Nanomedicine-Based Targeting of Inflammatory Macrophages in Diabetic Wound Repair

基于纳米药物的炎症巨噬细胞靶向治疗糖尿病伤口修复

• 批准号: 10631233
• 负责人: Katherine Ann Gallagher
• 金额: $ 49.81万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631233
• 关键词: Acute; Address; Amputation; Animal Model; Anti-Inflammatory Agents; Biomedical Engineering; Caring; Cell Therapy; Cell physiology; Cells; Cellular Immunology; Cellular biology; Chemistry; Chronic; Clinic; Clinical; Clinical Research; Complex; Coxibs; Data; Debridement; Dextrans; Diabetes Mellitus; Diabetic mouse; Dinoprostone; Distant; Drug Carriers; Drug Delivery Systems; Drug Targeting; Engineering; Ensure; Evaluation; Exhibits; Expenditure; Failure; Flow Cytometry; Fluorescence Microscopy; Formulation; Goals; Granulation Tissue; Growth Factor; Human; Hydrogels; Image; Immune; Impaired healing; Impaired wound healing; Impairment; Infection; Inflammation; Inflammation Mediators; Inflammatory; Lower Extremity; Macrophage; Measures; Mediating; Molecular Immunology; Molecular Target; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Outcome; PTGS2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Polysaccharides; Pre-Clinical Model; Process; Prostaglandins; Radioisotopes; Reactive Oxygen Species; Regulation; Regulatory Pathway; Reporting; Risk Factors; Role; Route; Test Result; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Translating; Translations; Treatment Efficacy; United States; Vasodilator Agents; Work; Wound models; acute wound; angiogenesis; chronic wound; clinical translation; cytokine; diabetic; diabetic patient; diabetic ulcer; diabetic wound healing; drug development; drug release kinetics; efficacy evaluation; extracellular; healing; imaging agent; imaging probe; immunoregulation; in vivo; inhibitor; lead candidate; molecular pathology; monocyte; mouse model; multimodality; nanocarrier; nanoengineering; nanolabel; nanomaterials; nanomedicine; non-diabetic; non-healing wounds; novel; nuclear imaging; pathogen; patient population; pharmacologic; pre-clinical; preclinical development; prevent; primary outcome; radiopharmacology; receptor; recruit; release factor; repaired; research clinical testing; side effect; standard of care; systemic toxicity; targeted delivery; targeted imaging; therapeutic target; tissue repair; uptake; wound; wound closure; wound healing

ABSTRACT The inability of wounds to heal in diabetic patients is the leading cause of lower extremity amputation in the United States. Chronic, localized inflammation is believed to be a causative factor in the slow healing of diabetic wounds, and macrophage cells are implicated as primary mediators of this inflammation. In non-diabetic patients, macrophages are initially in a pro-inflammatory state in wounds and shift over time to an anti-inflammatory phenotype that promotes tissue repair. In diabetic patients, the inflammatory macrophage phenotype persists, resulting in impairment of angiogenesis, granulation tissue formation, and wound contraction required for healing. Systemically administered pharmacological agents that are anti-inflammatory or immunomodulatory do not improve healing in the clinic or in preclinical animal models and, in fact, further impair healing, likely due to off- target effects in other immune or structural cells that facilitate tissue repair. This proposal focuses on the development of drug carriers based on targeted nanomaterials to reroute the delivery of pharmacological agents selectively to inflammatory macrophages in wounds after local administration to eliminate off-target effects. We are particularly focused on inhibiting overactive pathways that generate inflammatory prostaglandins. In our preliminary data, we show that polysaccharide-based nanocarriers can deliver cyclooxygenase 2 inhibitors to wound macrophages to potently diminish inflammatory cytokine expression and expedite wound healing in diabetic mouse models. Aim 1 of this proposal is to optimize formulations that maximize the efficiency of targeted delivery to inflammatory macrophages in wounds using fluorescent and radioisotopically labeled nanocarriers, evaluated in vivo by nuclear imaging and ex vivo by flow cytometry, gamma well counting, and fluorescence microscopy. Aim 2 is to optimize the efficacy and drug release rate of a therapeutic formulation that targets different regulatory pathways of prostaglandin synthesis toward diabetic wound healing. Aim 3 is to evaluate efficacy and off-target effects in multiple murine acute and chronic wound healing models of type 2 diabetes, as well as monocyte-derived macrophages from diabetic patients. Fundamental outcomes of this work will be an understanding of nanomaterial transport in wounds and receptor-mediated mechanisms to target macrophage subpopulations, as well as an understanding of the role of prostaglandin-driven inflammatory processes in macrophages within diabetic wounds. The nanocarrier delivery agents are based on materials already in broad clinical use, which may expedite clinical testing of the resulting therapeutic agents if preclinical results are promising. This work will be undertaken by an interdisciplinary team comprising bioengineers (Andrew Smith Lab) who focus on nanomaterial-based drug delivery and imaging agents, experts in molecular and cellular immunology and mechanisms of diabetic wound healing (Katherine Gallagher Lab), and experts in nuclear imaging and radiopharmacology (Wawrzyniec Dobrucki Lab).

抽象的 糖尿病患者的伤口无法治愈的是下肢截肢的主要原因 美国。慢性局部炎症被认为是糖尿病缓慢愈合缓慢的因素 伤口和巨噬细胞被视为这种炎症的主要介体。在非糖尿病患者中 巨噬细胞最初处于伤口的促炎状态，随着时间的流逝转移到抗炎 促进组织修复的表型。在糖尿病患者中，炎症性巨噬细胞表型持续存在， 导致血管生成，肉芽组织形成和愈合所需的伤口收缩。 抗炎或免疫调节的全身施用的药理学剂 改善诊所或临床前动物模型中的愈合，实际上，进一步损害了愈合 靶向促进组织修复的其他免疫或结构细胞中的靶标。该提议重点是 基于靶向纳米材料的药物携带者的开发以重新布局的药理剂的递送 在地方给药后，在伤口中有选择地对炎症性巨噬细胞，以消除脱靶效应。我们 特别专注于抑制产生炎症性前列腺素的过度活跃途径。在我们的 初步数据，我们表明，基于多糖的纳米载体可以将环氧合酶2抑制剂传递给 伤口巨噬细胞有效地减少炎症细胞因子的表达并加快伤口愈合 糖尿病小鼠模型。该建议的目标1是优化最大化目标效率的配方 使用荧光和放射性化标记的纳米载体中的伤口中的炎症巨噬细胞递送， 通过核成像在体内通过流式细胞仪，伽马孔计数和荧光评估 显微镜。 AIM 2是优化针对的治疗配方的功效和药物释放率 前列腺素合成对糖尿病伤口愈合的不同调节途径。目标3是评估 2型糖尿病的多种鼠急性和慢性伤口愈合模型的功效和脱靶作用 以及来自糖尿病患者的单核细胞衍生的巨噬细胞。这项工作的基本结果将是 了解靶向巨噬细胞的伤口和受体介导的机制中的纳米材料转运 亚群，以及对前列腺素驱动过程中的作用的理解 糖尿病伤口内的巨噬细胞。纳米载体输送剂基于已经广泛的材料 临床用途，如果临床前结果为 有希望的。这项工作将由一个由生物工程组成的跨学科团队（安德鲁·史密斯（Andrew Smith））进行 实验室）专注于纳米材料的药物输送和成像剂，分子和细胞专家 糖尿病伤口愈合的免疫学和机制（凯瑟琳·加拉格尔实验室）和核专家 成像和放射药学（Wawrzyniec Dobrucki Lab）。