EAGER: Preliminary Study on Novel self-assembled Toroidal-Spiral MicroParticles (TSMPs) for sustained release of therapeutic proteins and peptides: theory and experiments

EAGER：用于持续释放治疗性蛋白质和肽的新型自组装环形螺旋微粒（TSMP）的初步研究：理论和实验

• 批准号: 1039531
• 负责人: Ying Liu
• 金额: $ 6万
• 依托单位: University of Illinois at Chicago
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1039531&HistoricalAwards=false
• 关键词: EAGER; Preliminary; Study; Novel; self

The research objective of the proposal is to test the hypothesis that self-assembly by interaction of viscous sedimentation, diffusion, and cross-linking kinetics can produce a new category of polymeric micro-particles with a toroidal-spiral internal structure that offers advantages for sustained drug release. More specifically, during the particle formation, therapeutic proteins and peptides are simultaneously encapsulated into the toroidal-spiral channels. In contrast with prevailing protein delivery methods, toroidal-spiral micro-particles(TSMPs) can be formed and loaded with proteins entirely within the aqueous phase, under benign conditions (room temperature, low shear and low interfacial tensions) that preserve delicate macromolecular conformations and thereby maximize bioactivity and bioavailability. To validate this novel idea, and thereby mitigate conceptual risk for the longer project, we request support for one-year of research to provide more preliminary results for a regular proposal in future. Within the one-year period proposed here, two key aspects will be addressed: (1) protein self-loading into the toroidal-spiral particles, and (2) scaling down toroidal-spiral particles from the millimeter scale (currently achievable) to micron dimensions. On the basis of preliminary experimental and theoretical work, we expect success in both endeavors. The research plan below includes contingency plans in case the initial approach does not work as anticipated. Intellectual Merit. Integrating laboratory investigation with versatile computer simulations, this proposal addresses the fundamental fluid mechanics and mass transfer that enable a new category of polymeric drug-delivery particles for local sustained release of therapeutic proteins and peptides. TSMPs will be generated by light-triggered flash polymerization of intricately wound liquid structures. These liquid structures form by hydrodynamic forces when a water-miscible, polymeric drop sediments at low Reynolds number through an aqueous solution. The initial impact of the polymeric droplets into the aqueous pool (forming bell shapes of vortex rings) for arbitrary viscosity ratio and non-Newtonian rheology represents a largely unexplored regime in fluid mechanics, to which both quantitative visualization experiments and computer modeling will be applied. The anticipated findings will greatly enhance our quantitative understanding of new self-assembly processes, thereby providing a quantum leap in producing microparticles with novel structures. Broader Impacts. This project provides a technological platform that can potentially be translated into medical treatments for many complex diseases. Research will impact the ChE curriculum through a new graduate microfluidics course, two modules for the undergraduate Transport Phenomena sequence and a sequence of undergraduate research projects. A dedicated website (www.microfluidtech.org) will publish a suite of Java-based educational modules designed for college and pre-college students, also to be described in an educational journal article. The highly visual nature of the experiments and theoretical results, as well as the societal relevance of the biomedical applications, represent a natural draw for students being recruited into chemical engineering through ongoing departmental relationships with Chicago land high schools. This project leverages ongoing outreach, recruitment and retention efforts by Liu and Nitsche among women and underrepresented minority students.

该方案的研究目的是验证一种假设，即通过粘性沉积、扩散和交联动力学的相互作用进行自组装可以产生一种新的具有环形螺旋内部结构的聚合物微粒，从而为药物的持续释放提供有利条件。更具体地说，在颗粒形成过程中，治疗性蛋白质和多肽同时被包裹到环形螺旋通道中。与目前流行的蛋白质输送方法相比，环形螺旋微粒(TSMPS)可以在温和的条件下(室温、低剪切和低界面张力)完全在水相中形成并负载蛋白质，从而保持微细的大分子构象，从而最大限度地提高生物活性和生物利用度。为了验证这一新想法，从而减轻较长项目的概念性风险，我们请求支持为期一年的研究，以便为未来的常规提案提供更多初步结果。在这里提出的一年时间内，将讨论两个关键方面：(1)蛋白质自负载到环形螺旋粒子中，以及(2)将环形螺旋粒子从毫米级(目前可以实现的)缩小到微米级。在前期实验和理论工作的基础上，我们预计这两项工作都会取得成功。下面的研究计划包括应急计划，以防最初的方法不能如预期那样奏效。智力上的功绩。将实验室研究与多功能计算机模拟相结合，这一建议解决了基本的流体力学和质量传递问题，使一种新类型的聚合物药物输送颗粒能够局部持续释放治疗性蛋白质和多肽。TSMPS将通过复杂缠绕的液体结构的光触发闪光聚合生成。当水可混溶的聚合物液滴在低雷诺数下通过水溶液沉积时，这些液体结构是由水动力形成的。对于任意粘度比和非牛顿流变学，聚合物液滴在水池中的初始冲击(形成涡环的钟形)代表了流体力学中一个很大程度上未知的区域，将应用定量可视化实验和计算机模拟。这些预期的发现将极大地提高我们对新的自组装过程的定量理解，从而在生产具有新结构的微粒方面实现巨大的飞跃。更广泛的影响。该项目提供了一个技术平台，可以潜在地转化为许多复杂疾病的医疗治疗。研究将通过一门新的研究生微流体学课程、本科生交通现象序列的两个模块和一系列本科生研究项目来影响CHE课程。一个专门的网站(www.microfluidtech.org)将发布一套为大学生和大学预科学生设计的基于Java的教育模块，也将在一篇教育期刊文章中介绍。实验和理论结果的高度可视化，以及生物医学应用的社会相关性，代表了通过与芝加哥土地高中持续的部门关系被招募到化学工程专业的学生的自然吸引力。该项目利用刘和Nitsche在女性和代表性不足的少数族裔学生中正在进行的外展、招聘和留住努力。