Understanding the essentials of photodynamic therapy for dental practitioners: Shining a spotlight

Mechanism of photodynamic therapy

A photoactivable substance that is PS, binds to the target cell and can be activated by light of a suitable wavelength.

The essential components required for the PDT are PS, light, and oxygen^[4] [Figure 2].

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Figure 2:

Venn diagram showing factors for successful photodynamic therapy.

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PS agents are unique substances that may be injected, swallowed, or used topically and are utilized in PDT. Commercial availability, affordability, ease of use, long wavelength absorption capacity, significant photocytotoxicity but low dark toxicity, good selectivity toward target cells, and quick elimination are among the best qualities.

They can be classified based on their chemical structure but are more commonly grouped into three broad families based on their clinical characteristics.

First generation

First-generation PSs include substituted derivatives of bacteriochlorin, chlorin, and porphyrin. They are cyclic tetrapyrroles and have been in use since the early 1980s and 1970s. Hemaporphyrin structural derivatives are substances of clinical significance. The following are some of these medications’ drawbacks: high aggregation, poor selectivity, limited solubility, and phototoxicity. Due to this, the majority of PSs are no longer suitable for use in PDT; nonetheless, they have been used as a source for new PSs that adhere to modern pharmaceutical requirements.^[6,7]

Second generation

The creation of second-generation PSs started in the late 1980s with the goals of improving pharmacokinetic properties, lowering toxicity, and increasing the efficacy of first-generation medications. Compared to compounds from the first generation, these PSs exhibit near-infrared absorption and strong singlet oxygen (¹O₂) production. Chlorins, bacteriochlorins, phthalocyanines, macrocyclic compounds, fullerenes, and tetrapyrrolic compounds are a few examples. Tetrapyrrolic compounds and fullerenes, a carbon allotrope structure, are some more novel second-generation PSs.^[6,7]

Third-generation PSs are recently created compounds with significant medical applications. They can be conjugated with biological molecules or have inherent “photo-quenching” capabilities, activating at their target location. These compounds can be carrier molecules such as liposomes, polymers, monoclonal antibodies, and polymeric nanoparticles. For the former, they can activate tumor surface markers, receptors, and transporters. The latter group includes tumor surface markers, receptors, and transporters. Polyethylene glycol conjugation of fullerenes improves their solubility in water-based solvents and in vivo biological settings, as well as their tumor localization.^[6,7]

The clinical strategy for PDT involves selecting the right light, delivering it to activate the PS, and ensuring an adequate PS concentration in the presence of oxygen at the target tissue. The optimal light spectrum for PDT is between 600 and 900 nm, with wavelengths below 600 nm being inappropriate due to the absorption of most incoming photons by endogenous substances. Photon energy levels beyond 900 nm are insufficient to produce ¹O₂ species. Most PSs in clinical use are activated by red light, with a wavelength between 630 and 700 nm and a penetration depth range of 0.5 and 1.5 cm. To enable dosage estimates during therapy, the generated light’s intensity should be constant. The earliest PDT light sources were non-coherent lamps, such as metal halide lamps, tungsten filament, quartz halogen, phosphor-coated sodium lamps, and xenon arc lamps. These lamps are safe, affordable, easy to use, and can cover large areas. However, they are not often used due to their high heat, low light intensity, and poor dose control.^[6,7]

The photodynamic process in biological systems is oxygen-dependent, requiring the final element oxygen to occur. This oxygen dependence is crucial for the creation of ¹O₂ and reactive oxygen species (ROS), which are responsible for most photodynamic reactions. Excitation of a PS by a light source initiates the photodynamic process, leading to cell death through photochemical interactions with cellular substrates or molecular oxygen.^[6,7]

Classic PDT involves administering a PS to the patient, selectively retaining it in target tissues, and using photochemical reactions, light radiation, and targeted tissue elimination^[8] [Figure 3].

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Figure 3:

Diagram showing mechanism of photodynamic therapy (type I and type II reactions). PS: photosensitizer, ROS: reactive oxygen species, O₂: singlet oxygen, HO: hydroxide, H₂O₂: hydrogen peroxide, ISC: intersystem crossing, hv: Energy (E=hv). [Adapted from Donohoe et al. 2019].^[9]

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The PS transitions from an excited singlet state to a low-energy ground state on light exposure, which can either decay back with fluorescent emission or transform into a triplet state, allowing for two different reactions.^[7]

• Type I: It involves the removal of electrons and hydrogen from a substrate molecule to produce free radicals, generating ions, or directly transferring electrons and hydrogen from the PS. Superoxide, hydroxyl radicals, and hydrogen peroxide are examples of the extremely ROS that are produced when these radicals react quickly with oxygen

• Type II: Singlet oxygen, a highly reactive and electrically excited state of oxygen, is produced by the processes.

Types I and II processes both contribute, suggesting that oxygen tension and PS concentration affect the damage mechanism.

Consequently, low doses of PDT-related damage most often lead to apoptosis, whereas high-level damage mainly leads to necrosis.^[9]

PDT has been effective against both Gram-positive and Gram-negative bacteria^[4] [Figure 4].

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Figure 4:

Mechanism of type I and type II reactions.

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Oxidative stress, caused by an imbalance between ROS production and cell repair capacity, leads to various cell death mechanisms. In PDT, apoptosis, autophagy, and necrosis are well-studied forms of death. Necrosis is caused by high photo damage, while moderate damage results in apoptosis and adaptive autophagy. The extent of damage can trigger other controlled cell death pathways^[9] [Figure 5].

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Figure 5:

Figure showing frequent pathways of apoptosis [Adapted from Donohoe et al. 2019].^[9]

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The treatment enhances healing with minimal intrusive techniques, targeting parasitic protozoa, fungi, yeasts, viruses, and bacteria. It is effective regardless of antibiotic resistance, has no side effects, reduces cancer recurrence likelihood, and is cost-effective to operate. The prevalent clinical applications of PDT in dentistry encompass the treatment of gingivitis, periodontitis, peri-implantitis, halitosis, herpes labialis, caries management, root canal disinfection, and candidiasis.^[4,6]

PDT’s efficacy may be compromised in deep tissues with low oxygen levels due to oxygen availability for photochemical reactions. Furthermore, PSs may accumulate under the skin, causing residual skin photosensitivity and potential burns when exposed to daylight. Therefore, direct sunlight exposure must be avoided until medication is completely removed.^[4,6]

PDT is a less widely known treatment method, which can lead to delayed or underutilized applications. It often involves specialized equipment, photosensitizing agents, and specific light sources, which can be expensive and limit its widespread adoption. PDT requires meticulous setup, including photosensitizing chemicals and light exposure, which may take time and require collaboration between medical specialists. In addition, logistical difficulties may arise due to controlled lighting requirements in clinical settings. In some cases, the intricacy of the preparation may render PDT impractical, necessitating skilled individuals for its proper implementation.