CROSS LINKED OR BRANCHED POLYANHYDRIDES/COIMIDES AND PEPTIDE/PROTEIN RELEASE

在过去的三十年里，药物控制释放技术吸引了世界各地的研究人员，因为它已被证明是一种有效的方法，可以给患有各种疾病的患者施用生物活性药物。随着基因工程产品的日益普及，控制药物释放系统由于其高健康和经济潜力而引起了人们新的关注。在各种已知的释放药物的方式中，已知以可预测的速度释放药物的方式，可降解聚合物系统脱颖而出，因为它们一旦植入就不必移除，而且许多生物相容性聚合物是已知的。在可降解系统中，多酸酐在控制药物释放应用中得到了广泛的研究，目前聚合物药物基质可用于治疗人类脑肿瘤。然而，大多数聚酸酐是线性的。它们的骨干断裂通常导致“内部”侵蚀锋的形成，其药物释放率变化，并且它们在人类中的使用仅限于短期（一到两个月）应用。该项目的目标是开发一种基于交联或支链、含氨基酸的多酸酐的单体型聚合物药物基质，该基质能够在植入动物和人类体内数月甚至数年后以可预测的速率释放肽和蛋白质。潜在的假设是，这些新的聚酸酐可以通过改变它们的化学结构或基质配方程序在表面降解。具体目的是：1)合成和表征基于含氨基酸的预聚物和空间分子如己二酸、乙醇酸或l -乳酸的预聚物的交联或支链聚（酸酐-co-亚胺）；2)以合成的聚合物为基础，以猪胰岛素或环孢素A为试验蛋白配制聚合物-药物基质；3)在水介质中培养这些基质，并确定聚合物降解/药物释放率；4)在整个基质配制和培养过程中确定试验蛋白的活性；5)对聚合物药物基质进行广泛的力学测试，以评估其在体内的有效性；6)将聚合物-药物基质植入糖尿病（胰岛素负载基质）和正常（环孢素a负载基质）中，以确定聚合物降解和药物释放率。提出的方法包括聚合物的合成和利用各种色谱和分光光度技术进行表征；新制备和降解聚合物药物基质的力学试验利用酶和放射免疫测定技术检测包埋肽和蛋白质的活性；聚合物-胰岛素和聚合物-环孢素A基质在大鼠体内的植入和随访。这种综合方法涉及基础聚合物化学，以及体外和体内测试，将导致这些多酸酐挖掘基质的更合理设计，并揭示它们在糖尿病和免疫抑制的长期治疗中的潜在用途。

Over the last three decades, controlled drug release technology has attracted researchers around the world because it has proven to be an efficient means of administering bioactive agents to patients suffering from a variety of diseases. With genetic engineering products becoming increasingly available, controlled drug release systems have attained a new level of interest due to their high health and economic potential. Of the various modalities known to release drugs modalities known to release drugs at predictable rates, the erodible polymeric systems stand out because they do not have to be removed once implanted and many biocompatible polymers are known. Among the erodible systems, polyanhydrides have been studied extensively in controlled drug release applications to the point where polymer-drug matrices are now available for treating human brain tumors. However, most polyanhydrides are linear. Their backbone cleavage generally leads to the formation of "internal" erosion fronts with variable drug release rates, and their use in humans is limited to short-term (one to two months) applications. The goal of this project is to develop a monolith-type, polymer -drug matrix based on cross-linked or branched, amino acid-containing polyanhydrides capable of releasing peptides and proteins at predictable rates for months and even years after implantation in animals and humans. The underlying hypothesis is that these new polyanhydrides can be made to degrade at the surface by altering their chemical structure or the matrix formulation procedure. The specific aims are: 1) to synthesize and characterize cross-linked or branched poly(anhydride-co- imides) based on an amino acid-containing pre-polymer and a pre-polymer of a space molecule such as sebacic acid, glycolic acid, or L-lactic acid; 2) to formulate polymer-drug matrices based on the polymers synthesized and either porcine insulin or cyclosporin A as test proteins: 3) to incubate these matrices in aqueous media and determine the polymer degradation/drug release rates: 4) to determine the activity of the test proteins throughout the matrix formulation and incubation procedures; 5) to perform extensive mechanical tests on the polymer-drug matrices to assess their usefulness in vivo; and 6) to implant the polymer-drug matrices in diabetic (insulin-loaded matrices) and normal (cyclosporin A-loaded matrices) rates to determine the polymer degradation and drug release rates. The methods proposed include polymer synthesis and characterization using various chromatographic and spectrophotometric techniques; mechanical testing of freshly prepared and degraded polymer-drug matrices; activity testing of the entrapped peptides and protein using enzymatic and radioimmunoassay techniques; and in vivo implantation and follow-up of the polymer-insulin and polymer-cyclosporin A matrices in rats. The integrated approach involving fundamental polymer chemistry, as well as in vitro and in vivo testing, will lead to a more rational design of these polyanhydride-dug matrices and shed light on their potential use in long-term therapies for diabetes and immunosuppression.