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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

基本信息

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
项目类别：
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

项目摘要

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的发现，社会一直受到挑战，有害的和改变生活的副作用，通过细胞突变产生的耐药性，以及分布的非- 代谢的药物回到环境中，这对野生动物有长期的影响，供水。我的团队对介孔二氧化硅的孔环境进行了合成控制，纳米颗粒（MSN）提供了一个独特的视角，提供活性，非均相催化物种，细胞利用已经知道的关于通过内吞作用内化MSN的大量知识库，交付，我们将设计生物相容性多孔纳米材料，将进入细胞与无机和生物催化剂被截留在孔内。没有生物活性的受保护分子将一旦它们遇到催化活性位点就被激活。提供的密闭空间中孔将保护催化物质（栓系的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环境，使我们能够控制内化和稳定细胞内沿着与催化特性.目前递送生物活性分子的技术包含许多缺点定点合成可以消除。科学创新包括系统的调查研究新型多孔，生物材料截留金属催化剂和酶，研究合成和细胞内前药和前荧光团分子的活化。假设如果催化剂可以在MSN的孔结构中得到支撑和保护，被细胞内化，然后可以在细胞内进行生物正交化学反应，在现场产生生物活性分子，有副作用并导致抗药性。本项目的教学创新之处在于合作式、团队式的研究活动参与者从高中到PI。学生将接受实践培训，许多最先进的仪器沿着化学合成、表征和生化技术这项研究也将用于指导每周的本科生生物化学实验室实验，侧重于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。的冲击学生是第一手的经验，合作和基本技能，进入科学研究和理解，如适当控制，统计分析，科学和工程所需的沟通技巧。