## 2 Photosensitizers  
Most photosensitizers are based on the tetrapyrrole structure, presenting unique photodynamic and photoddiagnostic abilities [10; 11]. Other common photosensitizers present the chemical structure of phenothiazze dyes (like toluidine and methylene blue), cyanines, and polycyclic aromatic compounds (like hypericin) [11]. Among tetrapyroles, portimer sodium (Photofrin) was the first photosensitizer used in clinical practice. From the synthetic point of view, it allows modifications and structural changes in peripheral pyrrol positions that can lead to new macrocycles [42]. However, its outcome is limited by the low absorption coefficient at 630 nm, the need for high fluence (100 to 200 J/cm\({}^{2}\)), long exposures, low solubility in polar solvents, and intravenous administration [10; 19; 42; 43]. High persistence in some tissues is associated with prolonged patient photosensitivity [44; 45; 46]. Portimer sodium and other hematoporphyrins constituted the first generation of photosensitizers. The second generation includes photosensitizers like hypericin and benzoporphyrin derivatives and other porphyrins, chlorins, bacteriochlorins, and phthalocyanines. These are more optimized molecules with higher purity, higher absorption in the therapeutic window (600-800 nm, Figure 2B), and higher ROS yields [10]. Temoporfin (meta-tetra(hydroxyphenyl)chlorine, mTHPC) was introduced in the European Union in 2001 under the name Foscan as a palliative or local treatment for patients with advanced head and neck cancer who did not respond to previous therapies and who were not indicated for chemotherapy or radiotherapy [47]. With an absorption band at a deeper penetrating wavelength (652 nm) and a high singlet oxygen yield, it was considered 100 times more effective than first-generation photosensitizers [48]. Despite the advantages from a photochemical point of view, there were weaknesses associated with its clinical application. Excessive lighting can result in fibrosis, scarring, and fistulas, and it can take up to six weeks to be eliminated [33; 49]. The benzoporphyrin derivative monoacid ring A (BPD-MA, Verteporfin, Visudyne), initially developed to treat macular degeneration, presents advantages in cancer treatment. It has absorption at 690 nm and is quickly eliminated, avoiding cutaneous photosensitization [50]. The mono-L-aspartyl chlorin e6 (NPe6, Talaporfin sodium, Laserphyrin) is water-soluble, has an absorption band at 664 nm, and has a high singlet oxygen yield. Despite a low accumulation period in neoplastic tissue, patients may experience prolonged skin photosensitivity [33; 51]. This photosensitizer is approved in Japan to treat superficial squamous cell carcinoma of the lung [33; 51; 52; 53]. As a precursor of protoporphyrin IX, 5-ALA (5-aminolevulinic acid) is a pro-drug metabolized through the heme pathway. Protoporphyrin IX activation wavelength is at 630 nm. The rapid clearance within 12 h results in a short photosensitivity period [10]. 5-ALA was frequently administered topically to treat actinic keratosis, basaliomas, and cutaneous T-cell lymphomas [54; 55; 56; 57]. Still, due to hydrophilic characteristics, 5-ALA's ability to penetrate the skin is limited [10]. Methyl and benzyl esters of 5-ALA overcome this limitation [58; 59], being used to treat actinic keratosis and basaliomas and photodiagnosis of bladder neoplasms [10; 60]. BODIPYs are highly photoactive agents that arose as potentially interesting photosensitizers and also for cancer theragnostics [61]. In addition to their high fluorescence potentially enabling image-guided PDT, they also demonstrated high ROS generation ability [62; 63]. The accumulations of first- and second-generation photosensitizers can reach 5:1 in neoplastic tissues compared to normal tissues [64]. Nevertheless, the mechanisms behind this effect are still questionable [10].