Revealing the propagation of singlet oxygen along double stranded DNA

Nucleic acid-targeting photodynamic therapy (PDT) is an innovative type of targeted therapy that is currently being studied. This treatment is based on photosensitizers, which are drugs that attach to specific regions in a cell’s DNA.

After the cells have been bound, they are irradiated at a specific frequency, which leads the photosensitizer to produce reactive oxygen species (ROS) or singlet oxygen (¹O₂) molecules. These chemicals oxidize neighboring nucleic acids, causing genetic damage and annihilating the irradiated cell.

Even though the entire process appears simple, there are some obstacles to overcome before this type of PDT is suitable for clinical use. One of them is that, while type II oxidation (induced by ¹O₂) has some benefits over type I oxidation (caused by ROS), there is limited knowledge on how far ¹O₂ molecules can travel once produced. Because of this knowledge gap, it is hard to determine which location in the DNA should be targeted to produce the best result.

Investigators from the Tokyo Institute of Technology, Japan, attempted to address this issue in their recent research. The researchers, guided by Professor Hideya Yuasa, used a unique approach to explore how ¹O₂ propagates through double strand DNA and how well it can oxidize neighboring guanine (G) sites depending on the distance to the photosensitizer. The study was published in the journal Scientific Reports.

The researchers created a series of double-stranded DNA molecules containing several G sites at various places relative to the photosensitizer’s anchoring point. They then examined which G sites were regularly oxidized after irradiating the DNA.

It is indeed worth noting that the photosensitizer they employed was based on earlier research guided by Prof. Yuasa. The photosensitizer in this case was a biphenyl group “hanging” from a short, freely rotatable linker attached to thymine, one of the DNA building blocks.

The small size of this photosensitizer, which ensured that ¹O₂ diffusion was not greatly affected, and its surprisingly high tendency to create ¹O₂ solely upon irradiation when compared to other photosensitizers, made it particularly effective for this study.

The researchers identified the optimal distances to the photosensitizer to obtain the maximum oxidation of G after multiple experiments and theoretical studies. Furthermore, they provided insight into specific electronic mechanisms that inhibit G oxidation at places closer to the photosensitizer.

Our study provides information about how ¹O₂ travels along DNA duplexes in more detail than ever, thereby offering clues on how to overcome the low reactivity of type II photooxidation in nucleic acid targeting PDT.”

Hideya Yuasa, Professor, Tokyo Institute of Technology

The observations of this study inch toward next-generation PDT, which could be a powerful tool in the fight against cancer.

Our mapping of the diffusion of ¹O₂ along DNA duplexes will be important to develop efficient and selective photosensitizer agents for PDT. It also serves as an experimental demonstration of the diffusion of particles along a cylindrical surface at the molecular level.”

Hideya Yuasa, Professor, Tokyo Institute of Technology