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

在过去的三十年里，药物控释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，管理生物活性剂的患者患有各种疾病。随着基因工程产品变得越来越可用，药物控释系统由于其高的健康和经济潜力而获得了新的关注水平。在已知以可预测的速率释放药物的各种模式中，可侵蚀的聚合物系统脱颖而出，因为它们一旦植入就不必被移除，并且许多生物相容性聚合物是已知的。在可侵蚀系统中，聚酸酐在药物控释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。它们的主链裂解通常导致形成具有可变药物释放速率的“内部”侵蚀前沿，并且它们在人类中的使用限于短期（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的含氨基酸聚酐的单片型聚合物-药物基质，其能够在植入动物和人类后以可预测的速率释放肽和蛋白质数月甚至数年。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制程序在表面降解。具体目标是：1）合成和表征交联或支化聚2）基于合成的聚合物和作为测试蛋白的猪胰岛素或环孢菌素A配制聚合物-药物基质：3）在水性介质中温育这些基质并测定聚合物降解/药物释放速率：4）在整个基质配制和温育过程中测定测试蛋白质的活性; 5）对聚合物-药物基质进行广泛的机械测试以评估其在体内的有用性;和6）将聚合物-药物基质植入糖尿病（负载胰岛素的基质）和正常（负载环孢菌素A的基质）速率，以确定聚合物降解和药物释放速率。提出的方法包括聚合物的合成和表征，使用各种色谱和分光光度技术;新鲜制备和降解的聚合物-药物基质的机械测试;活性测试的截留肽和蛋白质，使用酶和放射免疫测定技术;和在体内植入和后续的聚合物-胰岛素和聚合物-环孢素A矩阵在大鼠。涉及基本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苯胺-dug基质的更合理的设计，并揭示其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.