A novel approach for long term protein delivery

一种长期蛋白质输送的新方法

• 批准号: 7141503
• 负责人: You Han Bae
• 金额: $ 22.72万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7141503
• 关键词: SDS polyacrylamide gel electrophoresis; anions; biodegradable product; chemical kinetics; chemical synthesis; chromatography; conformation; copolymer; diabetes mellitus; disease /disorder model; drug delivery systems; histidine; insulin; ionic bond; laboratory rat; matrix assisted laser desorption ionization; microcapsule; nuclear magnetic resonance spectroscopy; polyethylene glycols; polymers; protein structure function; radioimmunoassay; ultraviolet spectrometry; water solution

DESCRIPTION (provided by applicant): Poly(lactide-co-glycolide) (PLGA) has been widely applied in microspheres (MS) as a protein delivery carrier. However, proteins undergo physical and chemical denaturation during the fabrication of PLGA MS and release in the body. In addition, such formulations often cause undesirable and unpredictable release profiles, characterized by a burst effect and incomplete release. This makes PLGA MS appraoch unsuccessful for most labile proteins. The results from our preliminary study are a clear pointer to the validity of the role played by PEG-polycation (poly(L-histidine)) as a pH-dependent 'reversible molecular shield' in 1) preserving protein structure and preventing aggregation at water/organic interface, 2) exerting a pH buffering (protein sponge effect) in PLGA MS, 3) enhancing protein's physical stability in solution and in MS, and 4) an overall better control over release of the proteins from the PLGA MS ('all-in-one' concept). Although our preliminary results demonstrate the feasibility, there are still a number of variables which can be altered to optimize or tailor this polymer design for specific proteins, such as insulin. This includes changing the size of polyHis and copolymerizing with other amino acids to alter charge spacing or polyHis conformation. The proposal goes well beyond therapeutic proteins in suggesting potential applications for enzymes and other applications. The long-term goal of this project is to preserve >90 % bioactivity of a model protein, insulin, when released from PLGA MS and to achieve pseudozero-order release kinetics for more than one month period in in vitro and in vivo tests. The research specific aims include 1) experimental verification of optimized PEG-polyHis (or PEG-modified polyHis)/insulin complex for maximum insulin stability in aqueous solutions, in PLGA MS and during release, 2) a better control over release profile and 3) in vivo performance tests combined with biocompatibility and the fate of the diblock copolymer.

描述（由申请人提供）：聚（乳酸 - 糖糖苷）（PLGA）已广泛应用于微球（MS）作为蛋白质递送载体。但是，蛋白质在制造PLGA MS期间会经历物理和化学变性，并在体内释放。此外，这种制剂通常会引起不良且不可预测的释放曲线，其特征是爆发效果和不完整的释放。这使得对大多数不稳定蛋白质的PLGA MS Archaoch失败。我们的初步研究的结果是清楚地指向peg聚解作用（poly（l-histidine））作为pH依赖性的“可逆分子屏蔽”的有效性1）在1）在蛋白质/有机界面中保持蛋白质结构并防止在ph shopfering（蛋白质喷头效应）中保持蛋白质结构，并防止在ph offering（蛋白质启用）中，在PLENGE（蛋白质启用）中，在PLEGE（蛋白质启用）中，在PLEGE效应中，在PLEGE效应中，在PLEGE效应中，在PLGA效应中，在PLGA效应中，在PLAGE效应中，3）在PLEGE效应中，3）在PLEGE效应中，3）在PLEGE效应中，3）在PLANES上效应，3）总体上可以更好地控制PLGA MS（“一为”概念）的蛋白质释放。尽管我们的初步结果证明了可行性，但仍有许多变量可以更改以优化或调整针对特定蛋白质（例如胰岛素）的这种聚合物设计。这包括改变多面体的大小，并与其他氨基酸共聚以改变电荷间距或多面体构象。该提案远远超出了治疗蛋白的建议，这些蛋白在建议酶和其他应用的潜在应用中。该项目的长期目标是在从PLGA MS释放并实现假阶释放动力学的模型蛋白胰岛素的生物活性> 90％的生物活性，以在体外和体内测试中超过一个月。研究具体目的包括1）实验验证优化的PEG-Polyhis（或PEG修饰的Polyhis）/胰岛素复合物，以在水溶液中，PLGA MS和发行期间为最大的胰岛素稳定性，在发行版中，2）更好地控制释放配置文件和3）在体内性能测试中，结合了生物相容性和生物相结合的Copolymermermermerysermersermersermersermeryser。