1. What is photodynamic therapy (PDT)?

Photodynamic therapy (PDT) uses the local activation of a photosensitizer accumulated in a tumor by means of light. In the presence of tissue oxygen, this activation brings about a photochemical reaction that destroys tumor cells. The PDT mechanism can be described as follows. When a photosensitizer molecule absorbs a quantum of light, it goes to an excited triplet state. The excited molecule can undergo photochemical reactions of two types.

In the first type, the molecule reacts directly with biological molecules. This leads to the generation of free radicals. In the second type, an excited photosensitizer molecule reacts with an oxygen molecule. As a result, singlet oxygen is produced. This substance is a strong oxidant, which is cytotoxic in action.

Soon after its development, the photodynamic effect was used in oncology. It proved to be beneficial in the treatment of cancer.

2. What are the advantages and prospects of PDT in cancer treatment?

Above all, one needs to estimate the prevalence of this pathology and the economic damage caused by malignant tumors.

Everybody on Earth feels the negative psychogenic effect of cancer. According to the World Health Organization, in 2001, cancer was first diagnosed in more than 10 million people, and more than 6 million people died of cancer. Most often, cancer strikes the lung and gastrointestinal tract (stomach cancer, esophagus cancer, colon cancer, and rectum cancer). Lung and gastrointestinal cancer constitutes 47 percent of ten most frequent cancer localizations. They also account for 42 percent of cancer-provoked deaths around the world.

Cancer causes a substantial damage to economy. According to the National Institute of Health, the economic damage of cancer in 2001 reached $180.2 billion in the U.S. alone.

By way of example, consider the economic efficiency of PDT in the treatment of the most frequent forms of cancer. Let us consider accessible tumors. As is known, PDT is most efficient at early stages. Lung and gastrointestinal cancer can be rarely be diagnosed at early stages. As a result, despite all of its merits, PDT contributes little to the economy in these cases. The situation changes drastically in the case of skin cancer.

Photodynamic therapy, both in Russia and abroad, is applied in 65 to 70 percent of patients with skin cancer. In this case, PDT yields a 100-percent therapeutic efficiency.

Photodynamic therapy of skin cancer normally requires a single session under outpatient conditions, whereas a routine close-focus X-ray therapy lasts for 2 to 3 weeks. In this sense, PDT provides a much better economic efficiency.

Photodynamic therapy has a similar effect in the case of other superficial malignant tumors. For example, it goes for recurrences and intradermal metastases of breast cancer, primary tumors and multiple recurrences (up to 60 – 70 percent) of tongue cancer, cancer of oral mucosa, lower-lip cancer, intradermal metastases of melanoma, and other tumors.

Endoscopic PDT yields good clinical and economic results. In this case, PDT makes it possible to recover lumen of a tumor-obturated esophagus, trachea, and large bronchi. Endoscopic PDT can treat other tumor-stricken internal organs. For example, it can be used in the treatment of hard-to-get-at tumors localized in the pancreaticoduodenal area and common bile duct.

Hence, PDT advantages are as follows:

• Photodynamic therapy is applied when surgery is contraindicated because of the tumor spread and serious associated diseases. Photodynamic therapy is targeted at tumor cells, and it causes no damage to healthy tissues. Due to this, when PDT has destroyed a tumor, normal cells begin to propagate and fill the organ’s frame. This is of special importance for PDT of thin-walled and tubular organs (such as the stomach, colon, esophagus, trachea, bronchi, and bladder). Photodynamic therapy allows avoiding the organ wall perforation. Thus, the cancer patient with nonresectable tumor has a chance for treatment with usage of PDT.
• Photodynamic therapy produces a targeted effect. A photosensitizer is selectively accumulated in a tumor, and it is rapidly eliminated from healthy tissues that surround the tumor. Due to this, red light selectively damages the tumor, whereas surrounding tissues remain intact.
• Photodynamic therapy avoids the systemic effect on the human being (in the case of chemotherapy of tumors, this effect does take place). Photodynamic therapy treats an area exposed to light. As a result, the patient is not subjected to an unwanted systemic effect. This makes it possible to prevent the patient from all side effects, typical of chemotherapy (such as nausea, vomiting, stomatitis, loss of hair, and inhibition of hematopoiesis).
• Photodynamic therapy is cost-effective. For a majority of patients, PDT is a noninvasive or minimally invasive method. It is also a tolerant, local, and inexpensive technique, which can treat a variety of malignant tumors (primary tumors, recurrent tumors, and metastatic tumors).

The Ministry of Health of Russia analyzed the results of PDT application in Moscow Medical Centers. Photodynamic therapy was employed to treat malignant tumors of the skin, breast, oral mucosa, tongue, lower lip, larynx, lung, esophagus, stomach, bladder, and rectum. From 1992 to 2001, PDT was used to treat more than 1,600 tumors in 408 patients. Most of the patients had been treated earlier with routine methods (such as surgery, radiotherapy, and combined treatment). Some of the patients had not been treated earlier owing to serious age-related and associated diseases. The rest of the patients received palliative PDT. They had extended obturating tumors of the esophagus, trachea, colon, large bronchi, and the cardia. Photodynamic therapy was performed to recanalize stenosed organs and to improve the quality of life.

Follow-up studies had been made for 2 months to 9 years. Photodynamic therapy produced a beneficial effect in 94.4 percent of the patients. Of these, 56.2 percent showed a total tumor resorption, and 38.2 percent showed a partial tumor resorption.

Photodynamic therapy is an advanced therapeutic technique, which is employed in Russia with success. At present, new photosensitizers and light sources are being developed for PDT and fluorescent diagnosis.

3. What are the basic problems of PDT development at the present stage?

Among the major problems of PDT development is the increase in the selectivity of photosensitizer accumulation in a tumor. Poor selectivity results in poor treatment efficiency and skin hypersensitivity to daylight.

A serious PDT drawback is the limited penetration depth of laser radiation. Clinical photosensitizers have maxima of photodynamic action at 620 to 690 nm. In this range, optical radiation penetrates biological tissues poorly (at a depth of several millimeters). Maximum penetration lies in the far-red and near-infrared bands - from 750 to 1,500 nm. Many commercial lasers operate in these ranges. Hence, we need photosensitizers that would effectively generate singlet oxygen in these ranges. They will considerably widen PDT application.

Such photosensitizers are actively sought among chlorin, bacteriochlorin, purpurin, benzoporphyrin, texaphyrin, etiopurpurin, naphthalocyanine, and phthalocyanine derivatives. Special interest is shown to photosensitizers that can be both rapidly accumulated and decomposed. One day, a bank of tumor-targeting photosensitizers will be created (as it has been done for tumor chemotherapy). Such tumor-targeting photosensitizers will be effective for specific nosological and histological forms of cancer.

4. Is it feasible to specify the main requirements to an optimum photosensitizer?

Yes, of course. These requirements are as follows:

• low toxicity at therapeutic doses in darkness;
• high tumor-targeting accumulation;
• fast elimination from the skin and epithelium;
• absorption peaks in the low-loss transmission window of biological tissues (the far-red and near-infrared bands);
• optimum ratio of the fluorescence quantum yield to the interconversion quantum yield (the former parameter determines the photosensitizer diagnostic capabilities, it plays a key role in monitoring the photosensitizer accumulation in tissues and its elimination from them; the latter parameter determines the photosensitizer ability to generate singlet oxygen);
• high quantum yield of singlet oxygen production in-vivo;
• available manufacturing and synthesis;
• homogeneous composition;
• high solubility in water, injection solutions, and blood substitutes;
• storage and application light stability.

5. Could you please tell us about the application efficiency of chlorin-type photosensitizers in more detail?

E.Snyder (USA) was the first to suggest in 1942 that water-soluble chlorophyll derivatives should be used for medical purposes. Chlorin mixtures were composed mainly of chlorin p6. They were administered orally or intravenously. These compounds were nontoxic, hypotensive, antisclerotic, spasmolytic, anesthetic, and antirheumatoid in action. They also produced a favorable effect on biochemical indices of blood. Their daily oral administration at a dose of 1 g for 30 days decreased the cholesterol count of blood by a factor of 1.5 to 2. Due to this, water-soluble chlorins were employed to prevent and treat cardiovascular diseases, atherosclerosis, and rheumatoid arthritis.

Pheophorbid A derivatives were the first chlorin-type derivatives used in PDT. In 1984, some of them were patented in Japan as potential photosensitizers for PDT.

The application of chlorin-type derivatives in PDT was reported in 1986. A research team from the U.S., which included J.Bommer, Z.Sveida, and B.Burnham, analyzed mono-L-aspartyl chlorin e6 (MACE) properties. This compound showed good tumor tropism and strong absorption in the far-red band. It thus met the most vital PDT requirements. This compound was put to tests in Japan, and now it passes the final stage of clinical trials. J.Bommer and B.Burnham, working with the Nippon Petrochemicals Company (Japan), filed a U.S. patent for some functional derivatives of chlorin e6 and bacteriopheophorbid A.

From 1994 to 2001, Russia carried out comprehensive investigations of tetrapyrrol chlorin-type macrocycles (chlorophyll A derivatives). It has to establish the structural and functional features of their accumulation in tumors. It also needed to increase PDT efficiency and to create chlorin-type drugs. At that time, scientists developed a technique for extracting biologically active chlorins from plants. Plant chlorins were found to mainly contain chlorin e6. As a result, photosensitizers of the second generation were created. They were named Radachlorin and Photoditazine (Fotoditazin™).

These photosensitizers come correspondingly as 0.35-percent and 0.50-percent solutions for intravenous injections. They are composed of three cyclic chlorin-type tetrapyrrols with a hydrogenated ring D. Chlorin e6 is their main component. It accounts for 80 to 90 percent of the mixture. Radachlorin and Photoditazine are activated by optical radiation at wavelengths of 654 to 670 nm. This radiation can penetrate biological tissues at a depth of about 7 mm.

Radachlorin and Photoditazine exhibit a high degree of phototoxicity. This is associated with a high quantum yield of singlet oxygen, which one of the most toxic agents during PDT. Besides that, Radachlorin and Photoditazine show good fluorescence. So, they can be used for fluorescent diagnosis of malignant tumors. The photosensitizers are excited at one of the following wavelengths: 406, 506, 536, 608, or 662 nm. An intense fluorescence is observed at a wavelength of 668 nm. Radachlorin and Photoditazine are highly water-soluble compounds. They also exhibit good stability in storage. When stored in darkness at a temperature of 4 to 8°C, they retain their properties for 18 months.

In general, chlorin-type photosensitizers produced a better toxic effect, as compared to both porphyrin oligomeric compounds (Photofrin II, Photohem) and sulfonated phthalocyanine compounds (Photosense). Furthermore, the body eliminated water-soluble chlorin-type compounds much faster. For example, an organism retains Photofrin II, Photohem, and Photosense for more than 3 months, whereas it eliminates chlorin-type photosensitizers within from 1 till 2 days.

Radachlorin and Photoditazine produced radical changes in the PDT of malignant tumors. The application of porphyrin oligomeric and sulfonated phthalocyanine compounds relies on a long-term treatment under inpatient conditions, whereas the application of Radachlorin and Photoditazine avoids this stage. Instead, the patient receives a one-day or outpatient treatment. A tumor should be irradiated 2 hours after the photosensitizer injection.