Introduction

Photodynamic therapy (PDT) is a newer and well-researched treatment technique that has been used widely in dermatology and oncology. Photosensitising agents, or chemical substances that activate when exposed to a certain wavelength of light, are used in PDT. When these agents are activated, they release reactive oxygen species (ROS) into the targeted cells, causing oxidative stress and ultimately cellular damage and death. One of PDT's main benefits is its ability to target aberrant or infected cells specifically while causing the least amount of harm to neighbouring healthy tissue.¹

PDT has long been used in the treatment of cancer; its early therapeutic uses were for skin malignancies, namely basal cell carcinoma. With success, its application to bacterial illnesses has also been investigated. Still, research on PDT's potential as a therapy for viral infections is in its infancy. This new therapeutic alternative has special benefits, especially when it comes to overcoming obstacles like virus resistance to conventional antiviral medications. PDT offers a novel, non-invasive treatment that targets infected cells without the possibility of resistance. Therefore, PDT becomes a viable option for treating a variety of viral infections, as viruses grow more and more drug-resistant.²

Mechanism of action

Three elements make up PDT's basic mechanism: light, oxygen, and a photosensitiser. The administration of a photosensitiser can be done topically or systemically, based on the type of illness and location. The photosensitiser is absorbed by cells and then becomes dormant until it is exposed to a particular wavelength of light, usually in the visible or near-infrared range. The photosensitiser is activated by the light source, which causes a photochemical reaction that produces ROS, such as hydroxyl radicals, superoxide radicals, and singlet oxygen.³ These extremely reactive substances put the infected cells under oxidative stress, which destroys viral components like proteins, membranes, and nucleic acids.⁴

The metabolic distinctions between diseased and healthy cells serve as the foundation for PDT's ability to target infected cells with precision. In comparison to non-infected cells, virus-infected cells absorb and retain larger amounts of photosensitizers, which increase their susceptibility to oxidative damage.⁵ Infected cells are also frequently characterised by unusual metabolic activity. This selectivity is essential for minimising unintentional harm to healthy tissue and lowering adverse drug reactions.

Viral PDT photosensitisers

The choice of photosensitiser is critical to PDT performance since different compounds have varying:

• Absorbance spectra
• Capacities for tissue penetration
• Rates at which reactive oxygen species are generated

Numerous photosensitizers have been investigated for their potential antiviral effects.
One of the photosensitisers in PDT that has been investigated the most is porphyrins (class of pigments). Porphyrins, including hematoporphyrin derivatives, have shown noteworthy antiviral efficacy against human papillomavirus (HPV) and herpes simplex virus (HSV). They are efficient in causing damage to nucleic acids and viral membranes because of their capacity to produce copious levels of ROS.¹6

Phthalocyanines

Another class of photosensitisers with potent ROS-producing properties is phthalocyanines. Compared to porphyrins, they absorb longer wavelengths of light, enabling deeper tissue penetration. Because of this, phthalocyanines are especially well-suited for managing viral infections that impact the mucosal tissues and deeper layers of the skin.⁷

Recently developed photosensitisers

Research in the past several years has concentrated on creating photosensitisers that are more efficient, selective, and photostable while producing ROS. Compared to older photosensitisers, newer chemicals such as phenothiazinium dyes and benzoporphyrins have demonstrated more benefit and fewer adverse effects, suggesting that they may have promising antiviral qualities.⁸

Use in particular viral infections

Human Papillomavirus (HPV)

When it comes to PDT application, HPV-related infections have been studied the most. Many illnesses are brought on by HPV, such as cervical dysplasia and genital warts. Both of which have been treated using PDT. Clinical research has shown that HPV-induced lesions have good clearance rates and little recurrence following PDT. This is especially crucial in halting the development of cervical dysplasia into cervical cancer, which is a serious health issue.⁹

Herpes Simplex Virus (HSV)

Studies have indicated that PDT is effective in treating HSV infections, which usually impact the skin and mucosal areas. According to clinical investigations, PDT treatment significantly lowers viral loads and the extent of HSV lesions.¹⁰ The treatment is very good in decreasing the frequency of HSV outbreaks because of its localised approach, which targets the afflicted areas without harming the surrounding tissues.

HIV and other viral infections

Although preliminary research has produced encouraging findings, PDT treatment for HIV is still in its experimental stages. With PDT, latently infected cells are specifically targeted and destroyed, reducing HIV reservoirs. Furthermore, exploratory studies have looked into PDT's ability to fight newly developing viral diseases like COVID-19.¹¹ PDT may be useful in deactivating the virus on surfaces and lowering the likelihood of transmission, according to studies. However, more investigation is required to confirm these results.

Benefits of PDT compared to conventional medicines

PDT is a very attractive alternative for treating viral infections since it has several clear advantages over traditional antiviral medicines. PDT is a targeted, non-invasive treatment that only affects the affected area, which is one of its main advantages. The targeted action of PDT reduces toxicity and protects healthy tissues from harm, in contrast to systemic antiviral medications, which can have a variety of negative effects. Patients who are unable to handle systemic antiviral therapies because of their negative effects would particularly benefit from this.¹²
Treating viral infections, especially long-term illnesses like HIV and herpes, presents a serious challenge due to the growing issue of medication resistance. Viral resistance is lowered by PDT's method of action, which involves the non-specific breakdown of viral components by oxidative stress. This is because, in contrast to conventional antiviral medications, PDT does not specifically target viral proteins or enzymes.¹³ PDT lowers the danger of overall side effects by selectively targeting virus-infected cells, ensuring a highly localised course of treatment. Because the therapy concentrates on the infected areas while maintaining the integrity of the surrounding healthy tissues, this also enables higher treatment efficacy.¹⁴

Difficulties and restrictions

Although PDT has a lot of potential for treating viral infections, some issues must be resolved to fully realise its benefits. The need for light to activate the photosensitiser is one of PDT's main drawbacks. The application of PDT to surface or near-surface viral infections is limited by the light penetration depth in biological tissues. Because PDT can not penetrate deeply into tissues or organs, it is challenging to treat infections in these areas.¹⁵ This restriction might be addressed with the development of photosensitisers that absorb light at longer wavelengths and improvements in light delivery technologies. 

After PDT, some patients may have photosensitivity responses, which cause their skin to become excessively sensitive to light for a while. This results from the skin's buildup of photosensitisers, which sunshine can trigger. PDT patients have to take care not to expose themselves to sunlight, which can make the therapy less feasible in some situations.¹⁶
The effectiveness of PDT in treating localised viral infections, such as HPV and HSV, has been demonstrated. However, its application in treating systemic diseases, such as HIV, is still restricted. Because systemic infections include extensive viral presence in the body, PDT treatment can be more difficult because of the treatment's limited ability to address the infection as a whole.¹⁷ The development of methods to expand PDT's application to systemic illnesses must be the main emphasis of future research.

Present studies and upcoming paths

PDT is being studied for its ability to treat viral infections, including advances in photosensitisers and combination medications. To boost the efficacy of PDT in controlling deeper tissues, researchers are creating novel photosensitisers with improved properties such as increased choice, stronger wavelength absorption, and enhanced ROS generation. Combination therapy is also being investigated to lower viral loads while strengthening the immune system against recurrence. 

Clinical trials are being done to determine the effectiveness of PDT in treating various viral infections, including HPV, HSV, and novel viruses such as SARS-CoV-2. PDT's potential for combating viral pandemics is also being researched, notably in terms of removing viruses on surfaces and lowering transmission risks.^18,19,20

Summary

As a new treatment for viral infections, PDT holds considerable potential. It has advantages over standard medicines, such as reduced drug resistance and fewer side effects. PDT specifically targets virus-infected cells while preserving healthy tissues by generating ROS through photosensitizers activated by light. Clinical studies indicate that it is highly effective for localised infections such as HPV and HSV, with reduced recurrence and excellent lesion clearance.

Its applicability in systemic illnesses like HIV is still being studied, but obstacles like restricted light penetration and the possibility of photosensitivity reactions restrict its usage to surface infections. Notwithstanding these drawbacks, further investigation into sophisticated photosensitizers and combination treatments may increase PDT's efficacy. PDT can become a widely used therapeutic option as this field develops, for both developing and established viral infections like those that are resistant to traditional antiviral medications.