This is a grant renewal for the continuation of studies on controlled release systems for large molecular weight (MW is greater than 1000) drugs. The studies proposed have relevance for controlled release of small molecules as well. The grant first started in 1979. In the past grant period, we have 1) developed new models and Monte-Carlo techniques for analyzing protein transport and have used these approaches to design systems capable of releasing insulin for over 100 days, as well as release systems for other molecules, 2) developed new synthesis procedures for polyanhydrides that have yielded the first high molecular weight (M.W.is greater than 40,000) polyanhydrides; synthesized polymers, which can , by the choice of copolymer, degrade in tome periods ranging from 1 week to 3 years; developed microencapsulation approaches for polyanhydrides; conducted toxicology studies on these polymers; and initiated the development of (and created new techniques to analyze for) several new classes of biopolymers for drug delivery including pseudopolyaminoacids, polyiminocarbonates, and polyphosphazenes, 3) quantitated parameters such as magnetic field strength, magnet orientation, field frequency, and polymer composition which regulated a magnetically controlled release system and tested this system in vivo, initiated the development of ultrasonically controlled polymeric delivery systems and examined the effect of ultrasound on transdermal drug delivery; and developed an intelligent controlled release system using enzymes to regulated protein solubility and release rates. We now propose to conduct research in new areas that have grown out of work supported by this grant; 1) fundamental studies of protein inactivation in polymers under physiological conditions and developing rational strategies for stabilizing proteins inside polymers. This will involve a systematic study examining the effects of wetting, selected additives, and physicochemical characteristics of model proteins. Strategies to be examined for stabilizing proteins will involve additives, polymer microenvironment, chemical modification, and site directed mutagenesis, 2) synthesizing and examining a new class of polymers that we have proposed-pseudopolyaminoacids for biological applications. Model pseudopolyaminoacids, based both on hydroxyproline esters and phenylalanine-glutamine amide anhydrides, will be synthesized and characterized.
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