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： 药物输送代表了纳米医学领域中具有巨大潜力的平台。交付 直接对靶细胞的治疗剂可以大大减少治疗所需的剂量并消除 不需要的副作用和向脱靶组织传递。为了充分意识到纳米中的潜力 必须开发一般且有效的药物输送纳米颗粒，可以在相关尺度上产生 进行研究。最近，约翰逊实验室开发了一个刷臂聚合物（BASP）系统，可以 在体内和体外成功提供各种不同的治疗剂。 此外，可以在千克尺度上轻松生产BASP，目前正在临床前评估 小鼠试验。在此提案中，我们旨在创建一系列具有可控功能的新颖BASP来改变 用于靶向新疾病和组织的药代动力学特性。使用新的迭代肽 聚合物（IPP）合成技术，我们将能够构建IPP附加的basps，以允许完整 控制大小，电荷，手性，并以与治疗应用相关的尺度生产它们。后 BASP的合成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 我们希望得出结构性的关系，以开发可以通过 不同的机制。需要研究无药载体以更好地了解其基础的需求很高 在疾病模型中使用或使用之前的特性。因为BASP可以加载多种 治疗剂（不会改变其特性），我们希望最终开发一个技术平台 可以使用不同的BASP将任何治疗剂传递给在受控物中感兴趣的任何组织中的任何治疗剂 对此需求的回应。为这些系统建立基础工作将有望创造成功 许多疾病的治疗方法，并成为开发更先进系统的基础。