CONTROLLED RELEASE OF MACROMOLECULES

描述(改编自研究人员摘要)：这是一笔赠款 高分子控释研究的最新进展 重量(MW&GT；1,000道尔顿)药物，如多肽。的起源。 这项工作可以追溯到1979年，涉及到对物理学和 通过化学方法实现大分子的控制释放。在.期间 最近的授权期(1989-91年)，研究人员综合和 研究了一类新的聚合物--非酰胺连接的多氨基酸 键，并开启了蛋白质失活的基础研究 与治疗相关的条件。涉及的蛋白质失活工作 三种模型蛋白质，胰岛素(分子量6,000)、核糖核酸酶(分子量14,000)和血红蛋白 (兆瓦68,000)，并检查了湿润引起的聚集问题， 添加剂对润湿时蛋白质不溶解程度的影响 并评价了润湿过程中蛋白质的物理化学变化。这个 本提案旨在研究：1)治疗蛋白在体内的稳定性 固体；2)治疗性蛋白质在溶液中的稳定性。 了解这些细胞中蛋白质失活的基本机制 有两个条件是制造和使用受控的 蛋白质药物的释放系统。这些机械研究将得到帮助 通过数学建模，特别是蛋白质折叠和展开以及 将提供关于稳定/不稳定的驱动力的洞察 这些特工。具体地说，该工作将检查：1)在 蛋白质溶液；2)固态稳定性。

DESCRIPTION (adapted from investigator's abstract): This is a grant renewal application for the study of controlled release of high molecular weight (MW > 1,000 Daltons) drugs such as polypeptides. The genesis of this work dates to 1979 and involves a systematic study of physical and chemical methods to achieve controlled release of large molecules. During the most recent grant period (1989-91) the investigators synthesized and examined a new class of polymers-poly amino acids linked by non-amide bonds, and initiated fundamental studies of protein inactivation under therapeutically relevant conditions.The protein inactivation work involved three model proteins, insulin (MW 6,000), RNAase (MW 14,000) and hemoglobin (MW 68,000) and examined the issues of aggregation due to wetting, the effect of additives on the extent of protein insolubilization upon wetting, and evaluated the physico-chemical changes in proteins upon wetting. The present proposal intends to study:1) stability of therapeutic proteins in the solid state; and 2) stability of therapeutic proteins in solution. Understanding the fundamental mechanism of how proteins inactivate in these two conditions is fundamental to the fabrication and use of controlled release systems for protein drugs. These mechanistic studies will be aided by mathematical modelling, especially of protein folding and unfolding and will provide insight as to the driving forces for stability/instability of these agents. Specifically the work will examine: 1) aggregation in protein solutions, and 2) solid state stability.