# Photodynamic Therapy--An Up-to-Date Review
## 3 Photosensitizers  
One of the essential components of PDT, apart from light and oxygen, is the presence of photosensizers. These substances' intrinsic properties determine their therapeutic efficiency as PSs can absorb light of a specific wavelength and trigger photochemical or photophysical reactions [7; 32; 36]. An ideal PS should be chemically pure and uniform in composition, be an effective ROS generator, selectively accumulate in the target tissue, be innocuous in the absence of radiation, absorb light in the long-wave part of the spectrum (600-850 nm, a range called \"phototherapeutic window\"), be stable in solution, serum or plasma, be easily eliminated from the organism, and have an economical production route [8; 29; 37; 38; 39]. Photosensitizers were first introduced to the treatment on a commercial scale in the 1970s when Dr. [PERSON] and his colleagues tested the \"hematoporphyrin derivative\" (HpD), a water-soluble mixture of hematoporphyrin, protoporphyrin, deuteroporphyrin, their derivatives, monomers, dimers and oligomers and their esters [7; 8; 26]. Nowadays, more than 1000 natural and synthetic PSs are known [8] (Table 1), their development facing generations of iterative evolution towards ideal photonic and biological properties [25]. The first generation of PSs relies on various forms of HpDs that have been used upon thousands of patients in clinical trials for over 30 years [26]. The first clinically approved PS is commercially known as Photofrin(r) (Axcan Pharma, Mont-Saint-Hilaire, QC, Canada) and has been involved in treating several types of cancer, such as non-small lung, bladder, esophageal, and brain cancer [31; 40]. However, despite their wide application, first-generation PSs have a series of disadvantages. These PSs have a low chemical purity and can be efficiently activated only using wavelengths below 640 nm, limiting tissue penetration. Moreover, the long half-life of PSs renders the skin hypersensitive to light for several weeks, requiring patients treated with them to stay in a dark room for up to 6 weeks. To overcome these limitations, developing a new generation of PSs became imperative [7; 26]. Therefore, in the late 1980s, the next generation of photosensizers started being studied [7; 26]. Second-generation PSs consist of pure synthetic compounds with an aromatic macrocycle (e.g., porphyrins, benzoporphyrins, chlorins, bacteriochlorins, and phthalocyanines) [28]. PSs that are either clinically approved or were/are currently undertaking  
Figure 2: Schematic representation of photodynamic therapy (PDT) mechanism. Created based on literature references [2; 7; 8; 18; 26; 27; 28; 32; 33; 34; 25]. clinical trials include temporofin (Foscan(r), Biolitec, Gina, Germany), motexafin lutetium (Lutex(r), Pharmacylics, Sunnyvale, CA, USA), palladium bacteriophageophophorbide (Tookad(r)soluble, Negma-Lerads, Elancourt, France), tin ethyl etiopurpurin (Purlytin(r), Miravant, Santa Barbara, CA, USA), verteroporin (Visudyne(r), Novartis, Basel, Switzerland), talaporfin (Laserphyrin(r), Meiji Seika, Tokyo, Japan) [31]. In contrast with first-generation PSs, these porphyrinoid compounds allow a better tumor specificity and penetration to deeply located tissues, as their absorption spectrum is in the range of 650-800 nm. Moreover, they have a faster elimination from the body, resulting in fewer side effects and reduced time (under 2 weeks) spent by the patient in a dark room. However, their major drawback comes from their poor water solubility. This property causes second-generation PSs to aggregate under physiological conditions, reducing the yield of ROS production. The hydrophobic nature is also a limiting factor for intravenous administration, forcing the search for new drug delivery methods [7; 26]. Hence, developing another generation of photosensizers was needed to facilitate delivery and cell uptake and improve the therapeutic outcomes [41]. The development of the third-generation PSs primarily focuses on synthesizing structures with higher affinity for the target cells [7] (Figure 3).