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

• Applicant: Professor Dr. Ulrich Schatzschneider
• Subject Area: Pharmacy
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 284059745

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.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Professorin Roberta Foresti, Ph.D.