# Natural Photosensitizers in Clinical Trials
###### Abstract  
Photodynamic therapy (PDT) is a minimally invasive therapeutic method with high selectivity of action. It has gained great popularity in recent years as a new therapy for the treatment of cancer, but is also used in dermatology, ophthalmology, and antimicrobial treatment, among others. The therapeutic regimen involves the administration of a photosensitizer (PS) that selectively accumulates in tumor cells or is present in the blood vessels of the tumor prior to irradiation with light at a wavelength corresponding to the absorbance of the photosensitizer, leading to the generation of reactive oxygen species (ROS). Choosing the right PS is one of the most important steps in PDT and is crucial to the effectiveness of the therapy. Despite the many compounds discovered, the search for new molecules that could fulfill the functions of an optimal photosensitizer and improve the efficiency of PDT is still ongoing. Compounds of natural origin could contribute to achieving this goal. A number of photoactive substances as effective as synthetic photosensizers have been described in various plant and fungal species. With the increasing identification of photoactive natural products, many new photosensizers are expected to emerge. Some have already been clinically tested with promising results. In our work, we provide insights into this research and molecules, analyze their advantages and disadvantages, and point out gaps in current knowledge and future directions for their development. We also present natural photosensizers not yet tested in clinical trials and point out future potential directions for their development. photodynamic therapy; clinical trials; natural photosensizers +
Footnote †: journal: Medical  
stable excited triplet state. From this triplet state, the photosensitizer molecules can return to the ground state by a type I or type II photodynamic reaction. In a type I reaction, the activated photosensitizer transfers an electron to the substrate to form various reactive oxygen species, while in a type II reaction, energy is directly transferred to the molecular oxygen in the ground state, resulting in the formation of highly reactive singlet oxygen [7]. The type I mechanism, through the possibility of gaining or losing an electron, leads to the formation of a radical ion or anion. The generated radical anion has the ability to interact with oxygen, leading to the formation of a superoxide radical anion (O2*-). This process can lead to dismutation, i.e., one-electron reduction in the oxygen radical, resulting in the formation of hydrogen peroxide (H2O2), which in turn can undergo another one-electron reduction, leading to the formation of strong hydroxyl radicals (HO*). The process of producing reactive oxygen species (ROS) through a type II mechanism (which is described under Figure 1) is much simpler than type I. Most photosensitizers used in PDT work mainly through a type II mechanism rather than a type I one. Singlet oxygen and free radicals have specific and short lifetimes (10-320 ns), and their diffusion path in cells is only 10-55 nm [8]. The selection of an appropriate photosensitizer is the basis for the effectiveness of photodynamic therapy. The most commonly used PSs in medicine are porphyrins and their derivatives, phthalocyanines and their derivatives, and chlorines and their derivatives [9]. At the same time, new PSs are constantly being discovered to establish a compound with suitable therapeutic properties [10; 11; 12]. The mechanism of photodynamic action is presented in Figure 1.  
Figure 1: The general mechanisms of photodynamic action and type II reaction. The process occurs in several steps. A photosensitizer (PS) is administered to the patient and accumulates in the target tissue. This tissue is then irradiated with light of a certain wavelength, which is absorbed by the PS. After absorbing the photons, the PS goes from a ground (singlet) state to an excited (triplet) state.