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: 9765337
• 负责人: Nathan John Oldenhuis
• 金额: $ 6.03万
• 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 2020-08-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765337
• 关键词: Adoption; 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; Genetic Diseases; Glutamic Acid; Growth; Half-Life; 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; nanoparticle delivery; novel; novel strategies; polymerization; preclinical trial; response; scaffold; side effect; 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： 药物递送在纳米医学领域是一个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极大地减少治疗所需的剂量并消除 不想要的副作用和对非目标组织的传递。为了充分实现纳米医学的潜力，安全， 必须开发通用的、有效的药物输送纳米颗粒，以便能够在相应的规模上生产 为了学习。最近，约翰逊实验室开发了一种刷臂星形聚合物(BASP)系统，该系统可以 成功地在体内和体外以可控的比例输送各种不同的治疗剂。 此外，碱性磷酸酶可以很容易地以公斤为单位生产，目前正在进行临床前评估。 在老鼠身上进行试验。在这项提议中，我们的目标是创建一系列具有可控功能的新型BASP 靶向新疾病和新组织的药代动力学特性。使用一种新的迭代多肽 聚合物(IPP)合成技术，我们将能够构建IPP附加的BASP，这将允许完成 控制大小、电荷、手性，并以治疗应用相关的规模生产它们。之后 BASPS的合成我们将广泛研究它们的药代动力学性质。通过研究蛋白质日冕 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 我们希望通过推导结构-性质关系来开发可以通过以下方式靶向各种组织的BASPs 不同的机制。对无毒品携带者的研究需求很高，以更好地了解他们的基础 在治疗性使用或用于疾病模型之前的特性。因为BASP可以装载各种 治疗剂(不改变其性质)，我们希望最终开发出一种技术平台， 不同的BASP可用于将任何治疗剂输送到在受控物质中感兴趣的任何组织 对这一需求的回应。为这些系统奠定基础将有望创造成功 治疗多种疾病，并作为开发更先进系统的基础。