PLGA Protein Microspheres: Single Particle Engineering

描述(由申请人提供)：我们提案的目标是为将蛋白质和多肽作为药物以及它们作为聚合物/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，预计到2018年，蛋白质疗法的市场渗透率将达到400亿美元，有效的药物传递成为下一个重大障碍。在这项提案中，我们采取了一种量化的方法，扩大了这一已建立但尚未完全优化的聚合物药物和制剂输送领域中现有的知识基金。我们遵循一个相对简单的研究设计--单颗粒研究(实验和理论)，然后是散体悬浮液的组成、结构和功能的表征。通过连续研究SA1中的单个液滴和单个组分，计划获得用任何其他方法都不容易获得的关键测量结果，即液滴中每个组分的动态浓度，与降水、粘性变化、微结构夹杂物和硬化时间等事件相关。微球的水解和蛋白质释放也可以在单个微球上测量到。然后，特定目标2寻求将这些测量结果与作为散装悬浮液的微球的物理和化学特征和属性进行建模。而SA3通过直接将微球的蛋白质释放和蛋白质功能与工艺和组成变量联系起来，形成了微球的微观结构，从而完成了这一研究。在SA4中开发了新的创新，我们将在其中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。这些数据将对开发芋螺毒素缓释系统(SA5)至关重要，从而解决疼痛控制的重要问题。该项目完成后，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，并使微球仿制技术成为可能，特别是环境敏感型蛋白质和多肽。

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.