactivation range from deamination and hydrolysis to oxidation and aggregation. We plan to examine the mechanisms involved in the inactivation and use this understanding to formulate protein-stabilizing release systems. The aspects of this work will be: 1) to elucidate the conformational and chemical changes that occur during the microencapsulation process; 2) to determine causes to activity loss; 3) to formulate appropriate release systems and 4) to quantitate release and monitor bioactivity upon release from the device. We plan to investigate a series of cytokines (IL-2, IL-6, IL-12), and if time permits squalamine, radiolabeled antibodies, and combinations thereof as they are encapsulated and released from biodegradable polymer systems.
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