Carbon monoxide-releasing molecules as therapeutic agents to promote wound healing

慢性伤口是与高住院费用和发病率相关的主要医疗保健问题，特别是对于糖尿病患者。 除了伤口敷料和抗生素之外，目前在决定采用哪种药物治疗来促进伤口修复时，选择非常有限。通常，伤口愈合由三个重叠的阶段组成，包括炎症、新血管形成和组织重塑。新的研究结果表明，血红素加氧酶-1 (HO-1) 的激活可能是伤口愈合过程中非常相关的途径。这种酶将血红素降解为铁、胆绿素和一氧化碳 (CO)，一氧化碳是细胞抵抗氧化应激和损伤所必需的普遍存在的信号分子。确凿的证据表明 HO-1/CO 途径对于恢复细胞稳态至关重要，因此可能在愈合和修复过程中发挥重要作用。研究发现，受伤后 HO-1 在皮肤中高度表达，并且使用 HO-1 抑制剂治疗可延迟伤口闭合。相比之下，角质形成细胞中过度表达 HO-1 的小鼠表现出新血管形成的改善和伤口愈合的加速。 CO 释放分子 (CORM) 是一类能够向组织输送精确量的 CO 并发挥有益和抗炎作用的化合物，它的出现为利用 CO 治疗这种疾病提供了一种非常有前景的技术。在这里，我们提出了一种综合研究方法，重点关注两个主要领域，即用于局部应用的新型光敏CORM和CORM纳米材料的合成和优化，以及这些系统在体外和体内的促愈合作用的研究。我们将合成并表征由低能红光触发释放 CO 的新 CORM 以及 CORM 纳米材料，以最大限度地提高 CO 的递送、功效和特异性。我们希望研究这些系统在调节与伤口愈合相关的过程中的作用，例如角质形成细胞/成纤维细胞增殖和迁移、内皮细胞的血管生成活性以及巨噬细胞的炎症。这些新型 CORM 的功效也将在类似糖尿病的情况下进行评估。最有前途的 CORM 将作为新型外用制剂进行体内测试，以刺激正常和糖尿病小鼠的伤口愈合。化学、细胞生物学和药理学合作伙伴的多学科性质和专业知识清楚地代表了该项目的实力和附加值。局部使用专为治疗伤口而设计的 CORM 是一种新颖的技术方法，也是该项目的主要任务。这两个合作伙伴是欧洲公认的领导者，拥有该研究项目成功所需的所有专业知识。因此，他们的国际合作不仅代表了附加值，而且代表了推进 CORM 治疗应用的真正竞争优势。

Chronic wounds are a major healthcare problem associated with high hospitalization costs and morbidity, in particular in diabetic patients. Apart from wound dressings and antibiotics, there is presently very limited choice when deciding which drug therapy to employ for promoting wound repair. Normally, wound healing consists of three overlapping phases that include inflammation, new blood vessel formation, and tissue remodelling. Emerging findings reveal that activation of heme oxygenase-1 (HO-1) might be a very relevant pathway in the context of wound healing. This enzyme degrades heme to iron, biliverdin and carbon monoxide (CO), a ubiquitous signalling molecule necessary for cells to counteract oxidative stress and injury. Corroborating evidence indicates that the HO-1/CO pathway is essential in the restoration of cellular homeostasis and thus may have an important role in healing and repair processes. HO-1 has been found to be highly expressed in the skin after wounding and treatment with an HO-1 inhibitor delayed wound closure. In contrast, mice over-expressing HO-1 in keratinocytes displayed an improved neovascularisation and accelerated wound healing. The advent of CO-releasing molecules (CORMs), a class of compounds that deliver precise amounts of CO to tissues and exerting beneficial and anti-inflammatory effects, provides a very promising technology for the therapeutic exploitation of CO in this disorder. Here we propose a comprehensive research approach that focuses on two major areas, namely the synthesis and optimization of novel photoactivable CORMs and CORMs nanomaterials for topical applications and studies on the pro-healing actions of these systems in vitro and in vivo. We will synthesize and characterize new CORMs that are triggered by low-energy red light to release CO as well as CORM nanomaterials that will maximize the delivery, efficacy and specificity of CO. We want to study the effect of these systems in modulating processes relevant to wound healing such as keratinocytes/fibroblast proliferation and migration, angiogenic activity of endothelial cells, and inflammation in macrophages. The efficacy of these novel CORMs will also be assessed in diabetes-like conditions. The most promising CORMs will be tested in vivo as novel topical agents to stimulate wound healing in normal and diabetic mice. The multidisciplinary nature and the expertise of the partners in chemistry, cell biology and pharmacology clearly represent the strength and added value of this project. The topical use of CORMs specifically tailored for the treatment of wounds is a novel technological approach and the major task of the project. The two partners are well-recognized leaders in Europe and possess all know-how necessary for the success of this research project. Thus, their international collaboration not only represents an added value but a true competitive advantage to advance therapeutic application of CORMs.