Chiral polymer nanoparticles for probing biological systems

用于探测生物系统的手性聚合物纳米粒子

• 批准号: 9396956
• 负责人: Nathan John Oldenhuis
• 金额: $ 5.63万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396956
• 关键词: Adoption; Adverse effects; Affect; Amino Acids; Arginine; Biodistribution; Biological; Blood Circulation; Cells; Charge; Clinic; Clinical; Complex; Confocal Microscopy; Crosslinker; Degenerative Disorder; Development; Disease; Disease model; Dose; Drug Delivery Systems; Drug Kinetics; Endocytosis Pathway; Erythrocytes; Exposure to; Extravasation; Fluorescence Microscopy; Glutamic Acid; Growth; Half-Life; Hereditary Disease; Histologic; In Vitro; Inbred BALB C Mice; Incubated; Kilogram; Kinetics; Label; Laboratories; Letters; Literature; Malignant Neoplasms; Mass Spectrum Analysis; Maximum Tolerated Dose; Measures; Methods; Modeling; Molecular; Molecular Structure; Mus; Pathway interactions; Penetration; Peptides; Plasma; Plasma Proteins; Polyethylene Glycols; Polymers; Production; Property; Proteins; Proteomics; Reporting; Reproducibility; Research; Research Contracts; Series; Serine; Shapes; Structure; Surface; System; Techniques; Technology; Therapeutic; Therapeutic Agents; Therapeutic Uses; Time; Tissue Sample; Tissues; Toxic effect; Translating; Translations; advanced system; arm; base; biological systems; cytotoxicity; design; immunogenicity; in vivo; insight; interest; nanomedicine; nanoparticle; novel; novel strategies; polymerization; preclinical trial; response; scaffold; subcutaneous; tumor; uptake; zeta potential

Project Summary/Abstract: Drug delivery represents a platform of tremendous potential in the field of nanomedicine. Delivery of therapeutic agents directly to target cells can drastically reduce the doses required for treatment and eliminate unwanted side effects and delivery to off-target tissues. To fully realize the potential of nanomedicince, safe, general, and efficient drug delivery nanoparticles must be developed which can be produced at relevant scales for study. Recently, the Johnson lab has developed a brush-arm star polymer (BASP) system that can successfully deliver a wide variety of different therapeutic agents in controllable ratios both in vivo and in vitro. Additionally, BASPs can be produced readily on kilogram scales, and are being currently evaluated in preclinical trials in mice. In this proposal, we aim to create a series of novel BASPs with controllable functionality to alter the pharmacokinetic properties for targeting new diseases and tissues for delivery. Using a new iterative peptide polymer (IPP) synthesis technique, we will be able to construct IPP appended BASPs that will allow for complete control over size, charge, chirality, and produce them at scales relevant for therapeutic applications. After synthesis of the BASPs we will extensively study their pharmacokinetic properties. By studying protein corona composition, uptake pathways, uptake kinetics, toxicity, immunogenicity, biodistribution and biological half-life we hope to derive structure-property relationships to develop BASPs that can target a variety of tissues via different mechanisms. There is a high demand to study drugless carriers to better understand their base properties before therapeutic use or use in disease models. Because the BASPs can be loaded with a variety of therapeutic agents (which do not alter its properties), we hope to ultimately develop a technology platform where different BASPs could be used to deliver any therapeutic agent to any tissue of interest in a controlled matter in response to this demand. Establishing the groundwork for these systems will hopefully create successful treatments for many diseases, and serve as a base for the development of even more advanced systems.

项目概要/摘要： 药物递送是纳米医学领域中具有巨大潜力的平台。交付 直接作用于靶细胞的治疗剂可以大大减少治疗所需的剂量，并消除 不需要的副作用和递送到非靶组织。为了充分发挥纳米医学的潜力，安全， 必须开发出通用的、有效的药物递送纳米颗粒，其可以在相关规模下生产 为了学习最近，约翰逊实验室开发了一种刷臂星星聚合物（BASP）系统， 成功地在体内和体外以可控比例递送多种不同的治疗剂。 此外，BASP可以容易地以千克规模生产，并且目前正在临床前评估中。 在老鼠身上的试验在这个建议中，我们的目标是创建一系列具有可控功能的新颖BASP，以改变 靶向新疾病和组织递送的药代动力学特性。使用新的迭代肽 聚合物（IPP）的合成技术，我们将能够构建IPP附加BASP，将允许完整的 控制尺寸、电荷、手性，并以与治疗应用相关的规模生产它们。后 在BASP的合成中，我们将广泛研究它们的药代动力学性质。通过研究蛋白质冠 组成、摄取途径、摄取动力学、毒性、免疫原性、生物分布和生物半衰期 我们希望获得结构-性质关系，以开发能够靶向多种组织的BASP， 不同的机制。有一个很高的需求，研究无毒载体，以更好地了解他们的基础 在治疗用途或用于疾病模型之前的性质。因为BASP可以加载各种 治疗剂（不改变其性质），我们希望最终开发一种技术平台， 不同的BASP可用于将任何治疗剂以受控物质递送到任何感兴趣的组织， 回应这一要求。建立这些系统的基础将有望创造成功的 治疗许多疾病，并作为一个基础的发展，甚至更先进的系统。