Photodynamic therapy (PDT) is a procedure in which light is used to activate a photosensitizer or PDT drug, which is a chemical agent, that eventually leads to the destruction of cancer or a diseased cell. It is a multidisciplinary approach that has seen significant growth worldwide.

Basic Principle of PDT

Photodynamic therapy uses light to activate the photosensitizer or PDT drug. The drug is given to the cancer site either through injection or topical application, similar to certain skin cancers. Then, light of a specific wavelength is applied, which the photosensitizer can absorb. This absorbed light causes the PDT drug to produce reactive oxygen species, which can destroy the tumor.

Key steps in PDT

• Giving the PDT drug to the patient
• PDT drug stays in the cancerous tissue for a longer time
• Light is applied, usually from a laser, to the cancerous tissue
• PDT drug absorbs the light and creates reactive oxygen species that destroy cancer cells while minimizing harm to healthy cells nearby
• Removing the drug after PDT to reduce sensitivity to sunlight

For cancers within internal organs like the lungs, light is delivered through a minimally invasive method using a flexible fiber-optic endoscopic system. In the case of superficial skin cancer, a direct illumination technique can be employed. Since the light does not need to have specific coherence properties, various light sources like lamps or laser beams can be used. However, lasers are commonly utilized due to their ability to provide the desired power density at the necessary wavelength. Also, lasers make it easier to deliver light through fiber-optic cables.

Mechanism of photodynamic photo-oxidation 

The light activation process of a PDT drug begins with the absorption of light, leading to the creation of an excited singlet state (S1 or 1P*, where P* shows the excited photosensitizer). This excited state then undergoes transitions to a long-lasting triplet state (T1 or 3P*) through the intersystem crossing. It is primarily the long-lived triplet state that generates the reactive oxygen species.

There are two types of processes that can create reactive species to oxidize cellular components:

• Type I process: This process involves the generation of reactive free radicals, peroxides, and superoxides through electron or hydrogen transfer reactions with water or biomolecules. These reactions lead to a cytotoxic outcome.
• Type II process: In this process, the excited triplet state of the photosensitizer interacts with oxygen in the tissue, converting the oxygen molecule from its normal triplet state to a highly reactive excited singlet-state form.

The type II process is the main pathway for photodynamic therapy (PDT).

Singlet oxygen produced by an excited PDT photosensitizer can be detected through spectroscopic or chemical methods. The spectroscopic method involves observing phosphorescence emissions around ~1290 nm, which correspond to the transition from the excited singlet state of oxygen to its triplet ground state.

Mechanism of photodynamic action

To enhance the effectiveness of photodynamic therapy while minimizing adverse effects, understanding the mechanisms of photodynamic action at the cellular and tissue levels is important. There are mainly three mechanisms of photodynamic action: cellular, vascular and immunological.

• Cellular targeting by PDT

Cellular damage resulting from photodynamic therapy occur through the specific targeting of subcellular sites or organelles by certain photosensitizers. This damage is primarily caused by the action of singlet oxygen generated by the photosensitizer. Due to the short lifetime of singlet oxygen (microseconds), the resulting photodamage is expected to be confined to a very small radius (<0.02 mm) around the targeted subcellular component, such as an organelle, where the photosensitizer accumulates due to its chemical affinity. The main subcellular sites susceptible to photodamage are mitochondria, plasma or internal membranes, and lysosomes.

Photosensitizers like Photofrin® localize in mitochondria, while 5-Aminolevalinic acid (ALA)-induced photoporphyrin IX is generated specifically in mitochondria. Photosensitizers that target mitochondria are believed to induce photodamage through the process of apoptosis, leading to cell death. Apoptosis involves the activation of cellular enzymes, resulting in nuclear DNA fragmentation and the formation of membrane-bound particles that neighboring cells eventually engulf. Another group of photosensitizers that also target mitochondria are cationic photosensitizers, which accumulate in mitochondria along the membrane potential gradient. On the other hand, photosensitizers such as phthalocyanines localize in plasma membranes and are believed to cause necrosis, a different form of cell death.

• Vascular Damage 

Vascular damage caused by photodynamic therapy (PDT) plays a significant role in tumor destruction. PDT with Porphyrin® induces rapid vascular stasis, vascular hemorrhage, and tumor cell death through direct damage and hypoxia/anoxia. The extent of vascular damage and blood flow interruption is closely linked to the level of photosensitizer present during irradiation. The initial step in vascular damage involves endothelial cell damage, leading to cytoskeletal rearrangement and cell shrinkage. This exposes the vascular basement membranes, promoting platelet binding and aggregation. Activated platelets release vasoactive mediators triggering various events, including platelet activation, thrombosis, vasoconstriction, and increased permeability. These events ultimately lead to blood flow stasis, tissue hypoxia, and shutdown of the vasculature.

• Immunological Response

PDT triggers a strong inflammatory reaction that contributes to tumor destruction. Inflammatory processes release cytokines and other mediators, aiding in tumor control. The role of inflammation varies with different photosensitizers, with more significance observed in certain cases like Photofrin®. Inflammation concentrates the immune response and causes collateral damage, which adds to tumor destruction. The extent of inflammation's role may be influenced by the mode of cell death induced by PDT and the specific model studied. Mediators like interleukin 6 (IL-6) can enhance or inhibit the PDT response, depending on the context. The release of IL-6 by PDT amplifies the role of inflammation in tumor destruction and the immune response to tumor antigens.

Some of the PDT Drugs

• 5-Aminolaevulinic Acid (ALA)
• Benzoporphyrin Derivatives
• Cationic Photosensitizers
• Chlorins and Bacteriochlorins
• Dendritic Photosensitizers
• Phthalocyanines and Naphthalocyanines
• Porphyrin Derivatives
• Texaphyrins

Choosing a PDT drug

• The photosensitizer should selectively accumulate in cancerous and precancerous tissues.
• It should have a hydrophobic nature to easily penetrate cell membranes.
• If administered intravenously, it should be amphiphilic, allowing it to disperse in the bloodstream by being both hydrophilic and hydrophobic.
• The photosensitizer should absorb light significantly at a wavelength within the biological tissue's maximum transparency region. Wavelengths longer than 900 nm are too low in energy to excite triplet oxygen to a singlet state.
• It should exhibit minimal toxicity in the absence of light activation to ensure maximum benefits and minimize side effects.
• The photosensitizer should have a high quantum yield and a long lifetime for the triplet state, increasing the chances of producing cytotoxic effects upon excitation.
• Aggregation of the photosensitizer should be avoided as it can reduce the extinction coefficient and shorten the lifetime and quantum yield of the excited triplet state.
• Rapid excretion from the body is desirable to minimize systemic toxicity and reduce sunlight sensitivity after PDT treatment.

Applications of PDT

Photodynamic therapy has a wide range of potential applications across various fields. PDT is an effective approach for treating different types of cancers. It offers advantages such as precise tumor targeting, minimal invasiveness, and reduced systemic side effects compared to traditional therapies. PDT can be used to treat superficial and early-stage cancers, as well as tumors located in challenging areas like the lungs, brain, and gastrointestinal tract.

It is employed in dermatology to treat skin conditions such as non-melanoma skin cancers, precancerous lesions, acne, and photodamage. It is particularly suitable for lesions on the face and scalp, where preservation of cosmetic appearance is important.

PDT has demonstrated success in managing certain eye conditions, such as age-related macular degeneration (AMD). By selectively targeting abnormal blood vessels in the eye, PDT can help slow down the progression of AMD and preserve vision.

It shows potential in combating infections caused by bacteria, viruses, and fungi. PDT can be utilized for wound healing, treating oral infections, and managing conditions like periodontitis and bacterial keratitis.

PDT is being explored for applications beyond cancer treatment. It has shown promise in cardiovascular interventions like angioplasty to prevent restenosis, management of chronic skin diseases like psoriasis, and controlling autoimmune diseases such as rheumatoid arthritis.

It continues to be an active area of research, with ongoing studies exploring its potential in various fields. This includes the development of targeted therapies, combination treatments with other modalities, and the design of new photosensitizers to improve treatment efficacy and selectivity.