Photodynamic therapy is based on certain photosensitizers which, under light activation, generate reactive oxygen species (ROS). This serves to cause cytotoxic impacts, with a greater focus on cancer and antimicrobial treatments. The production of ROS is dependent on certain photochemical pathways following the recent research delineating mechanisms into greater depth and advances in designing photosensitizers used to optimize the production of ROS. Upon photons' absorption, a photosensitizer is moved from its singlet state (S₀) to an excited singlet state (S₁). Afterwards, it transforms through intersystem crossing (ISC) into a triple excited state (T₁), and this transition is central to generating ROS.

The excited photosensitizer in the triplet state interacts with molecular oxygen through different mechanisms, namely: Type I and Type II photochemical pathways. The Type II mechanism is where the energy shift from the triplet photosensitizer to the molecular oxygen (N237;1;override) generates a highly reactive singlet oxygen (¹O₂). ¹O₂ is poison in that cell damage is mainly enabled through oxidative harm caused to vital cellular components such as lipids, nucleic acids, and proteins. Although there is a high level of reactivity, singlet oxygen has a limited diffusion distance and lifetime, which confines adverse impacts to the photosensitizer's immediate vicinity, hence enhancing spatial specificity within Photodynamic Therapy (PDT). In the Type I mechanism, there is a transfer of electrons or hydrogen from the photosensitizer to the substrate or oxygen, and this results in the genesis of radical species like superoxide anion (O₂⁻•), hydroxyl radicals (•OH), and hydrogen peroxide (H₂O₂) (Allison & Moghissi, 2013).

These radicals start a cascade of oxidative reactions, which eventually leads to cell demise. The balance between Type I and Type II mechanisms is dependent on the photosensitizer's electron properties, environmental conditions, and temperature. The latest advances focus on designing photosensitizers that prefer efficient ISC and maximize the output of ROS. Triplet state generation and ROS output efficiency is augmented by heavy atomic integration, rigid molecular frameworks, and donor-acceptor structures (Zhao et al., 2021). Innovatively, nanostructured photosensitizers and precise delivery strategies can be deployed to optimize ROS-mediated therapeutic outcomes by augmenting cellular uptake and localization (Zhou et al., 2022).

In brief, during the Photodynamic Therapy (PDT), photosensitizers derive the ROS primarily via Type I and Type II photochemical pathways involving their triplet excited state. Advances in the strategies and delivery systems employed for photosensitizers continue to aid in augmenting therapeutic impacts and ROS generation efficiency.

References:

Allison, R. R., & Moghissi, K. (2013). Oncologic photodynamic therapy photosensitizers: A clinical review. Photo-diagnosis and Photodynamic Therapy, 10(4), 301–311.

Zhao, J., Wu, W., Sun, J., & Guo, S. (2021). Triplet photosensitizers: from molecular design to applications. Chemical Society Reviews, 50(7), 4185–4219.

Zhou, Z., Song, J., Nie, L., & Chen, X. (2022). Reactive oxygen species generating systems meeting challenges of photodynamic cancer therapy. Chemical Society Reviews, 51(9), 3081–3108.

Photodynamic therapy (PDT) relies on light-activated molecules called photosensitizers (PS) to produce cytotoxic reactive oxygen species (ROS), which induce oxidative stress and cell death in targeted tissues. The process begins when the photosensitizer absorbs light of a specific wavelength, promoting it from the ground state (S₀) to an excited singlet state (¹PS). Due to its short lifetime, ¹PS undergoes intersystem crossing (ISC) to form a more stable excited triplet state (³PS*). This triplet state is crucial for ROS generation, as it can interact with surrounding molecules through two primary pathways: Type I (electron transfer) and Type II (energy transfer) reactions.

In Type I reactions, the triplet-state photosensitizer (³PS*) directly transfers an electron or hydrogen atom to a substrate (e.g., cellular biomolecules or molecular oxygen). This generates free radicals such as the superoxide anion (O₂⁻•), which can further react to form hydrogen peroxide (H₂O₂) and the highly reactive hydroxyl radical (•OH) via enzymatic or metal-catalyzed reactions (e.g., the Fenton reaction). These radicals cause oxidative damage to lipids, proteins, and DNA, contributing to cell death.

In contrast, Type II reactions involve energy transfer from ³PS* to ground-state triplet oxygen (³O₂), producing singlet oxygen (¹O₂), a highly reactive and cytotoxic species. Singlet oxygen is the primary mediator of PDT-induced cell damage, oxidizing cellular components and triggering apoptosis or necrosis. The dominance of Type I or Type II mechanisms depends on factors such as oxygen availability, photosensitizer properties, and the local microenvironment. For instance, Type II reactions are favored under normal oxygen conditions, whereas Type I mechanisms may become more significant in hypoxic environments.

Additionally, secondary ROS generation pathways may occur, including electron transfer from cellular reductants (e.g., NADH) or photosensitizer self-reactions. The resulting oxidative stress leads to lipid peroxidation, protein denaturation, DNA damage, and activation of cell death pathways, making PDT an effective treatment for cancer, infections, and other diseases.

Understanding these mechanisms is essential for optimizing PDT efficacy, particularly in tailoring photosensitizers and light dosimetry to enhance ROS production while minimizing off-target effects. Future advancements may focus on developing next-generation photosensitizers with improved selectivity and reduced side effects.