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

职业：药物输送系统仿生微粒的新科学：将蛋白质聚合物科学整合到材料科学与工程中

• 批准号: 2143126
• 负责人: Minkyu Kim
• 金额: $ 60.1万
• 依托单位: University of Arizona
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2143126&HistoricalAwards=false
• 关键词: CAREER; New; Science; Biomimetic; Microparticles

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.

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）非技术性摘要：每年有数百万患者接受静脉注射药物治疗。为了确保疗效而不使用可能导致不良副作用的不必要的大量药物注射，已经开发了纳米/微米颗粒。这些颗粒将药物从静脉内溶液递送到靶向疾病位置，以用于以少量药物有效施用。然而，生物器官过滤器，如肾脏或肝脏，从血流中除去这些递送颗粒，大大降低了治疗的功效。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。目前的颗粒不具备机械性能，以避免在血液中过滤。然而，已知天然生物颗粒，例如红细胞，表现出适当的机械特性以通过器官过滤器。基于这一观察结果，该CAREER项目提出了基于蛋白质聚合物的药物递送微粒的突破性发展，该蛋白质聚合物将模仿天然生物颗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，为药物递送系统中有效的仿生微粒建立了新的科学基础。该项目还实施了包容性的教育生态系统和课程改革，并提供跨学科的研究经验，以准备和培养一批多样化的学生，这些学生将在材料科学与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。技术概述：在目前的非生物颗粒基药物递送模式中，高达90%的颗粒被身体的过滤器官去除;从而降低了静脉内治疗疾病的功效。相比之下，天然生物颗粒，如红细胞，对器官过滤免疫。非生物颗粒和生物颗粒在机械行为上有所不同，这是避免过滤的关键属性。这个CAREER项目的目标是设计，合成和表征蛋白质基材料，由交联蛋白质共聚物组成，具有定制的机械性能，模仿天然生物颗粒的组成材料。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）以及分子到宏观力学的革命性工具。利用这些工具，本研究将（1）建立确定具有特殊机械性能的合成蛋白质共聚物拓扑结构的科学原理，（2）研究蛋白质共聚物拓扑结构对蛋白质基材料的形成，结构和整体机械性能的影响，以及（3）检查基于蛋白质的红细胞模拟微粒的形态和流体传输特性。该项目填补了生物聚合物网络材料的知识空白，涉及构成性机械蛋白质共聚物结构与外部施加力下的机械响应之间的多尺度关系，重点是可逆拉伸性和抗疲劳性。为了培养下一代生物聚合物材料科学家和工程师，该项目将通过在MSE课程中包括生物聚合物和合成生物学的非常规材料的设计和加工原理，并通过实施包容性的学生研究经验，彻底改变MSE中生物聚合物科学的教学。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准。

项目成果

Non-Covalently Associated Streptavidin Multi-Arm Nanohubs Exhibit Mechanical and Thermal Stability in Cross-Linked Protein-Network Materials.

• DOI: 10.1021/acs.biomac.2c00544
• 发表时间: 2022-10-10
• 期刊: BIOMACROMOLECULES
• 影响因子: 6.2
• 作者: Knoff, David S.;Kim, Samuel;Cortes, Kareen A. Fajardo;Rivera, Jocelyne;Cathey, Marcus V. J.;Altamirano, Dallas;Camp, Christopher;Kim, Minkyu
• 通讯作者: Kim, Minkyu

Ligand-Mediated Mechanical Enhancement in Protein Complexes at Nano- and Macro-Scale

• DOI: 10.1021/acsami.3c14653
• 发表时间: 2023-12-19
• 期刊: ACS APPLIED MATERIALS & INTERFACES
• 影响因子: 9.5
• 作者: Kim，Samuel;Cathey，Marcus V. J.;Kim，Minkyu
• 通讯作者: Kim，Minkyu