Activation of Monocytes and Macrophages by Polymeric Micelles

聚合物胶束激活单核细胞和巨噬细胞

• 批准号: 9182613
• 负责人: RICHARD A GEMEINHART
• 金额: $ 23.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9182613
• 关键词: Adsorption; Adverse effects; Affect; Affinity; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Architecture; Biochemical; Biodistribution; Blood; Blood Cells; Blood Circulation; Cells; Chemistry; Complex Mixtures; Data; Dendritic Cells; Disease; Disease model; Drosophila pros protein; Drug Delivery Systems; Effectiveness; Event; Excision; Exhibits; Exploratory/Developmental Grant; Future; Goals; Half-Life; Human; In Vitro; Incubated; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Interferon Type II; Interleukin-4; Length; Light; Liposomes; Liquid substance; Macrophage Activation; Malignant Neoplasms; Measures; Methods; Micelles; Modeling; Molecular Models; Mononuclear; Mus; Outcome; Particulate; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Phenotype; Plasma; Play; Polymers; Property; Proteins; Proteomics; Recommendation; Reporting; Research; Risk; Role; Route; Serum; Serum Proteins; Shapes; Signal Transduction; Source; Structure; Supplementation; Surface; System; Testing; Therapeutic; Up-Regulation; Work; Wound Healing; absorption; abstracting; base; caprolactone; cell type; cytokine; density; design; ethylene glycol; expectation; improved; in vitro Assay; in vivo; innovation; macrophage; molecular modeling; monocyte; nanoparticle; novel; particle; premature; research study; response; uptake

Project Summary/Abstract Intravenously administered drug delivery systems, including polymer particles, liposomes, niosomes, and micelles, interact with many blood components that subsequently influence their ability to achieve optimal therapy. Even `stealth' particles absorb proteins that then signal specific biologic responses in cells that they contact. Of particular importance are the signaling events that occur in mononuclear phagocyte system (MPS) cells. It is well established that inflammatory events occur in response to some particle injections. Additionally, there are differences in the phagocytosis response to particles that are related to the proteins that are absorbed to the surface. In recent preliminary experiments, we have examined several micelles some of which exhibit a serum protein dependent anti-inflammation response in macrophages, specifically a surprising up regulation of pro-resolving macrophage markers. Despite similar physical micelle properties (size, shape, ζ- potential, and chemistry), a second micelle type examined elicited a pro-inflammatory (M1 or classically activated) phenotype. We believe this difference in macrophage response is due to the difference in proteins— amount of protein and identity of proteins—that absorb to the surface of micelles from serum. Based upon this observation, we designed this exploratory/developmental grant application (R21) to focus on the goal of improving the design of nanoparticle drug delivery systems, particularly by understanding the monocyte and macrophage response to nanoparticles and their protein corona. Our central hypothesis is that the protein corona can modulate the activation toward both pro-inflammatory (M1) and pro-resolving (M2) macrophage and monocyte phenotypes. To achieve the overall goals of the project, we have designed two aims that will be examined in parallel. In the first aim we will determine and quantify the proteins absorbed by micelles from human plasma and serum (Gemeinhart and Hong). In the second aim, we will measure the response of monocytes and macrophages to micelles (Gemeinhart and Koh). The information obtained from the aims in vitro and in vivo will be correlated to establish recommendations to inform design of micelles and how these criteria can influence the response of monocytes and macrophages. In future work, we will strive to extend this to other MPS cells and examine the influence of these particles in specific disease models.

项目概要/摘要 静脉给药的药物递送系统，包括聚合物颗粒、脂质体、脂质体和 胶束与许多血液成分相互作用，随后影响其达到最佳效果的能力 甚至“隐形”颗粒也会吸收蛋白质，然后在细胞中发出特定的生物反应信号。 特别重要的是单核吞噬细胞系统（MPS）中发生的信号事件。 众所周知，某些颗粒注射会发生炎症反应。 对与蛋白质相关的颗粒的吞噬反应存在差异 在最近的初步实验中，我们检查了几种胶束，其中一些胶束被吸收到表面。 在巨噬细胞中表现出血清蛋白依赖性抗炎反应，特别是令人惊讶的 尽管具有相似的物理胶束特性（大小、形状、ze-），但促解析巨噬细胞标记物的调节。 潜力和化学），检查的第二种胶束类型引起促炎（M1或经典 我们认为巨噬细胞反应的这种差异是由于蛋白质的差异造成的—— 蛋白质的量和蛋白质的特性——从血清中吸收到胶束表面。 观察，我们设计了这个探索性/开发性资助申请（R21）来重点关注以下目标： 改进纳米颗粒药物输送系统的设计，特别是通过了解单核细胞和 巨噬细胞对纳米粒子及其蛋白质冠的反应我们的中心假设是蛋白质。 电晕可以调节促炎 (M1) 和促消解 (M2) 巨噬细胞的激活 为了实现该项目的总体目标，我们设计了两个目标： 在第一个目标中，我们将确定并量化胶束吸收的蛋白质。 人类血浆和血清（Gemeinhart 和 Hong）在第二个目标中，我们将测量 单核细胞和巨噬细胞到胶束（Gemeinhart 和 Koh）中的目标获得的信息。 体外和体内将相互关联，以建立建议，以告知胶束的设计以及这些建议如何 标准可以影响单核细胞和巨噬细胞的反应，在未来的工作中，我们将努力扩展这一点。 到其他 MPS 细胞并检查这些颗粒在特定疾病模型中的影响。