Silver Lining: The Promising Revolution of Photo-Dynamic Therapy (PDT) Against Cancer

Silver Lining:

The Promising Revolution of Photo-Dynamic Therapy (PDT) Against Cancer

Written by: Utso Bhattacharyya 

Introduction:

In the past few decades, apart from cardiovascular diseases, various types of cancer have emerged as one of the leading causes of death worldwide. The World Health Organization (WHO) study revealed a sensational information: “By the year 2030, approximately 1.3 million people will die of cancer worldwide!” This data is not an exaggeration; the number of victims from lethal cancer is increasing every year, but the good news is that the number of people recovering from the deadly disease is also increasing  annually. A big thanks to the interdisciplinary researchers and scientists; they are working tirelessly and  coming up with new innovations to quickly detect and treat various type of cancer. Mass-awareness has also played  pivotal role to prevent casualties.

         Lung cancer is the single most common cause of death among various cancers. Smoking is one of the prominent reasons that have come up again for this type of cancer. Oral cancer is also caused by tobacco intoxicants. On the other hand, the free entry of harmful ultraviolet rays through the ozone hole, caused by pollution, is being seen as one of the dominant causes of skin cancer. A pigment called melanin, which is more abundant in the skin of African aboriginals and people from the Indian subcontinent, provides some protection to the skin from those harmful rays. The risk of skin cancer is higher in white people as their skin has less pigment.

      All conventional treatments for cancer, including surgery, common chemotherapy and radiation therapy, can have dire side effects. First of all, early detection of the disease is very crucial. Otherwise, treatment complications increase and chances of complete recovery decrease. In the later stages of the disease, several complex patterns develop. One of them is ‘Metastasis’. In a nutshell,  it is the terrible process by which malignant cancer cells spread from the primary site to distant parts of the body through the blood or lymph circulation. Obviously, prevention of disease by local surgery at this level is not possible at all. There is also a risk of spread to distant sites through  blood circulation during surgery. Cancer cells as well as healthy cells are bound to get  damaged in response to conventional chemotherapy or radiation therapy. The body of the patient becomes very weak and  the immunity is immensely affected.

    In the relentless pursuit of research to find effective cancer treatments, researchers have turned their attention to innovative approaches. Cervical cancer vaccine has come that way. The application of the vaccine is able to reduce the risk of cervical cancer in women to a large extent. This cancer is primarily caused by infection with the human papilloma virus (HPV), so is relatively easily preventable through vaccination.

 Another bright star on the horizon of cancer prevention research is Photo-Dynamic Therapy (PDT). This state-of-the-art method harnesses the power of light to specifically target cancer cells and destroy them. This relatively new treatment methodology offers silver lining in the fight against the dreaded cancer.

Principles of Photo-Dynamic Therapy:

Now, let us know the basic principles of this treatment methodology in brief:

There are actually three main components to this therapy, namely:

1. A photosensitizer or light-sensitive substance,

2. Light of certain wavelengths

 and

3. Oxygen.

The patient is first administered a photosensitizing agent or light-sensitive substance, usually by injection or topical application. The agent waits to be activated and circulates in the body’s blood until it accumulates in selective processes within cancer cells. Once absorbed into the cancerous cells, the agent is purposefully activated by specific wavelengths of light. Photofrin®  is the first photodynamic therapeutic drug approved by the US FDA (Food and Drug Administration). But the solubility of this organic drug in blood and human body was very low. There were also some serious side effects. Later, attempts were made to overcome the above limitation by complex compounds of metals that are tolerated by the human body. Not only the water solubility of those compounds is high, but also they have the ability to specifically target and be absorbed by cancerous cells predominantly. These are called Targeted Photo-Dynamic Therapeutic Agents (TPDTA). A notable feature of cancer cells is ‘Angiogenesis’.  That is, much more blood vessels than normal cells are generated and connected around cancerous cells. Those evil cells need more nutrients to grow at a faster rate. So this is the system to collect those nutrients. Taking advantage of this system, many of the therapeutic agents are used as bait. Different  types of nutrients, specifically, sugars, peptides, various vitamins are attached to those agents in disguise. Because of angiogenesis, those baits are taken up by the malignant cells as tempting food. Now just waiting to make the ‘Trojan Horse’ especially active!

Expression of Actual Capacity in the Presence of Light:

In the second step, precisely the light source of the appropriate wavelength is absorbed by the therapeutic  agent. This light activates the photosensitizer and excites it to cause a photochemical reaction. This reaction produces highly unstable  reactive oxygen species (ROS), such as singlet oxygen (by Type II pathway : energy transfer) or, hydroxyl or other radicals (by Type I pathway : electron transfer), which initiate the destruction of cancer cells. Oxidative stress or inflammation caused by these reactive species damages cellular components, triggering a cascade of reactions that ultimately leads to cell death. This cascade of events leads to programmed cell death, or “apoptosis.” Un-programmed cell death or “necrosis” like inflammation causes the death of surrounding healthy cells. But in this process only cancerous cells are destroyed.  Early on, specific wavelengths of light were activated in the blue or green part of visible light. But later efforts to construct specific therapeutic agents with special chemical structures which can be  activated in the red and infrared regions, have come to fruition. Its two major advantages are:

1. The penetrating power of this ray in the human body is the best.

2. These rays are not absorbed by blood pigments (Hemoglobin) or other biological substances.

Better Targeting and Reduced Side-effects:

One of the significant advantages of PDT is its ability to selectively destroy cancer cells while sparing healthy tissue. While conventional treatments such as chemotherapy can cause extensive damage to the body, the precise targeting of PDT greatly reduces the chance of collateral damage. In applying this targeted approach, researchers are working tirelessly to deliver on the promise of reducing side effects and improving the overall quality of life of patients undergoing treatment. A modified version of this method is Targeted Photodynamic Therapy (TPDT): This method has two distinct mode of targets that specifically ensure the destruction of malignant cancer cells sparing the normal ones.

1. By exploiting the ‘angiogenesis’ property of cancer cells through the use of nutrients as ‘bait’, the agent is delivered to malignant cells, specifically instead  of the healthy cells.

2. The destructive action of the photosensitizing agent is accelerated immediately after exposure to the light beam. That is, the drug does not reach healthy cells in particular , or, if it reaches in very little portion at all, since it  is not subjected to light exposure, it does not cause significant damage.

Useful for various types of cancer:

The multifaceted promise of PDT extends to a wide variety of cancer types. This curative approach is considered very important for both localized and superficial cancers. Skin cancer, oral cavity cancer, certain types of lung cancer and early stage prostate cancer, etc., have been identified as some of the most suitable cancers for PDT application. Scientists are constantly doing research. They aim to expand the use of PDT to more advanced stages and other types of malignancy.

Limitations, Challenges and Future Projects:

Although PDT is a cancer curative approach with great potential, its limitations and challenges remain. Limited penetration of light into tissues or organs limits the application of PDT to superficial tumors. In addition, refining the cancer cell specific delivery of photosensitizers has emerged as another active area of research. Researchers are also exploring ways to further increase the selectivity of photosensitizers for specific cancer cells. If the harmful effects on healthy tissue can be reduced further, it will become a completely side-effect-free approach.

Conclusion:

It goes without saying that photodynamic therapy continues to be a beacon of progress in the development of cancer cure research. The specificity of this approach (TPDT i.e. Targeted Photo-Dynamic Therapy which is more comprehensive), relatively few side effects and adaptability and spread across multiple types of cancer, recognize it as a compelling and valuable weapon in the ever-expanding arsenal of medicine against this complex disease.

References:

1. Curcumin “Drug” Stabilized in Oxidovanadium(IV)-BODIPY Conjugates for Mitochondria-Targeted Photocytotoxicity,  Inorg. Chem. 2017, 56, 20, 12457–12468. https://doi.org/10.1021/acs.inorgchem.7b01924

2. Ruthenium(II) Conjugates of Boron-Dipyrromethene and Biotin for Targeted Photodynamic Therapy in Red Light, Inorg. Chem. 2020, 59, 1, 913–924. https://doi.org/10.1021/acs.inorgchem.9b03178

3. Structurally Characterized BODIPY-Appended Oxidovanadium(IV) β-Diketonates for Mitochondria-Targeted Photocytotoxicity, ACS Omega 2020, 5, 8, 4282–4292. https://doi.org/10.1021/acsomega.9b04204

4. Bichromophoric Ruthenium(II) bis-terpyridine-BODIPY based photosensitizers for cellular imaging and photodynamic therapy, Dalton Trans., 2022,51, 10392-10405. https://doi.org/10.1039/D2DT01137A

5. Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions, Pharmaceutics. 2021 Sep; 13(9): 1332. https://doi.org/10.3390%2Fpharmaceutics13091332