Controlled Oxygen Release from Pyridone Endoperoxides Promotes Cell Survival under Anoxic Conditions

Abstract

In tissue engineering, survival of larger constructs remains challenging due to limited supply with oxygen caused by a lack of early vascularization. Controlled release of oxygen from small organic molecules represents a possible strategy to prevent cell death under anoxic conditions. A comprehensive study of methylated pyridone-derived endoperoxides has led to the development of water-soluble molecules that undergo retro Diels-Alder reactions in aqueous environment releasing oxygen in high yield and with half-lives of up to 13 hours. These molecules in combination with vitamin C as singlet oxygen quencher significantly improved survival of 3T3 fibroblasts and rat smooth muscle cells challenged with oxygendepleted conditions. ABSTRACT. In tissue engineering, survival of larger constructs remains challenging due to limited supply with oxygen caused by a lack of early vascularization. Controlled release of oxygen from small organic molecules represents a possible strategy to prevent cell death under anoxic conditions. A comprehensive study of methylated pyridone-derived endoperoxides has led to the development of water-soluble molecules that undergo retro Diels-Alder reactions in aqueous environment releasing oxygen in high yield and with half-lives of up to 13 hours. These molecules in combination with vitamin C as singlet oxygen quencher significantly improved survival of 3T3 fibroblasts and rat smooth muscle cells challenged with oxygen-depleted conditions.

Oxygen delivering biomaterials for tissue engineering

“…To address this concern, Benz et al incorporated endoperoxides into small organic molecules for oxygen release. 78 When in contact with water, these molecules release oxygen via a retro Diels-Alder reaction. The endoperoxides were added into solution at various concentrations, achieving oxygen release for 8–13 hours.…”

Molecular devices based on reversible singlet oxygen binding in optical and photomedical applications

“…46 Jessen and co-workers reported the controlled release of oxygen from water-soluble methylated pyridone endoperoxides as a method to rescue cells from death under anoxic conditions. 47 These molecules, combined with ascorbic acid as singlet oxygen quencher, allowed survival of 3T3 fibroblasts (FBs) and rat smooth muscle cells (RSM) under oxygen-depleted conditions. In order to study the rate and efficiency of oxygen release from pyridone-derived endoperoxides, a series of substituted 2-pyridones was synthesized and then subjected to photooxygenation in the presence of 5,10,15,20-tetraphenylporphyrin.…”

“…Interestingly, here endoperoxide thermolysis was not accompanied by ring rearrangement, particularly the Kornblum-Delamare reaction, 49 as opposed to the 2-pyridone derivatives studied by Jessen and co-workers. 47 Oxidation of the mustard gas simulant, 2-chloroethyl ethyl sulfide (CEES), by singlet oxygen released in the dark from the molecule 22 was demonstrated, too. Obviously, molecules such as 22, possess significant potential for photomedical applications.…”

Stem Cells in Functional Bladder Engineering

“…Therefore, further TE approaches to improve cell survival after transplantation, e.g. the use of oxygen-releasing biomaterials [93] and scaffold modifications using in vivo light activated adhesive peptides to enhance vascularization [94], have been developed. Such biomaterial-based methods can be combined with primary endothelial cells (ECs) to form pre-vascularized networks to facilitate rapid blood supply in the transplanted tissues [95,96].…”