CAREER: Self-assembling Nanofibers as Next Generation Antimicrobial Biomaterials

职业：自组装纳米纤维作为下一代抗菌生物材料

• 批准号: 1824614
• 负责人: He Dong
• 金额: $ 45.7万
• 依托单位: University of Texas at Arlington
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1824614&HistoricalAwards=false
• 关键词: CAREER; Self; assembling; Nanofibers; Next

Non-technical section:The full range of antibiotic-resistant microbes found in hospitals and the broader environment represent a "clear and present danger" to the general public, first responders, and military personnel. Effective response to this public health challenge necessitates adoption of an "outside-the-box" strategy for the de novo design of novel classes of microbicides. The goal of this NSF Career award is to develop a novel self-assembling antimicrobial nanofiber (SAAN) platform for safer and more effective therapeutic administration of antimicrobial peptides (AMPs) compared to conventional treatment options. Systematic engineering of SAANs has minimized host cell cytotoxicity, improved their protease-resistance and their antimicrobial activity against broad-spectrum bacteria. The success of the proposed work will open new avenues for AMP-based antimicrobial therapy to treat a variety of infectious diseases found in both civilian hospitals and military facilities. The fundamental knowledge developed from the proposed research activities will provide a powerful new glossary of fundamental design principles for the synthesis and deployment of AMPs. It will have a transformative impact on the multi-billion-dollar research focused on conventional antibiotics and AMPs by re-engineering and "re-formatting" thousands of available AMPs in the peptide databank to form SAANs, thereby greatly boosting their therapeutic potential. The multidisciplinary research involving chemistry, microbiology, engineering, nanoscience, and pharmaceutical sciences provides ample opportunities to train and educate students at all levels. The fundamental biomaterials design, supramolecular chemistry and antimicrobial delivery principle will be integrated into various research and educational activities, particularly through summer research opportunities provided to high school students to promote their scientific research interests and enhance their career awareness. Educational partnership with local high school will be established to provide summer research internship to high school teachers to incorporate the fundamental knowledge of the proposed research into various high school curriculum.Technical section:The discovery of antimicrobial peptides (AMPs) has brought tremendous opportunities to overcome the prevalence of bacterial resistance to commonly used antibiotics due to their direct action against bacterial membrane. However, despite AMPs' exceptional bactericidal activity in vitro, their susceptibility to proteases, limited circulation half-lives and severe host cell toxicity represent critical hurdles to their widespread use. This CAREER award supported by the Biomaterials program in the Division of Materials Research to Clarkson University focuses on a new paradigm of Self-Assembled Antimicrobial Nanofibers (SAANs) as a vehicle-free AMP delivery system to alleviate the drawback associated with conventional AMPs. In SAANs, AMPs serve as both therapeutics and key structural components to program and direct the assembly through highly specific intermolecular interactions. Through the proposed work, we will build a toolbox of cationic de novo designed peptides with expanded chemical functionality by which to construct various SAANs families, and explore the effect of new functional groups on the molecular and supramolecular packing of SAANs, antimicrobial activity and hemocompatibility. Fundamental knowledge about the structure-activity relationship is essential for the design of new antimicrobial nanomaterials with precise control over molecular structure, nanostructure, stimuli-responsive antimicrobial activity and exquisite biocompatibility. The impact of this proposal lies in that SAANs could potentially be established as a new and unique AMP delivery platform with well-defined filamentous structure and the ease of incorporating multi-therapeutics for combinatorial antimicrobial and chemotherapy to treat various human diseases. The proposed project will integrate supramolecular chemistry, biomaterials design and antimicrobial delivery principles and techniques with various education and outreach activities for students at all levels.

非技术部分：在医院和更广泛的环境中发现的各种耐药微生物对公众、急救人员和军事人员构成了“明确和现实的危险”。要有效应对这一公共卫生挑战，就必须采用“开箱即用”的战略，重新设计新型杀微生物剂。该NSF职业奖的目标是开发一种新的自组装抗菌肽（SAAN）平台，与传统治疗方案相比，抗菌肽（AMP）的治疗管理更安全，更有效。SAAN的系统工程已经最小化了宿主细胞的细胞毒性，提高了它们的蛋白酶抗性和它们对广谱细菌的抗微生物活性。拟议工作的成功将为基于AMP的抗菌治疗开辟新的途径，以治疗在民用医院和军事设施中发现的各种传染病。从拟议的研究活动开发的基本知识将提供一个强大的新的词汇表的基本设计原则的综合和部署的AMP。它将通过重新设计和“重新格式化”肽数据库中数千种可用的抗菌肽以形成SAAN，从而极大地提高其治疗潜力，对专注于传统抗生素和抗菌肽的数十亿美元研究产生变革性影响。潜力。涉及化学，微生物学，工程，纳米科学和制药科学的多学科研究为各级学生提供了充足的培训和教育机会。基本的生物材料设计，超分子化学和抗菌传递原理将被整合到各种研究和教育活动中，特别是通过为高中生提供的暑期研究机会，以促进他们的科学研究兴趣和提高他们的职业意识。将与当地高中建立教育合作伙伴关系，为高中教师提供暑期研究实习机会，将拟议研究的基础知识融入各种高中课程。技术部分：抗菌肽（Amps）的发现为克服细菌对常用抗生素的普遍耐药性带来了巨大的机会，因为它们直接作用于细菌膜。然而，尽管AMP在体外具有出色的杀菌活性，但它们对蛋白酶的易感性、有限的循环半衰期和严重的宿主细胞毒性代表了它们广泛使用的关键障碍。该职业奖由克拉克森大学材料研究部的生物材料项目支持，重点关注自组装抗菌纳米纤维（SAAN）作为无载体AMP输送系统的新范例，以减轻与传统AMP相关的缺点。在SAAN中，AMP作为治疗剂和关键结构组分，通过高度特异性的分子间相互作用来编程和指导组装。通过上述工作，我们将构建一个具有扩展化学功能的阳离子从头设计肽的工具箱，通过该工具箱构建各种SAAN家族，并探索新官能团对SAAN的分子和超分子包装，抗菌活性和血液相容性的影响。有关结构-活性关系的基础知识对于设计具有精确控制分子结构、纳米结构、刺激响应性抗菌活性和精致生物相容性的新型抗菌纳米材料至关重要。这一提议的影响在于，SAAN可能被建立为一种新的独特的AMP递送平台，其具有明确的丝状结构，并且易于合并用于组合抗微生物剂和化疗的多种治疗剂以治疗各种人类疾病。拟议的项目将把超分子化学、生物材料设计和抗菌剂输送原理和技术与各级学生的各种教育和外展活动结合起来。

项目成果

Design and fabrication of reduction-sensitive cell penetrating nanofibers for enhanced drug efficacy

设计和制造还原敏感细胞穿透纳米纤维以增强药物功效

• DOI: 10.1039/c8tb00728d
• 发表时间: 2018
• 期刊: Journal of Materials Chemistry B
• 影响因子: 7
• 作者: Yang, Su;Xu, Dawei;Dong, He
• 通讯作者: Dong, He

Bacterial acidity-triggered antimicrobial activity of self-assembling peptide nanofibers

• DOI: 10.1039/c9tb00134d
• 发表时间: 2019-05-14
• 期刊: JOURNAL OF MATERIALS CHEMISTRY B
• 影响因子: 7
• 作者: Chen, Weike;Li, Shuxin;Dong, He
• 通讯作者: Dong, He

Supramolecular Peptide Nanofiber/PLGA Nanocomposites for Enhancing Pulmonary Drug Delivery

• DOI: 10.1021/acsami.2c15204
• 发表时间: 2022-12-07
• 期刊: ACS APPLIED MATERIALS & INTERFACES
• 影响因子: 9.5
• 作者: Chintapula，Uday;Yang，Su;Nguyen，Kytai T.
• 通讯作者: Nguyen，Kytai T.

Alkaline-responsive polydiacetylene-peptide hydrogel for pH-sensing and on-demand antimicrobial release

• DOI: 10.1016/j.mtadv.2022.100288
• 发表时间: 2022-12
• 期刊: Materials Today Advances
• 影响因子: 10
• 作者: Weike Chen;Shan Hazoor;R. Madigan;Ashley A. Adones;Uday Chintapula;K. Nguyen;Liping Tang;F. Foss;He Dong

Modular Design of Supramolecular Ionic Peptides with Cell‐Selective Membrane Activity

• DOI: 10.1002/cbic.202100323
• 发表时间: 2021-09
• 期刊: ChemBioChem
• 影响因子: 3.2
• 作者: Su Yang;Yan Chang;Shan Hazoor;C. Brautigam;F. Foss;Zui Pan;He Dong