Photodynamic therapy – A non-toxic way to fight cancer

Doctors can treat certain types of cancers with non-toxic light-emitting molecules, photosensitizers, and light. This is the essence of Photodynamic therapy, an up and coming treatment model for certain cancers. And research is pushing the technology further into many forms of cancer treatments.

In photodynamic therapy, a patient with malignant cancer has a fiber optic light either inserted into, or placed just outside their body. This light emits visible wavelengths. It reacts with photosensitizer molecules (photodynamic drugs), provides energy to oxygen in the microenvironment which, in turn, generates non-toxic singlet oxygen species to shrink or kill the tumor.

Singlet oxygen species are chemically reactive chemical varieties containing oxygen.

Also known as light therapy, photodynamic therapy is a treatment for cancers that are near the surface of a body’s tissue, where the light can act on the chemical substances.

This is not like radiation therapy, which uses radicals and a toxic light source. Nor does it cause systematic side effects like chemotherapy. The light and molecules photodynamic therapy uses are non-toxic and benign. The treatment typically lasts one hour, and patients normally have it done just one time. Molecules can always be reinjected and light can be applied during a subsequent session.

Photodynamic Therapy uses light to activate drug molecules that fight cancer cells when such molecules are excited by certain light sources. Gang Han, Ph. D, the principal investigator at Han Lab, an Associate professor of Biochemistry and Molecular Pharmacology at the University of Massachusetts-Medical School is pushing the technology further into deep tissue and large-sized cancer treatment. He is doing so by using a technique known to chemists for quite some time, but which has never been used in photodynamic therapy.

 “We do it with light to illuminate certain tumor regions. Only by doing so, will this avoid having systematic side effects in the body,” Han said. “The light illuminates only the tumor cells and kills them.”

The light is introduced through fiber optics.

“You need three things for photodynamic therapy: light, a molecule as the mediator, and the oxygen in the micro-environment. The product of this reaction, a reactive singlet oxygen species compound, kills the cancer,” he said.

Most currently used treatments can only be applied to superficial tissue like skin and small lesions. The problem researchers have to deal with is using photodynamic therapy in the visible region.“There is a shallow penetration of the visible light,” Han said. “So that’s the limitation of photodynamic therapy for clinical practice.”

So far, this therapytherapy has been used to treat colon cancer, ovarian cancer, cervical cancer, and skin cancer. Sometimes it will shrink a tumor in order to allow it to be surgically removed.

“The main advantage of Photodynamic Therapy is that the treatment can be repeated multiple times safely, without producing immunosuppressive and myelosuppressive effects and can be administered even after surgery, chemotherapy or radiotherapy,” according to the National Institues of Health.

Photodynamic therapy may be an option for treating superficial, non-small cell lung cancers that haven't spread beyond the lungs and those that are located in areas easily reached with the tools used during the treatment, according to Dr. Timothy Moynihan of the Mayo Clinic.

Han wants to create a new version of Photodynamic Therapy drug that has amplified near-infrared absorptions, with a much better tissue-penetrating light. In this way, one can go deeper into the tissue to treat cancer, such as in the lung, breast or liver.

Han makes new molecules with two components: one with a standard, strong near-infrared (NIR)-absorbing fluorescence property and the other with a receptor with weak fluorescence signals. Yet the energy can now be transferred to the long lifetime triplet state of the dim fluorescence receptor. That can be useful for the generation of singlet oxygen generation species when and where such a new photodynamic molecule is injected into the treatment site. The singlet oxygen species can be reactive with the malignant cells and go on to kill these cancer cells buried in large tumors that are located deep inside the body.

Photodynamic therapy treats premalignant growths by using drugs called photosensitizing agents, along with light, to kill pre-cancerous cells, according to the American Society for Dermatologic Surgery. The drugs only work after being activated by certain wavelengths of light. The process also is known as photoradiation therapy, phototherapy and photochemotherapy.

Benefits dermatologically include no long-term side effects, that it’s minimally invasive, and it can be administered in a doctor's office multiple times to the same treatment area. It leaves little or no scarring and can improve skin appearance, tone, color and texture. 

The entire body is sensitive to light after Photodynamic Therapy, and the patient needs to avoid any exposure to bright light for up to eight weeks after treatment.

“Photodynamic therapy isn't effective for cancer that has spread beyond the lung or tumors that can't be reached by the bronchoscope,” Moynihan said.

“The idea that we are utilizing is called Förster Resonance Energy Transfer (FRET),” Han said. “Typically,  there are two fluorescence molecules. You link them tighter. These are both emitters that emit light quickly. We then use a different receptor, i.e., a bad fluorescence molecule. Absorbed light energy is not useful for emissions. In this way, we can elongate this molecule’s absorption to NIR infrared to amplify the singlet oxygen species.”

Han uses HORIBA instruments, including the FluoroMax® and Fluorolog® spectrofluorometers, along with a number of modular functions to measure the FRET energy transfer process, allowing his research group to quantify the efficiency of the singlet oxygen species.

Han’s group did a study with mice with metastasized breast cancer. His group showed that when they injected their new molecules into mice, they shrunk the tumor via infrared LED light, which was applied from outside the body, for 30-minutes. They observed positive results soon thereafter.

Han’s group has been treating triple-negative breast cancer, which does not test positive for three common measures, in mice. These mice were found to exhibit significant shrinking of tumors with low powered radiation. This is not a radiation therapy, though, as it uses non-toxic light and chemicals.

“There are only two photosensitizers on the market that just respond to visible light,” he said. “We did this initial work and this new molecule was promising. It does not produce the toxicity of other therapies. The next test beyond that of small animals must be conducted before clinical trials. We have some way to go.”

Han must test the procedure on other subjects, in order to verify the nontoxicity and efficiency.

The NIR infrared study took about a year from concept and design to experiment and publishing.

“We are very excited about our new technology,” Han noted. “People have known about FRET  for a long time but had not previously thought about borrowing it for photodynamic therapy. With FRET, we can elongate the absorption and shift it from the visible to the near-infrared region.¹”

For premalignant growths, “the procedure requires three steps: application, incubation and light activation. First the drug is applied to the skin in the treatment area, usually in the form of a liquid or cream,” according to the society.

“The drug is allowed to air dry, and then incubated anywhere from 30 to 60 minutes up to 18 hours, depending on the condition and treatment site. The skin is exposed to a special blue light source. The photosensitizing agent and light treatment activates an oxygen molecule that can destroy nearby cells.

The patient may feel a slight tingling or warmth. Sometimes a fan is used to cool the treatment area. Following treatment, the treated area is cleansed and a sunscreen is applied.”

Risks include light reaction similar to a sunburn, burning, discoloration, pain, blisters, scabs, allergic reactions and sun sensitivity.

The Mayo Clinic uses photodynamic therapy to treat a variety of conditions, including esophageal cancer, Barrett's esophagus, bile duct cancer, certain skin diseases, including precancerous skin changes (actinic keratosis), nonmelanoma skin cancer, lung cancer and stomach cancer.

Photodynamic therapy is a potential antitumoral treatment for surgically inoperable osteosarcoma, the most common type of cancer that starts in the bones, according to a study published by the National Institues of Health in 2018. The research used mice to study the technique.

In Photodynamic Therapy for Cancer, the National Cancer Institute describes photodynamic therapy as a multi-step process beginning with the injection of a photosensatizing agent into the bloodstream. It’s absorbed by the body but stays in cancer cells longer than normal cells. Once most of the agent has left the normal cells but remains in the cancerous cells, the tumor is exposed to light.

The photosensitizer in the tumor absorbs the light and produces an active form of oxygen that destroys nearby cancer cells. Photodynamic Therapy for Cancer was originally published by the National Cancer Institute.

¹This work was published in Advanced materials entitled “Enhancing Photodynamic Therapy through Resonance Energy Transfer Constructed Near‐Infrared Photosensitized Nanoparticles” (L. Huang, Z. Li, Y. Zhao, J. Yang, Y. Yang, A. I. Pendharkar, Y. Zhang, S. Kelmar, L. Chen, W. Wu, J. Zhao, G. Han, Adv. Mater. 2017, 29, 1604789. https://doi.org/10.1002/adma.201604789).

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