PLGA Protein Microspheres: Single Particle Engineering

描述（由申请人提供）：我们提案的目标是为处理蛋白质和肽作为药物及其作为聚合物/蛋白质微球的配方的原理和实践带来新的见解和使能技术。随着全球对创新蛋白质疗法的需求以每年30%的速度增长，到2018年，全球蛋白质疗法的市场渗透率预计将达到400亿美元，有效的药物输送成为下一个重大障碍。在这个建议中，我们正在采取一种定量的方法，扩展现有的知识基金，这些知识已经存在于这个已建立但尚未完全优化的基于聚合物的药物和药物递送领域。我们正在遵循一个相对简单的研究设计-单颗粒研究（实验和理论），然后是体积悬浮液的组成，结构和功能表征。通过在SA1中对单个液滴和单个组分进行连续研究，计划获得其他任何方法都难以获得的关键测量数据，即液滴中每种组分的动态浓度，与沉淀、粘性变化、微观结构夹杂物和硬化时间等事件相关。微球水解和蛋白质释放也可在单个微球上测量。然后，Specific Aim 2将这些测量和建模与微球作为散装悬浮液的物理和化学特性和性质联系起来。SA3通过将微球蛋白释放和蛋白功能与工艺和组成变量直接联系起来，并建立了微球微观结构。SA4开发了新的创新，我们将形成玻璃化的蛋白质纳米球，以提高蛋白质的稳定性和分散性。这些数据对于开发concontoxins （SA5）的持续释放系统至关重要，从而解决疼痛控制的重要问题。在这个项目完成后，我们的目标是为蛋白质药物的特定配方提供更详细的配方，并在此过程中，能够提供更完整的设计工程方法和微球制备技术，特别是对环境敏感的蛋白质和肽。

DESCRIPTION (provided by applicant): The goal of our proposal is to bring new insights and enabling technology to the principles and practice of handling proteins and peptides as drugs and their formulation as polymer/protein microspheres. With the world-wide demand for innovative protein therapeutics growing at 30% per year, and a market penetration for protein therapeutics estimated to reach $40 billion worldwide by 2018, effective drug delivery becomes the next significant obstacle. In this proposal we are taking a quantitative approach that expands on the existing fund of knowledge already present in this established, yet not fully optimized, field of polymer-based drug and agent delivery. We are following a relatively straightforward research design -single particle studies (experiment and theory) followed by bulk suspension characterization of composition, structure, and function. By studying individual droplets and individual components serially in SA1, the plan is to obtain crucial measurements not easily obtained by any other method, i.e., the dynamic concentration of each component in the droplet, correlated with events such as precipitation, viscous changes, microstructural inclusions, and time for hardening. Microsphere hydrolysis and protein release are also measurable on single microspheres. Specific Aim 2 then looks to correlate these measurements, and modeling with the physical and chemical characteristics and properties of the microspheres as bulk suspensions. And SA3 completes the investigation by directly relating microsphere protein release and protein function, to processs and compositional variables and developed microsphere microstructure. New innovation is developed in SA4 where we will form glassified protein nanospheres for improved protein stability and dispersion. These data will be crucial for developing a sustained release system for conotoxins (SA5) and thus address the important problem of pain control. Upon completion of this project then we aim to provide a more detailed recipe for specific formulations of protein drugs, and in the process, to be able to offer a more complete design engineering methodology, and enabling technology for microsphere brmulation, especially for environment-sensitive proteins and peptides.