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

在过去的三十年里，受控药物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手段，为患有各种疾病的患者提供生物活性物质。随着基因工程产品的日益普及，受控药物释放系统因其高度的健康和经济潜力而引起了人们的新的兴趣。在已知的以可预测的速度释放药物的各种方式中，可侵蚀聚合物系统脱颖而出，因为它们一旦植入就不必被移除，而且许多生物相容的聚合物是已知的。在可腐蚀的体系中，聚酸酐在药物控制释放应用中得到了广泛的研究，以至于聚合物药物骨架现在可以用于治疗人脑肿瘤。然而，大多数聚酸酐都是线性的。它们的主干裂解通常会导致形成具有不同药物释放速率的“内部”侵蚀前沿，它们在人体上的使用仅限于短期(一到两个月)应用。该项目的目标是开发一种基于交联型或支化的、含有氨基酸的聚酸酐的整体型聚合物药物基质，能够在动物和人类体内植入后数月甚至数年以可预测的速度释放多肽和蛋白质。潜在的假设是，通过改变它们的化学结构或基质配方过程，可以使这些新的聚酸酐在表面降解。其具体目的是：1)合成和表征基于氨基酸预聚体和空间分子预聚体的交联型或支化聚(酸酐-共亚胺)；2)以合成的聚合物为基础，以猪胰岛素或环孢菌素A为测试蛋白，制备聚合物药物骨架：3)在水介质中孵育这些骨架，并测定聚合物降解/药物释放速率：4)在骨架形成和孵育过程中测定测试蛋白质的活性；5)对聚合物药物骨架进行广泛的力学测试，以评估它们在体内的有效性；以及6)将聚合物药物骨架植入糖尿病(胰岛素载体)和正常(环孢素A载体)，以确定聚合物的降解率和药物释放速率。建议的方法包括使用各种层析和分光光度技术合成和表征聚合物；对新制备和降解的聚合物药物基质进行机械测试；使用酶和放射免疫分析技术测试包裹的多肽和蛋白质的活性；以及聚合物-胰岛素和聚合物-环孢素A骨架在大鼠体内的植入和随访。涉及基础聚合物化学以及体外和体内测试的综合方法将导致这些聚酸酐挖掘基质的更合理设计，并阐明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.