**1. Introduction**

Photodynamic is defined as the effect of light on living systems in combination with oxygen and chemical reagents. Photodynamic diagnosis (PDD), fluorescenceguided tumor surgery (FGS), and photodynamic therapy (PDT) are most recent types of photodynamic technology. FGS is the use of fluorescence imaging in surgery for defining tumor location and its margins. PDT and PDD are non- or minimally invasive therapeutic and diagnosis techniques. PDD is an effective diagnosis method with a wide application in medical diagnosis including dermatology, gastroenterology, urology, and oncology. Similar to PDT, the mechanism of PDD is based on light and tissue interaction but does not along with the destruction of the lesion. When a specific wavelength of light is irradiated to a tissue, endogenous or exogenous

fluorophores absorb the light energy leading to electrons being raised to an excited state, and subsequent relaxation and returning to the ground state lead to emission fluorescence of a specific wavelength [1–7].

Photodynamic therapy (PDT) is a form of phototherapy and the joint action of nontoxic photosensitizer (PS), a light source, and molecular form of oxygen. The PS, in the presence of oxygen, is activated by a suitable wavelength of light to generate reactive oxygen species (ROS) (**Figure 1**). This phototoxicity leads to oxidative stress and cytotoxicity to elicit cell injury and cell death [5, 8–10]. PDT has been used clinically to treat a wide range of neoplastic and non-malignant diseases with minimal side effects on the surrounding normal cells. PDT was approved by the US Food and Drug Administration as the first drug-device combination for cancer therapy [3, 11]. In addition to oncological diseases, PDT is a very efficient therapeutic modality for non-oncological diseases. Recently, PTD was used as a new approach for elimination of human pathogens too. Microbial infections continue to be an outstanding cause of morbidity and mortality worldwide. The wide utilization of antibiotics and vaccination strategies cannot avert the prevalence of microbial infections. Frequent and immeasurable utilization of antimicrobial drugs may be associated with side effects such as gastrointestinal disorders, liver toxicity, and secondary fungal infections. These factors sternly diminish the therapeutic effect of antimicrobials and develop drug resistance in microbes. By broad monitoring commissioned by the UK Government and Wellcome Trust in 2016, it has been estimated that mortality of antimicrobial resistance will rise to over 10 million worldwide by 2050. Some clinical trial studies have demonstrated that microbial infection could be diminished using PDT techniques. To this, PS as a photodynamic agent suitably is engineered to target the structural elements of microbial cells selectively. Despite PDT advantages, there are some limitations such as effective PS with properties of an ideal PS, leading to reduce the efficacy of PDT. Nanotechnology-based PDT and combination therapy including chemotherapy, radiotherapy (RT), immunotherapy and anti-angiogenesis therapy, hypothermia, and employment of antioxidants and receptor inhibition strategies

#### **Figure 1.**

*Schematic illustration of PDT mechanism. PS reaches to <sup>1</sup> PS\* through absorption of light with specific wavelength. The 1 PS\* undergoes intersystem crossing to an 3 PS\* (an electronically different excited state lower in energy). 3 PS\* generates ROS through interaction with the surrounding biomolecules.*

*Metal-Based Nanomaterials Photodynamic Action with a Focus on Au and Ag Nanomaterials DOI: http://dx.doi.org/10.5772/intechopen.109220*

during PDT are methods to overcome these obstacles. Nanotechnology has garnered a great deal of attention in PDT, due to targeting potential and selective accumulation at the desired site and reduced toxicity to normal cells and tissues, improving the solubility of hydrophobic PSs and controlling the released rate of PSs. Nanoparticles have been used as PSs, conjugating agents, and carriers for PSs, followed by the creation of the fourth generation of PSs [8, 12–15]. This review article addresses the metal nanomaterial-based photodynamic applications in recent years. The main focus of this paper is on the application of silver and gold nanomaterial-based photodynamic therapy in recent years.

## **2. Photosensitizers**

PSs are agents that absorb light of a specific wavelength, triggering the activation processes leading to the selective demolition of the improper cells [9]. Several PSs have already received FDA approval for use in photodynamic treatment for various types of cancer [2]. The physicochemical and biological characteristics of a PS could be summarized as the following: (1) composition uniformity, purity, and negligible of dark toxicity; (2) high clearance from the body patients [12]; (3) excellent solubility in body tissues; (4) stability at room temperature [9]; (5) potent absorption with a high extinction coefficient at near-infrared (NIR) wavelength range (700–1300 nm), where tissue penetration is increased, and the auto-absorption is reduced by other endogenous molecules (such as the hemoglobin); (6) inexpensive, affordable, and easy to synthesize; (7) the capability of high tumor selectivity and subcellular targeting [16].

There are different categorizations for PSs. PSs can be categorized based on their response to NIR light: direct NIR-responsive PSs and indirect NIR-responsive PSs. The direct PSs can directly convert light energy into the production of radical agents, and they are composed of NIR-responsive organic and inorganic PSs. The indirect PSs include UV- or visible light responsive PSs and an up-conversion nanomaterial.

Based on the time of application, PSs are classified into four distinct generation categories. The first generations are based on hematoporphyrin and its derivatives (e.g., Photofrin, Photosan, and Photocan), acridine dyes, and eosin solution. Photofrin (the trade name of sodium porfimer) is a mixture of purified porphyrin dimers and oligomers from hematoporphyrin derivatives. The limitations of the first-generation PSs include low penetration into tissues due to short wavelength of maximum absorption, low chemical purity, long half-life, and high accumulation in the skin that lead to skin hypersensitivity to light leading to investigate the next generation of PSs. The second generation of PSs, which have better chemical purity, consist of hematoporphyrin derivatives, synthetic PSs such as 5-aminolevulinic acid, and pure synthetic compounds of an aromatic macrocycle such as porphyrins, benzoporphyrins, and chlorins. Moreover, PSs of this generation show higher quantum yield of 1 O2 production, better tissue penetration due to maximum absorption in the wavelength of 650–800 nm, improved selectivity for target tissue, and fewer side effects, extended extinction coefficient. Despite such mentioned benefits of secondgeneration PSs, they have poor solubility in water, which limits their intravenous administration.

Third-generation PSs are developed by altering existing PSs from earlier generations and combining them with nanomaterials or substances that have a higher affinity for tumor tissue. These modifications can include combination with target

receptor ligand molecules and LDL lipoprotein, conjugation with a monoclonal antibody specific for cancer cell antigen, and the use of tumor surface markers. Increased selectivity, greater accumulation in the target site, better bioavailability, and reduced therapeutic doses to produce satisfactory therapeutic effects are among the benefits of third-generation photosensitizers [9, 11, 17].

Next generation of PSs are nanomaterial-based PSs and living-organism-derived, protein in the name of genetically encoded photosensitizers (GEPSs) has been developed. GEPSs are more beneficial than synthetic PSs due to their facility intracellular localization, spatiotemporal protein expression, and ROS generation through designing with genetic engineering methods as following selective and controlled expression by using particular promotors, efficient PSs owning to high speeding of intersystem crossing and excited triplet state generation, the study of the mechanisms that occur in living cells by recruitment chromophore-assisted light inactivation (CALI), PDT, correlative light-electron microscopy (CLEM) and photoablation, widely highspecific targeting capability, reducing toxicity by proteolysis and spatiotemporal inactivation of cellular proteins. Due to the mentioned features, GEPS is an effective tool in biomedical applications such as PDT, immune PDT, antimicrobial PDT


#### **Table 1.**

*Fluorescent protein photosensitizers.*


#### **Table 2.**

*Flavin-binding photosensitizers.*

(aPDT), and CALI. Oligomeric and monomeric types of GEPS have been utilized in cellular applications with photophysical features. GEPS-based photosensitizers could be categorized into fluorescent protein photosensitizers (FPPSs) (**Table 1**) and flavin-binding photosensitizers (FBPSs) (**Table 2**) [18].

## **2.1 PDT mechanism**

After light irradiation, PS absorbs a quantum of light and will reach its excited singlet state (1 PS\* ). The single excited PS undergoes intersystem crossing to an excited triplet state (3 PS\* ). During this transfer, part of the energy is irradiated in the form of a quantum of fluorescence.3 PS\* produces ROS through interaction with the surrounding biomolecules via type I and type II mechanisms. In the type I reaction, excited triplet state <sup>3</sup> PS\* reacts directly with biomolecules such as cell membrane, then transferring hydrogen or electron between PS and substrate, leading to the formation of highly reactive products of the PS and the substrate including hydroxyl radicals (HO<sup>∙</sup> ), superoxide anion (O2 –∙ ), and hydrogen peroxide (H2O2). After the start of the radical chain reactions, cell components will begin to be destroyed, which will cause the signaling pathways for autophagy or apoptosis to be triggered. In the type II mechanism, 3 PS\* transfers directly energy to the molecular oxygen in the ground triplet state to form excited singlet oxygen (1 O2) having high quantum yields. On the other hands, <sup>1</sup> O2 produced by type II reaction increases the level of ROS that causes damages to proteins, nucleic acids, lipids, membranes, and organelles, which can lead to activation of cell death processes such as apoptosis or necrosis [9, 10, 15].
