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Company Profile

Name: QLT Inc.
Location: Vancouver, BC
Type: Biopharmaceutical
Date Founded: 1981
Ownership: Public
Employees Total: 350

Basis for Research/Technology

Use of photodynamic therapy (PDT) to treat cancer, eye diseases and immune disorders.

Background- What is Photodynamic Therapy (PDT)?

Photodynamic therapy (PDT, also called photoradiation therapy, phototherapy and photochemotherapy) is a unique, minimally invasive treatment that specifically targets diseased cells³. It is a relatively safe way to treat a variety of diseases, with little damage to healthy cells surrounding the diseased cells. The theory behind PDT has been around since the turn of the century: in 1900, Raab noticed that treating living tissues with certain compounds rendered them more sensitive to damage and death when they were exposed to light². In the 1970's, these chemicals, known as photosensitizers, began to be used for therapeutic purposes².

In photodynamic therapy, an inactive molecule called a photosensitizer is injected into the patient, where it circulates in the body and is allowed to accumulate in diseased cells. A photosensitizer is generally a kind of tetrapyrrole molecule (also known as a porphyrin) that absorbs energy from light and uses this energy to enable chemical reactions to take place².

Some examples of photosensitizers are shown below:

Figure 1. Haematoporphyrin.

Figure 2. Protoporphyrin.

Different photosensitizers have slightly different structures, and target different areas of the body. For example, QLT's Visudyne photosensitizer attaches to low-density lipoproteins (which normally carry cholesterol in the bloodstream). The circulatory system carries the lipoprotein-bound photosensitizer throughout the body. Cells undergoing rapid growth (such as cells forming abnormal blood vessels like cancerous cells or those involved in age-related macular degeneration) require an above-average supply of lipoproteins, so the photosensitizer is preferentially delivered to and taken up by these types of cells, concentrates there (probably in the cell membrane), and tends to remain in the unhealthy cells longer than in healthy ones^1,3. However, at this point the drug is still inactive and has very low toxicity.

		Figure 3. QLT's Visudyne treatment.

In the next step of the treatment, a non-burning, fixed frequency laser is focused at the site of damaged tissue to be eliminated for a specific length of time (from 200 to 1000 seconds). The light emits a particular wavelength of light that specifically activates the photosensitizer, causing it to form a singlet oxygen molecule in cells that have taken up the drug. Singlet oxygen is highly toxic and causes irreversible damage to the cell's plasma membrane, mitochondrial membrane, lysosomes, nuclear membrane and protein modifications. This disrupts normal cell functions and ultimately causes the cells to die^1,3. Because the light is focused on the area to be treated, and because the photosensitizer is concentrated in the diseased cells, damage to normal cells is limited and as a result there are few side effects. In addition, singlet oxygen only last a short time (less than 0.04 microseconds) and can travel only a very short distance in the cells, which also minimizes damage to surrounding tissue¹.

PDT is a "cold" photochemical process; this means there is no tissue heating so surrounding connective tissue (e.g. collagen and elastin in cartilage and muscle) is largely unaffected compared to thermal laser treatments and conventional surgery¹. Another advantage is that the treatment can be repeated many times and in combination with chemotherapy, radiation and/or surgery. It can also be performed outside of hospitals and is much less invasive than conventional treatments. Neither the light nor the photosensitizer has any effect alone; only the combination results in activity. Furthermore, after it has passed on its energy to form singlet oxygen, the photosensitizer returns to its starting state, where it is available to begin the whole process again if re-activated by another laser exposure.

Some drawbacks of the technique include that the combination of photosensitizers and lasers currently in use cannot penetrate more than 1-3 cm into a tissue, so can only be used to treat tumours on or just under the skin or on the lining of organs. As well, the therapy makes the patient's skin and eyes sensitive to light for 6 weeks or more after treatment, and patients must keep out of the sun to avoid burns. One of QLT's goals is to reduce these side effects and increase penetrance with the advent of new photosensitizers and lasers. The new "second-generation" of photosensitizers have several advantages, including shorter periods of photosensitivity after treatment, increased penetrance in tissue, higher yields of singlet oxygen (greater cytotoxicity) and better tumour selectivity¹.

		Figure 4. Treatment for macular degeneration.

Applications

QLT uses different products to treat different conditions. The product Visudyne is used to treat macular degeneration. Macular degeneration is a disease of the eye's retina that leads to blindness. It occurs in two forms: one known as the "dry" form, the other known as the "wet" form. About 90% of cases are the dry form, but the 10% that acquire the wet form suffer from the most damage. QLT's treatment is for this less prevalent but more severe form of macular degeneration. For this treatment, a diode laser is shone through the slit lamp of a microscope into a patient's eye. This activates the photosensitizer that has accumulated in the cells of the abnormal blood vessels in the retina of eye that cause this disease. By destroying this abnormal blood vessels that accumulate in wet macular degeneration, the on-set of blindness can be prevented.
For a full description of macular degeneration, please see the Eye Canada site at or its US equivalent: Macular Degeneration Foundatio (USA)

Another disease that could be treated by this method is cancer. PDT offers the advantage of being able to target areas of the body that cannot tolerate radiation because of the sensitivity of surrounding tissues. For example, the head and neck, mouth and peritoneum are good candidates for PDT as the underlying brain and internal organs are too easily damaged by radiation for conventional treatment, but are minimally affected in PDT. For these treatments, fiber optics are used to deliver laser light to internal cavities (e.g. lung, esophagus) while light -emitting diodes (LEDs) are used for skin cancer.

		Figure 5. Setup for PDT.   (Image Source: The Lancet -- see reference 1)

Some photos of PDT treatment:

		(Image Source : Medical College of Wisconsin) (Image Source: Closing in on Cancer)
		Figure 6. Photos of PDT Treatment.

QLT is developing a product called tariquidar that targets a protein named P-glycoprotein. This protein is highly expressed in cancer cells that have become resistant to drugs used in chemotherapy. Similarly, a drug called Verteporfin (already used for macular degeneration) is being tested for use in treating multiple melanoma skin cancer lesions. Other applications of PDT in cancer might be targeting the invisible cancerous cells left-over after surgical removal of a primary tumour, to help prevent remittance. Furthermore, some photosensitizers fluoresce as they form singlet oxygen. This could be used to develop cancer imaging techniques to pinpoint tumour locations based on fluorescence¹.

Lastly, a new molecular named QLT0074 may have uses in treating benign prostatic hyperplasia (a very common form of prostate disease developed by over 50% of males) and androgenetic alopecia (male pattern baldness responsible for over 90% of hair loss in males) if it proves successful in PDT trials.

Other diseases that could potentially be treated by PDT include psoriasis (an immune-mediated chronic skin disease - see The National Psoriasis Foundation) and other dermatological disorders, bacterial infections (see Centre for Photobiology and Photodynamic Therapy), cardiovascular diseases (see Mirivant Medical) and inflammation (see Pharmacyclics Inc.).

Currently, there are three PDT drugs approved for use. One is QLT's verteporfin used in macular degeneration¹. Another is Photofrin, the original photosensitizer first used in PDT in the 1970's. It is licensed for use in the esophagus, lung, stomach, cervix and bladder, but has low penetrance (0.5 cm) in tissue, is not very cytotoxic and skin sensitivity after treatment can last for several weeks². Lastly, R-aminolaevulanic acid (ALA) is a naturally occurring precursor in the heme (a component of hemoglobin in blood) biosynthetic pathway and is used for treating a non-malignant disorder that is often the first warning sign of future skin cancer: actinic keratosis.

Commercial Products

Visudyne® for the treatment of wet age-related macular degeneration (AMD), pathologic myopia and presumed ocular histoplasmosis

QLT has partnerships with medical device companies to develop the PDT-lights used in the therapies.

Website

http://www.qltinc.com

Other companies doing similar work:

Miravant Medical Technologies
http://www.miravant.com/

Pharmacyclics, Inc.
http://www.pharmacyclics.com/webpage_templates/home.php3

LumaCare
http://www.lumacare.com/

Axcan Scandipharm Inc.- Distrubutors of Photofrin ®
http://www.axcanscandipharm.com/products/photofrin_pl.html

Luvulan ® -Photosensitizer from DUSA Pharmaceuticals
http://www.dusapharma.com/html/products.htm

References:

1. Hopper C. 2000. Photodynamic Therapy: a clinical reality in the treatment of cancer. The Lancet Oncology 1: 212-219.
   
2. Konan YN, Gurny R, Allemann E. 2002. State of the art in the delivery of photosensitizers for photodynamic therapy. J. Photochem Photobiol. 66: 89-109.
   
3. QLT website:
      http://www.qltinc.com

Links

Leeds University Centre for Photobiology and Photodynamic Therapy
http://www.bmb.leeds.ac.uk/pdt/index.html

Photobiology Online
http://www.pol-us.net/

University of Liverpool- Experimental Ophthalmology Unit
http://www.liv.ac.uk/ophthalmology/amd.htm

Queen's University photosensitizer's for cancer therapy
http://www.parteq.queensu.ca/techs/lifesci/porphyrin.html