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.

项目摘要： 自从发现抗癌和化学治疗药物以来，社会受到了挑战 通过有害和生命改变副作用，通过细胞突变的耐药性和分布的非 - 代谢化的药物重新回到环境，这对野生动植物和 供水。我的团队在介孔二氧化硅的孔环境中拥有的合成控制 纳米颗粒（MSN）提供了将活跃的异质催化物种传递到 细胞。利用已经通过内吞作用在内部化MSN上已经知道的庞大的知识库来进行药物 交付，我们将设计生物相容性的多孔纳米材料，该纳米材料将进入无机和 生物催化剂夹在毛孔中。不是生物活性的保护分子 一旦遇到催化活性位点，它们就会被激活。由 中孔将保护催化物种（束缚分子催化剂和外源性酶）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 环境，使我们能够在细胞内控制内在化和稳定以及催化 特性。提供生物活性分子的当前技术包含许多缺点 特异性的合成可以消除。科学创新包括系统调查 新型多孔的生物材料捕获金属催化剂和酶，以研究合成和 细胞内的前药和大量分子的激活。假设是如果催化剂 可以在MSN的孔结构和纳米材料的孔结构中受到支持和保护 通过细胞内化，然后可以在细胞内进行生物正交化学反应 在现场产生具有生物活性的分子，消除了药物分子递送的需求 具有有害的副作用并导致阻力。 该项目的教学创新是在合作和面向团队的研究活动中 参与高中通过PI的参与者。学生将接受动手培训 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的本科生物化学 实验室实验，侧重于生物分子与无机分子之间的重要相互作用 酶稳定的底物，作为讲座课程中课程的一部分。对 学生是合作工作的第一手经验，并且是科学的基本技能 研究和理解，例如适当控制的重要性，统计分析和 科学和工程中需要的沟通技巧。

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