Sebaceous gland targeting with photodynamic therapy

Vancouver, British Columbia - A new topical photodynamic therapy (PDT) agent may someday be added to the armamentarium of drugs to treat skin conditions with acne.

Speaking here at the Dermatology Update 2004, Dr. David Hunt, associate director of dermatology in the scientific affairs division of Vancouver-based QLT, Inc., the maker of lemuteporfin, also referred to as QLT0074, spoke of success obtained with PDT using lemuteporfin, a compound that is not yet approved for clinical use, in preclinical animal studies to shrink sebaceous glands. The compound is also being investigated in clinical trials for its efficacy in treating benign prostatic hyperplasia in an injectable formulation and androgenetic alopecia using a topical formulation.

How it works PDT involves light-activated drugs, or photosensitizers, to treat cancer, ocular and dermatological conditions, says Dr. Hunt, adjunct professor with the Department of Pathology and Laboratory Medicine at the University of British Columbia. Short-term contact PDT has shown promise in treating conditions like acne using the photosensitizer pro-drug aminolevulinic acid (ALA), with the only reported side effect being facial redness. The drug reaches sebaceous glands by entering the skin through the hair follicles.

"There have been reports of PDT in the treatment of acne," Dr. Hunt says.

QLT researchers observed that lemuteporfin did not effectively penetrate the outer stratum corneum layer, which protects the body against many environmental insults.

"One of the interesting observations we have made in animal studies is that it selectively penetrates sebaceous glands when applied topically," he says.

An unknown Since the activation of sebaceous glands fuels acne, effectively shutting the glands down would be a means of treating acne and avoiding future flare-ups. Dr. Hunt notes, however, that researchers do not know how the agent will behave when the gland outlet is plugged as may be the case for individuals with acne.

Standard agents of therapy such as iostretinoin (Accutane, Roche) are administered orally, and, therefore, may produce systemic side effects, explains Dr. Hunt.

Indeed, use of Accutane in women who are pregnant has resulted in birth defects including physical malformation with up to 50 percent of newborns being mentally disabled. Women who are trying to become pregnant have been advised against taking oral retinoids.

More common reported side effects of Accutane include conjunctivitis, dry or fragile skin, dry or cracked lips, dry mouth, dry nose, itching joint pains and nose bleeds. Less common side effects include bowel inflammation and pain, chest pain, decreased night vision, decreased tolerance to contact lenses, delay in wound healing, depression, fatigue, headache, nausea, peeling palms or soles, rash, skin infections, stomach and intestinal discomfort, sunburn-sensitive skin, thinning hair, urinary discomfort, vision problems and vomiting.

Treatment efficacy "Using PDT with topical application of the photodynamic agent may provide good treatment efficacy combined with the feature that the drug acts only in the target area, since the compound is only active when exposed to the red light," Dr. Hunt says. "Further, these QLT preclinical PDT studies showed that the size of mouse sebaceous glands could be substantially reduced without any overt skin damage."

For the mouse studies, a lemuteporfin skin contact time of about 30 minutes followed by exposure of the skin to a (non-thermal) red light dose of 100 J/cm² was required to produce the reductive effect on the sebaceous glands. Lemuteporfin is rapidly taken up by living cells which enter the cytoplasm and associates with mitochondria, an important feature which endows the photosensitizer with a potent cell-killing activity upon light activation.

"We may be able to achieve a good clinical response against acne with little systemic risk and relatively few treatments," Dr. Hunt says. "The compound is highly potent and clinicians would likely not need to get a large amount of the drug into the glands to achieve an effect. The skin doesn't need to be overwhelmed to produce a response, and the response that we do achieve is dependent upon the exposure to light."