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.

该奖项是根据2021年《美国救援计划法》（公法117-2）的全部或部分资助的非技术摘要：数百万患者每年接受静脉注射药物的治疗。为了确保无需使用不必要的大量药物而导致不良副作用的有效性，已经开发了纳米/微粒。这些颗粒将药物从静脉溶液中传递到有针对性疾病的位置，以有效给药，以少量药物量。然而，通过肾脏或肝脏等生物器官过滤器大大降低了治疗的有效性，这些过滤器从血液中去除这些递送颗粒。为了克服过滤，仍然需要更高的药物来确保有效性，这再次增加了不良副作用。电流颗粒没有机械性能来避免在血液中过滤。但是，已知天然生物学颗粒（例如红细胞）表现出适当的机械性能通过器官过滤器。基于这一观察结果，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开发，这些蛋白质聚合物将模仿天然生物学颗粒的材料构成的机械行为。该项目结合了材料科学和工程，合成生物学和多尺度机制的领域，以在药物输送系统中建立新科学的基础。该项目还实现了包容性的教育生态系统和当前的转变，并提供跨学科的研究经验，以准备和培训多样化的学生队列，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中构成未来的美国劳动力。技术摘要：在当前的非生物粒子剂量交付模态中，通过到90％的身体差异，将其转移到90％的身体上。因此，降低了疾病静脉治疗的效率。相比之下，天然生物学颗粒（例如红细胞）不受器官滤波的影响。非生物和生物学颗粒的机械行为不同，这是避免过滤的关键特性。该职业项目的目的是设计，合成和表征由蛋白质基于蛋白质的材料，该材料由交联的蛋白质共聚物组成，具有量身定制的机械性能，这些特性模仿了天然生物学颗粒的宪法材料。研究方法结合了合成生物学的革命性工具（利用基因工程的力量制造人为工程的蛋白质共聚物），材料科学和工程（MSE）以及分子到宏观机械的能力。 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.该项目填补了有关本构机械蛋白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的生物聚合物网络材料的知识差距，重点是可逆的可伸缩性和抗疲劳性。为了培训下一代生物聚合物材料科学家和工程师，该项目将通过包括生物聚合物和合成生物学在MSE课程中的设计和处理原理的设计和处理原理来彻底改变MSE中的生物聚合物科学的教学，并通过对全面的学生研究经验进行评估，以评估NSF的众多范围，以表达NSF的众多范围。 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

Tailoring the formation and stability of self-assembled structures from precisely engineered intrinsically disordered protein polymers: A comprehensive review

• DOI: 10.1016/j.giant.2023.100158
• 发表时间: 2023-04-27
• 期刊: GIANT
• 影响因子: 7
• 作者: Doole，Fathima T.;Camp，Christopher P.;Kim，Minkyu
• 通讯作者: Kim，Minkyu