Pharmaceutical Nanofactories: Intracellular synthesis of bioactive drug molecules

药物纳米工厂：生物活性药物分子的细胞内合成

• 批准号: 10439302
• 负责人: Brian Trewyn
• 金额: $ 41.88万
• 依托单位: COLORADO SCHOOL OF MINES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439302
• 关键词: 3-Dimensional; Active Sites; Back; Biochemical; Biochemistry; Biocompatible Materials; Biological; Cells; Chemicals; Chemistry; Communication; Complex; Confined Spaces; Disadvantaged; Drug Delivery Systems; Drug resistance; Educational Curriculum; Educational process of instructing; Endocytosis; Engineering; Environment; Enzymes; Fluorescence; Goals; Hela Cells; Hybrids; Hydrophobicity; In Vitro; Individual; Investigation; Knowledge; Lead; Life; Ligands; Long-Term Effects; Malignant Neoplasms; Metals; Molecular; Mutation; Participant; Pharmaceutical Preparations; Pharmaceutical Societies; Pharmacologic Substance; Prodrugs; Property; Proteins; Reaction; Research; Research Activity; Resistance; Science; Silicon Dioxide; Site; Statistical Data Interpretation; Structure; Students; Surface; System; Techniques; Technology; Testing; Training; Water Supply; anti-cancer; antitumor drug; base; biomaterial compatibility; catalyst; cell determination; cell type; chemical reaction; chemical synthesis; design; enzyme substrate; experience; high school; innovation; instrumentation; internal control; knowledge base; laboratory experiment; lectures; metal complex; nanomaterials; nanoparticle; novel; side effect; skills; undergraduate student

Project Summary: Since the discovery of anticancer and chemotherapeutic pharmaceuticals, society has been challenged by detrimental and life altering side effects, drug resistance via cellular mutations, and distributed non- metabolized pharmaceuticals back into the environment, which has long-term effects on wildlife and water supplies. The synthetic control my team has on the pore environment of mesoporous silica nanoparticles (MSN) offers a unique perspective of delivering active, heterogenous catalytic species to cells. Using the vast knowledge base already known on internalizing MSN via endocytosis for drug delivery, we will design biocompatible porous nanomaterials that will enter cells with inorganic and biological catalysts entrapped inside the pores. Protected molecules that are not biologically active will become activated once they encounter the catalytic active sites. The confined space offered by the mesopores will protect the catalytic species (tethered molecular catalysts and exogenous enzymes) from the reductive environment of the cells. We can selectively functionalize the external and internal pore environments, allowing us to control the internalization and stabilization intracellularly along with catalytic properties. Current technology to deliver biologically active molecules contains numerous disadvantages the site-specific synthesis could eliminate. The scientific innovation includes a systematic investigation of novel porous, biomaterials entrapping metal catalysts and enzymes to investigate the synthesis and activation of prodrug and profluorophore molecules intracellularly. The hypothesis is that if catalysts can be supported and protected in the pore structure of MSN and the nanomaterial will be internalized by cells, then bioorthogonal chemical reactions can be conducted intracellularly to produce biologically active molecules on site eliminating the need for delivery of drug molecules that have detrimental side effects and lead to resistance. The teaching innovation of this project is in the cooperative and team-oriented research activities involving participants from high school through the PI. Students will receive hands-on training on numerous state-of-the-art instrumentations along with chemical syntheses, characterization, and biochemical techniques. This research will also be used to guide weekly undergraduate biochemistry laboratory experiments, focused on important interactions between biomolecules and inorganic substrates for enzyme stabilization and as part of the curriculum in lecture courses. The impact to students is first-hand experience in working cooperatively and essential skills that go into scientific research and understanding, such as the importance of proper controls, statistical analysis, and communication skills that are required in science and engineering.

项目概要： 自从抗癌和化疗药物发现以来，社会一直面临着挑战 通过有害的和改变生活的副作用、细胞突变产生的耐药性以及分布式非 代谢后的药物回到环境中，这对野生动物和动物产生长期影响 供水。我团队对介孔二氧化硅孔隙环境的合成控制 纳米颗粒（MSN）提供了一种独特的视角，可以将活性、异质催化物质传递给 细胞。利用已知的通过药物内吞作用内化 MSN 的庞大知识库 交付后，我们将设计生物相容性多孔纳米材料，该材料将与无机和 生物催化剂被困在毛孔内。不具有生物活性的受保护分子将 一旦遇到催化活性位点就会被激活。所提供的有限空间 介孔将保护催化物质（束缚分子催化剂和外源酶）免受 细胞的还原环境。我们可以选择性地功能化外部和内部孔隙 环境，使我们能够控制细胞内的内化和稳定以及催化 特性。目前递送生物活性分子的技术存在许多缺点 位点特异性合成可以消除。科学创新包括系统研究 新型多孔生物材料包埋金属催化剂和酶，以研究其合成和 细胞内前药和前荧光团分子的激活。假设如果催化剂 可以在MSN的孔结构中得到支撑和保护，纳米材料将被 被细胞内化，然后可以在细胞内进行生物正交化学反应 现场产生生物活性分子，无需输送药物分子 具有有害的副作用并导致耐药性。 本项目的教学创新在于合作、团队导向的研究活动 通过 PI 吸引来自高中的参与者。学生将接受以下方面的实践培训 许多最先进的仪器以及化学合成、表征和 生化技术。这项研究还将用于指导每周本科生生物化学 实验室实验，重点关注生物分子和无机物之间的重要相互作用 酶稳定的底物并作为讲座课程的一部分。对的影响 学生可以获得合作工作的第一手经验以及进入科学领域的基本技能 研究和理解，例如适当控制、统计分析的重要性，以及 科学和工程所需的沟通技巧。

项目成果

Atrazine Degradation Using Immobilized Triazine Hydrolase from Arthrobacter aurescens TC1 in Mesoporous Silica Nanomaterials.

• DOI: 10.1021/acsenvironau.3c00036
• 发表时间: 2023-11-15
• 期刊: ACS ENVIRONMENTAL AU
• 作者: Diviesti, Karla;Russell-Parks, Glory A;Trewyn, Brian G;Holz, Richard C
• 通讯作者: Holz, Richard C