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

基本信息

项目摘要

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).
摘要

项目成果

期刊论文数量(0)
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Katherine Ann Gallagher其他文献

Macrophage-Specific Genetic Depletion of Cyclooxygenase-2 Improves Diabetic Wound Healing
  • DOI:
    10.1016/j.jamcollsurg.2020.07.704
  • 发表时间:
    2020-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    William J. Melvin;Frank Davis;Chris Audu;Emily Barrett;Aaron DenDekker;Sonya Wolf;Amrita Joshi;Katherine Ann Gallagher
  • 通讯作者:
    Katherine Ann Gallagher

Katherine Ann Gallagher的其他文献

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{{ truncateString('Katherine Ann Gallagher', 18)}}的其他基金

The epigenetic regulation of inflammation in tissue repair and vascular disease
组织修复和血管疾病中炎症的表观遗传调控
  • 批准号:
    10582010
  • 财政年份:
    2023
  • 资助金额:
    $ 49.81万
  • 项目类别:
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:
    10467856
  • 财政年份:
    2022
  • 资助金额:
    $ 49.81万
  • 项目类别:
Translational research training in cardiovascular science
心血管科学转化研究培训
  • 批准号:
    10554828
  • 财政年份:
    2022
  • 资助金额:
    $ 49.81万
  • 项目类别:
Notch signaling in diabetic wounds
糖尿病伤口中的Notch信号
  • 批准号:
    10230763
  • 财政年份:
    2021
  • 资助金额:
    $ 49.81万
  • 项目类别:
Notch signaling in diabetic wounds
糖尿病伤口中的Notch信号传导
  • 批准号:
    10604339
  • 财政年份:
    2021
  • 资助金额:
    $ 49.81万
  • 项目类别:
Targeting jmjd3 mitigates heterotopic ossification
靶向 jmjd3 可减轻异位骨化
  • 批准号:
    10441559
  • 财政年份:
    2021
  • 资助金额:
    $ 49.81万
  • 项目类别:
Notch signaling in diabetic wounds
糖尿病伤口中的Notch信号
  • 批准号:
    10398215
  • 财政年份:
    2021
  • 资助金额:
    $ 49.81万
  • 项目类别:
JMJD3 Regulates Abdominal Aortic Aneurysm Expansion
JMJD3 调节腹主动脉瘤扩张
  • 批准号:
    10374155
  • 财政年份:
    2021
  • 资助金额:
    $ 49.81万
  • 项目类别:
Targeting jmjd3 mitigates heterotopic ossification
靶向 jmjd3 可减轻异位骨化
  • 批准号:
    10315680
  • 财政年份:
    2021
  • 资助金额:
    $ 49.81万
  • 项目类别:
JMJD3 Regulates Abdominal Aortic Aneurysm Expansion
JMJD3 调节腹主动脉瘤扩张
  • 批准号:
    10231799
  • 财政年份:
    2021
  • 资助金额:
    $ 49.81万
  • 项目类别:

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