Macrophage-Targeted Nanocarriers for Localized Treatment of Chronic Inflammation in Diabetic Wounds
Impaired wound healing in diabetes is the leading cause of lower extremity amputation in the United States, resulting in 50% mortality after 5 years. Chronic, localized inflammation is believed to be a causative factor in slow healing in diabetic wounds, and macrophage cells are implicated as primary mediators. In normal wounds, macrophages shift over time from a phenotype that is pro-inflammatory to phenotypes that promote tissue repair, whereas inflammatory phenotypes persist in the diabetic state to inhibit angiogenesis, granulation tissue formation, and wound contraction required for healing. Systemically administered anti-inflammatory agents do not improve healing in the clinic or in preclinical models and in fact further exacerbate healing impairment, likely due to off-target effects in cells in which the drug targets facilitate tissue repair. The scientific premise of this Pilot and Feasibility proposal is that nanocarriers can reroute the delivery of pharmaceutical agents selectively to inflammatory macrophages in wounds after local administration to eliminate off-target effects. Preliminary data show that polysaccharide-based nanocarriers can deliver cyclooxygenase 2 (COX2) inhibitors to potently diminish inflammatory cytokine expression and expedite wound healing in diabetic mouse models. Aim 1 of this proposal is to evaluate formulations that maximize the efficiency of targeted delivery to inflammatory macrophages in wounds using fluorescent and radioisotopically labeled nanocarriers, evaluated ex vivo by flow cytometry and gamma well counting. Aim 2 is to evaluate the efficacy of COX2 inhibitor formulations toward diabetic wound healing and evaluate off-target effects. A fundamental outcome of this work will be an understanding of nanomaterial transport in wounds and receptor-mediated mechanisms to target macrophage subpopulations in wounds. The nanocarrier delivery agents are based on FDA-approved materials already in broad use, which may expedite clinical testing if preclinical evaluations are promising. This work will be undertaken by an interdisciplinary team comprising bioengineers (Smith Lab) who focus on nanomaterial-based drug delivery and imaging agents, and immunologists and vascular biologists (Gallagher Lab) who focus on molecular and cellular mechanisms of diabetic wound healing.

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