*2.1.2 Light source*

The light of a particular wavelength, where the PS has a very good ε value plays an important role in PDT. The selection of light source was done by considering other

#### **Figure 3.**

*Comparative tissue penetration ability of different wavelengths of light [25].*

factors also, such as the target location, photosensitizer used, and fluence rate of light (*i.e.,* number of photons per unit area) (**Figure 3**). A stable light source with excellent conformity helps in targeted PDT by enhancing tumor control impact and reducing collateral damage to nearby tissues. Uniform lighting can be obtained by mounting micro-lens or diffusing cover on the tip of optical fibers [26, 27]. **Figure 3** demonstrates different wavelength lights and their tissue penetration ability [25].

#### *2.1.3 Tissue oxygen*

The third major component in PDT is molecular oxygen. In many cases, reduced blood flow to grown tumors leads to hypoxia [28]. Molecular oxygen is one of the important components in therapy to produce ROS. There are two methods to increase the availability of oxygen in an affected specific area, *that is*, indirect and

*Porphyrinoid Photosensitizers for Targeted and Precise Photodynamic Therapy: Progress… DOI: http://dx.doi.org/10.5772/intechopen.109071*

direct introduction of oxygen. Conversion of intracellular hydrogen peroxide to oxygen by enzyme catalysis and to combat tumor hypoxia, oxygen carriers such as perfluorocarbons and hemoglobin are frequently introduced into photodynamic therapy [29].

#### **2.2 History of PDT**

The process of PDT entails selectively making tissues light-sensitive. From antiquity to the current era, light has been used as a therapeutic aid in medicine and surgery. Ancient Greece, Egypt, and India, all had phototherapy, but it was lost for many centuries before being rediscovered by western civilization around the turn of the twentieth century [8, 30, 31].

The Danish doctor Niels Finsen was the first to describe the use of modern phototherapy. To cure Lupus vulgaris, a skin disorder caused by tuberculosis, he used Finsen Lamp, a heat-filtered carbon-arc lamp, to effectively demonstrate photodynamic therapy. In 1903, he won the Nobel prize in medicine [30].

Oscar Raab, a student of Professor Hermann Von Tappeiner from Munich in 1901, was the first who described the idea of phototoxicity caused by the interaction of light and acridine orange. He observed the fatal effects of light and acridine orange combination on paramecium species (malaria-causing protozoa). Following the initial reports, PDT research found additional possible photosensitizers, primarily those connected to porphyrins. The timeline to PDT is explained very well in **Figure 4** [32, 33].

**Figure 4.** *Roadmap to photodynamic therapy.*

Later research in Von Tappeiner's lab popularized the term "Photodynamic action" and demonstrated the significance of oxygen in PDT. In 1907, Tappeiner first proposed the name "*Photodynamic therapy"* in one of his books to describe the process of oxygen-dependent photosensitization. Before 1907 itself, the group recorded the fluorescence of porphyrins from tumors, and tumor targeting through PDT was achieved [34, 35]. During the 1970s, T. Dougherty studied the photosensitizing ability of Fluorescein diacetate [8, 16]. Then K. Weishaupt and T. Dougherty discovered the requirement of singlet oxygen during the process of PDT [36]. Thus, in the initial days, more efficiently singlet oxygenproducing molecules with better deep skin penetration capacity were used as photosensitizers.

The scientist Hans Fischer got a Nobel prize in 1930 for his research on the synthesis of hemin and chlorophyll [37, 38]. Later, T. Dougherty rediscovered the potentials


#### **Table 1.**

*List of PSs approved clinically and reached until the clinical trial for PDT.*

#### *Porphyrinoid Photosensitizers for Targeted and Precise Photodynamic Therapy: Progress… DOI: http://dx.doi.org/10.5772/intechopen.109071*

of hematoporphyrin derivatives (HpD), which is also having singlet oxygen-producing capacity and tissue penetrating ability, purified it, and named it Photofrin [8, 10]. A significant development in the realm of photodynamic treatment was the Canadian health protection branch's 1993 approval of Photofrin (porfimer sodium) as PS in PDT. Later, Photofrin was approved by the FDA and other organizations, mostly for the treatment of lung and esophageal cancer. Recently, numerous trials involving this specific chemical have also been ongoing. Several nations, including the US, Japan, the Netherlands, China, and India, have approved additional substances, such as 5-aminolaevulinic acid (ALA), its esters, and benzoporphyrin derivatives.

Modern classifications of photosensitizers include first-, second-, and thirdgeneration photosensitizers. Hematoporphyrin derivatives (HpD), including its purified form Photofrin II, are considered first-generation. The HpD showed higher absorption (ε) in the lower wavelength region, and they showed relatively less tumor localization after purification. The second-generation PS has a well-defined chemical structure and improved absorption in the red region spectrum. They are Levulan, Foscan, Visudyne, texaphyrin, and protoporphyrin IX (PpIX), etc. Most of them have porphyrinoid structures. Another most commonly used prodrug in this class is the precursor of PpIX, named δ-aminolaevulinic acid (ALA) and its ester derivatives. Third-generation PS is in pipeline and going through the development stage and clinical trials. Few of them are PS with targeting ability formulated in nanoparticles and have NIR absorption and emission ability, for example, various chlorin e6 (Ce6) based nanoparticles [39]. Chlorin-based photosensitizers are gaining a lot of importance due to their ability to show better absorption in the red region, for example, photochlor, a chlorin-based PS under clinical trial (**Table 1**). Recently, PK Panda et al. reported a class of contracted chlorins with very good singlet oxygen quantum yield and better *in-vitro* PDT ability [49, 50].

The PDT was the new moniker given to it by Jhon Toth. For the treatment of precancerous skin lesions on the scalp and face, PDT become an efficient non-invasive, inexpensive targeted therapy approach in recent years. Used to treat different diseases

#### **Figure 5.**

*Advances in PDT based on nano-platforms, by functionalized nanomaterials integrated with photosensitizers toward enhanced efficacy by tumor-selectivity of photodynamic therapy [9].*

like cancer, acne vulgaris, periodontitis, age-related muscular degeneration, high-grade dysplasia, etc. [51] PDT has reached a higher level now, extending up to the introduction of phototheranostics, and nano photodynamic immunotherapy for disease mitigation. The role of targeting tumors to induce the PDT effect is shown in **Figure 5** [9].

Photofrin, an oligomer of hematoporphyrin derivative (HpD), was approved as the first porphyrinic photosensitizer for treatment (**Table 1**) [52]. These are the least polar compounds that are comparable with hematoporphyrin and showed a high tumor localizing capacity. Soon, later sodium porfimer (Photofrin II), was approved worldwide and replaced the above HpD because of its stability and purity. The efficiency of PDT relays on complex dosimetry. PDT can treat various types of cancers, such as skin, breast, bladder, glioblastoma, and lung cervical. PDT is used widely in cancer therapy as it is a non-invasive, targetable, cost-effective treatment methodology with less dosing frequency [53].

.In 2011, ALA, a precursor of PpIX, and its esters, specifically methyl 5-aminolevulinate, were approved for the treatment of actinic keratosis (AK). In 2016, the FDA approved ALA 10% gel for AK in the face and scalp. The FDA approved 5- ALA for PDT applications in the treatment of high-grade gliomas (HGG) in 2017. The 5- ALA-assisted fluorescence surgery destroyed more tumors than standard surgery. As a result, ALA was approved as a diagnostic tool. As shown in **Table 1**, two ALA ester derivatives were also approved clinically. In 2020, ALA was approved for the treatment of AK in the neck and trunk, as well as for the treatment of acne vulgaris [54]. In the sphere of research and clinical activities, NIR fluorescence imaging is a bioimaging technology that is rapidly increasing [55]. FDA-approved fluorophores include indocyanine green (800 nm fluorophore) and methylene blue (700 nm NIR fluorophore) [56].
