CAREER: A New Science for Biomimetic Microparticles in Drug Delivery Systems: Integrating Protein Polymer Science into Materials Science and Engineering

该奖项的全部或部分资金来自《2021年美国救援计划法案》(公法117-2)非技术性概述：每年有数百万患者接受静脉注射药物治疗。为了在不使用可能导致不良副作用的不必要的大量药物注射的情况下确保疗效，已经开发了纳米/微米颗粒。这些微粒将药物从静脉溶液输送到有针对性的疾病部位，以便用少量药物有效地给药。然而，生物器官过滤器，如肾脏或肝脏，会从血液中去除这些输送颗粒，从而大大降低了治疗的有效性。为了克服过滤，仍然需要更高的药物剂量来确保疗效，这再次增加了不良副作用。目前的颗粒不具有机械特性，以避免在血液中过滤。然而，众所周知，天然生物颗粒，如红细胞，具有通过器官过滤器的适当机械性能。基于这一观察，该职业项目提出了基于蛋白质聚合物的药物输送微粒的突破性发展，这种蛋白质聚合物将模拟天然生物微粒的材料成分的机械行为。该项目结合了材料科学与工程、合成生物学和多尺度力学领域，为药物输送系统中有效的仿生微粒奠定了新的科学基础。该项目还实施了包容性教育生态系统和课程改革，并提供跨学科的研究经验，以准备和培训一批多样化的学生，这些学生将在材料科学、工程和蛋白质聚合物科学的整合方面形成未来的美国劳动力。技术摘要：在目前的非生物颗粒给药方式中，高达90%的颗粒被人体的过滤器官清除；因此，静脉治疗疾病的有效性降低。相比之下，天然生物粒子，如红细胞，对器官过滤是免疫的。非生物颗粒和生物颗粒的机械行为不同，这是避免过滤的关键特性。这个职业项目的目标是设计、合成和表征基于蛋白质的材料，这些材料由交联的蛋白质共聚物组成，具有模拟天然生物颗粒构成材料的量身定制的机械性能。该研究方法结合了合成生物学(利用基因工程的力量制造人工工程蛋白质共聚物的能力)、材料科学与工程(MSE)和分子与宏观力学的革命性工具。利用这些工具，这项研究将(1)建立确定具有特殊机械性能的合成蛋白质共聚物的拓扑结构的科学原理，(2)研究蛋白质共聚物的拓扑结构对蛋白质基材料的形成、结构和整体力学性能的影响，以及(3)考察基于蛋白质的类红细胞微粒的形态和流体中的传输特性。该项目填补了生物聚合物网络材料在构造性机械蛋白质共聚物的结构和外力作用下的力学响应之间的多尺度关系方面的知识空白，重点是可逆延展性和抗疲劳性能。为了培养下一代生物聚合物材料科学家和工程师，该项目将通过将生物聚合物和合成生物学中的非常规材料的设计和加工原理纳入MSE课程，并通过实施包容性的学生研究经验，来彻底改变MSE的生物聚合物科学教学。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2)NON-TECHNICAL SUMMARY:Millions of patients are treated with intravenous drug injections every year. To ensure efficacy without using drug injections with unnecessarily large amounts that can lead to adverse side effects, nano-/micro-particles has been developed. These particles deliver the drugs from intravenous solutions to a targeted disease location for effective administration with small drug amounts. Yet, the efficacy of the treatment is greatly reduced by biological organ filters, such as kidney or liver, that remove these delivery particles from the bloodstream. To overcome filtering, higher drug doses are still required to ensure efficacy, which again increases adverse side effects. The current particles do not possess mechanical properties to avoid filtering in the bloodstream. However, natural biological particles, such as red blood cells, are known to exhibit the proper mechanical properties to pass through organ filters. Based on this observation, this CAREER project proposes the breakthrough development of drug delivery microparticles based on protein polymers that will mimic the mechanical behavior of materials constituents of natural biological particles. This project combines the fields of materials science and engineering, synthetic biology, and multiscale mechanics to build the foundation of a new science for effective biomimetic microparticles in drug delivery systems. This project also implements the inclusive educational ecosystem and curricular transformations, and offers transdisciplinary research experiences to prepare and train a diverse cohort of students that will form the future U.S. workforce in the integration of materials science and engineering and protein polymer science.TECHNICAL SUMMARY:In current non-biological particle-based drug delivery modalities, up to 90% of the particles are removed by the body’s filtering organs; thus, reducing the efficacy of intravenous treatments of diseases. In contrast, natural biological particles, such as erythrocytes, are immune to organ filtering. Non-biological and biological particles differ in their mechanical behavior, a key property to avoid filtering. The objective of this CAREER project is to design, synthesize and characterize protein-based materials, composed of crosslinked protein copolymers, with tailored mechanical properties that mimic those of constitutive materials of natural biological particles. The research approach combines the revolutionary tools of synthetic biology (the ability of harnessing the power of genetic engineering to fabricate artificially engineered protein copolymers), of materials science and engineering (MSE) and of molecular to macroscale mechanics. With these tools, this research will (1) establish the scientific principles that determine the topology of synthetic protein copolymers with exceptional mechanical properties, (2) investigate the effects of protein copolymer topology on the formation, structure, and bulk mechanical properties of protein-based materials and (3) examine the morphology and in-fluid transport properties of protein-based erythrocyte-mimetic microparticles. This project fills a knowledge gap in biopolymer-network materials regarding multiscale relationships between structures of constitutive mechanical protein copolymers and mechanical response under externally applied forces with an emphasis on reversible stretchability and fatigue resistance. To train the next generation of biopolymer materials scientists and engineers, this project will revolutionize the teaching of biopolymer science in MSE by including design and processing principles of nonconventional materials from biopolymers and synthetic biology in a MSE curriculum and by implementing inclusive student research experiences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.