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.

项目摘要/摘要： 药物输送代表了纳米医学领域具有巨大潜力的平台。交付 治疗剂直接作用于靶细胞可以大大减少治疗所需的剂量并消除 不良副作用和递送至非目标组织。充分发挥纳米医学的潜力，安全、 必须开发通用且有效的药物输送纳米颗粒，并能够以相关规模生产 用于学习。最近，约翰逊实验室开发了一种刷臂星形聚合物（BASP）系统，可以 在体内和体外成功地以可控比例递送多种不同的治疗剂。 此外，BASP 可以很容易地以公斤级生产，目前正在临床前评估 在小鼠身上进行的试验。在本提案中，我们的目标是创建一系列具有可控功能的新型 BASP，以改变 针对新疾病和组织进行递送的药代动力学特性。使用新的迭代肽 聚合物（IPP）合成技术，我们将能够构建附加 IPP 的 BASP，从而实现完整的 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 的合成过程中，我们将广泛研究其药代动力学特性。通过研究蛋白质电晕 成分、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 我们希望通过推导结构-性质关系来开发可以靶向多种组织的 BASP 不同的机制。迫切需要研究无药载体以更好地了解其基础 在治疗用途或用于疾病模型之前的特性。因为 BASP 可以加载各种 治疗剂（不改变其特性），我们希望最终开发一个技术平台，其中 不同的 BASP 可用于在受控物质中将任何治疗剂递送至任何感兴趣的组织 响应这一需求。为这些系统奠定基础有望创造成功 治疗许多疾病，并作为开发更先进系统的基础。