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

交联或支化聚酐/酰亚胺和肽/蛋白质释放

• 批准号: 6311584
• 负责人: CARLOS A RAMFREZ
• 金额: $ 5.66万
• 依托单位: UNIVERSITY OF PUERTO RICO MAYAGUEZ
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6311584
• 关键词: aminoacid; artificial endocrine pancreas; artificial immunosuppression; biomaterial compatibility; biomaterial development /preparation; biomaterial evaluation; crosslink; cyclosporines; diabetes mellitus therapy; drug vehicle; laboratory rat; peptide chemical synthesis; polymers; proteolysis; radioimmunoassay; slow release drug

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.

在过去的三十年中，受控药物释放技术吸引了世界各地的研究人员，因为事实证明，它是为患有多种疾病的患者提供生物活性剂的一种有效手段。随着基因工程产品的越来越多，受控药物释放系统由于其高健康和经济潜力而引起了新的兴趣。在已知释放以可预测速率释放药物的药物模态的各种模式中，可侵蚀的聚合物系统脱颖而出，因为一旦植入，它们就不必被去除，并且已知许多生物相容性聚合物。在可侵蚀的系统中，在受控的药物释放应用中进行了多酸酯的研究，以至于现在可以用于治疗人脑肿瘤的聚合物 - 药物基质。但是，大多数多苯胺是线性的。它们的骨干裂解通常会导致形成具有可变药物释放率的“内部”侵蚀前沿，并且它们在人类中的使用仅限于短期（一到两个月）的应用。该项目的目的是基于基于交联或分支，含氨基酸的多阳离子的聚合物 - 聚合物 - 药物基质，能够以可预测的速率释放肽和蛋白质，几个月甚至几年后在动物和人类中植入后几年。潜在的假设是，可以通过改变其化学结构或基质配方程序来使这些新的聚酸酯在表面降解。具体目的是：1）基于含氨基酸的前聚合物和空间分子的预聚合物（例如甲基乙酸，乙醇酸或l-乳酸酸）的综合和表征交联的或分支的聚（藻类含膜）和含有氨基酸的前聚合物； 2）基于合成的聚合物和猪胰岛素或环孢菌素A作为测试蛋白制定聚合物 - 药物矩阵：3）在水性培养基中孵育这些矩阵，并确定聚合物降解/药物释放速度：4）以确定整个基质蛋白的测试蛋白的活性，并确定整个基质构装过程的活性； 5）对聚合物 - 药水矩阵进行广泛的机械测试，以评估其在体内的有用性； 6）将聚合物 - 药物矩阵植入糖尿病（胰岛素加载的矩阵）和正常（环孢菌素A负载的矩阵）速率中，以确定聚合物降解和药物释放速率。提出的方法包括使用各种色谱和分光光度计技术的聚合物合成和表征。新鲜制备和降解的聚合物 - 药物矩阵的机械测试；使用酶和放射免疫测定技术对夹杂的肽和蛋白质进行活性测试；以及在大鼠中的聚合物 - 胰岛素和聚合物 - 胞孢菌素A基质的体内植入和随访。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对这些多丙二醇挖 - 挖矩阵的更合理设计，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。