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New Nanodisk Antibiotic Formulation Could Reduce Toxicity, Increase Efficacy

"We found we can make a new formu-lation, with particles that are much smaller and completely water soluble. These two features represent significant advantages that may be preferable in patient administration."

In a new study just published in the March 4th online Journal of Pharmaceutical Sciences, CHORI senior scientist Robert Ryan, PhD, reports on his laboratory’s development of a new formulation of the anti-fungal antibiotic, amphotericin B. Three lipid formulations of the antibiotic are already FDA-approved, however Dr. Ryan and his colleagues recognized that the human apolipoprotein-A (apo-A-I) molecules they had been studying in their basic research could potentially be added to an existing formulation, Amphotericin B Lipid Complex (ABLC) to form water-soluble, nanometer-scale, high density lipoprotein like particles, called nanodisks.

While fungal infections are not a problem for most individuals, many people, adults and children alike, who are immunocompromised for any reason, face severely increased risks of infection.

"It's known that the incidence of fungal infections is significantly on the increase," says Dr. Ryan. "Anyone who has any kind of depressed immune system, either because they've undergone transplants, cancer treatments, or have HIV, is at great risk of fungal infection."

Amphotericin B (AMB) has been the gold standard for the treatment of fungal infections for nearly 5 decades, but has always been hampered by its toxicity, which causes significant problems for patients. While the newer ABLC formulations approved within the last 10 years do confer protection against the toxicity that has been associated with AMB, Dr. Ryan's new AMB nanodisk (AMB-ND) formulation has unique properties that suggest it could have the potential to be used in the development of the next gold standard of treatment.

"One advantage is that it could be nebulized for aerosol delivery, which may be beneficial for patients or individuals who have a pulmonary fungal infection," explains Dr. Ryan.

"In addition, the nano-scale size is advantageous because it's going to allow entry of the molecule to locations and sites in body that may not be accessible to larger molecules, while also representing a more stable entity that can circulate longer in the blood stream."
Although this particular study utilized the already commercially available ABLC product as a starting material, Dr. Ryan would ultimately like to be able to use different lipid compositions to formulate the ND particles.

"A current goal is to modify AMB nanodisk particles by optimizing the formulation to generate the most efficacious, stable and effective delivery system for humans," says Dr. Ryan. "The protein component could be potentially engineered in such a way that we could actually target the vehicle to specific receptor sites in the body."

Dr. Ryan is the first to acknowledge, however, that there is still a great deal of distance to overcome between the novel development of AMB-ND and its use in the clinical environment.

"These are ideas and concepts we're putting forward which are not yet proven. What we have proven is that we're able to make those particles and that they maintain their efficacy," Dr. Ryan says. "This is just the first step."

However, with the creation of a start up biotechnology company that has been derived from research conducted
at CHORI to commercialize nanodisk technology, Lypro Biosciences Inc, and ongoing studies underway to test AMB-nanodisks in animal models and other in vivo studies, Dr. Ryan and colleague Dr. Michael Oda are moving forward as quickly as possible in the slow process of bringing AMB-nanodisks from the lab to the clinic. Drs. Ryan and Oda hope to achieve the financial backing to be able to launch a phase 1 human trial within the next 12 to 18 months.

"When you do basic research, you realize pretty quickly that it doesn't translate immediately into treatment," says Dr. Ryan. "We'd like to think, though, that by going through these steps, we have a real opportunity to translate the basic research knowledge we've gained into something useful for the patients at the bedside."

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Tuesday, May 17, 2011 8:19 AM

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