CARBON MONOXIDE-RELEASING MOLECULES (CO-RMs) AS THERAPEUTIC AGENTS TO PROMOTE WOUND HEALING – CO-HEAL

Chronic wounds are a major healthcare problem associated with high hospitalization costs and morbidity, affecting particularly diabetic patients. Apart from wound dressings and antibiotics, there is presently very limited choice for the medical community when deciding which drug therapy to employ for promoting wound repair. Wound healing consists of three overlapping phases that include inflammation, new blood vessel formation (angiogenesis), and tissue remodelling. This complex process involves a number of cell types, including neutrophils and macrophages, fibroblasts, keratinocytes and endothelial cells, all of which co-ordinately repair and regenerate the damaged tissue. Emerging findings reveal that 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 indicate that the HO-1/CO pathway can be seen as essential in the restoration of cellular homeostasis and thus may have an important role in the 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, supporting the concept that interventions aimed at amplifying the HO-1/CO pathway are useful strategies to improve wound healing. The advent of CO-releasing molecules (CO-RMs), a class of compounds that deliver precise amounts of CO to tissues and have been demonstrated by the French coordinator to exert 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 develops around two major areas, namely the synthesis and optimization of novel photoactivable CO-RMs and CO-RMs nanomaterials for topical applications and studies on the pro-healing actions of these substances in vitro and in vivo. The following objectives will be pursued. In Objective 1 we will design and characterize new CO-RMs that are triggered by light to release CO and CO-RMs nanomaterials that will maximize the delivery, efficacy and specificity of CO. In Objective 2 we will study the effect of these molecules 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 CO-RMs will also be assessed in diabetes-like conditions (cells cultured under high glucose and hypoxia). In Objective 3 the most promising CO-RMs 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 proposal. Dr. Foresti and Dr. Schatzschneider complement each other because of their mutual interest in CO-RMs and their therapeutic applications. The topical use of CO-RMs specifically tailored for the treatment of wounds is certainly a novel technological approach to tackle and the major task of the proposal. Furthermore, this joint proposal is well balanced since it combines the complementary expertise of Dr. Foresti on the pharmacological properties of CO-RMs and that of Dr. Schatzschneider on the synthesis of new photoCORMs and CO-RMs nanocarriers. The two partners are recognized leaders in Europe and possess the know-how necessary for the success of this research proposal. Thus, this international collaboration represents a true competitive advantage in the field.