Rizwan Masood, Ph.D.
Researchers at the Keck School of Medicine and the State University of New York at Buffalo (SUNY) have developed a method that increases the effectiveness of radiation therapy for head and neck cancer treatment in mouse models by more than 50 percent.
The study, “Gold nanorod–sphingosine kinase siRNA nanocomplexes: a novel therapeutic tool for potent radiosensitization of head and neck cancer,” was led by first author Rizwan Masood, Ph.D., assistant professor of research in otolaryngology and conducted in the laboratory of Uttam Sinha, M.D., associate professor of otolaryngology at the Keck School. The research was published in the journal Integrative Biology
The method developed by the team led by Masood and Sinha and SUNY’s Paras Prasad, Ph.D., is designed to defeat a built-in defense mechanism that most head and neck tumors have, helping them fight off radiation therapy. To get past this mechanism, oncologists typically must deliver large doses of radiation to patients, causing surrounding tissue damage and significant side effects.
The researchers developed a nanoparticle formulation that sensitizes the tumor, and as a result, increases the efficacy of radiation therapy in a mouse model of head and neck cancer by half.
“If we can deliver the least amount of radiation to the patient, they will suffer fewer side effects and have a much better quality of life,” said Masood.
Side effects include mucositis, a condition in which the patient experiences a painful burning sensation inside the mouth, difficulty swallowing and speaking, and chronic pain syndrome caused by scarring in the neck and shoulders. A patient who undergoes heavy radiation treatments and experiences a return of the cancer is also not eligible to undergo radiation treatment again, Sinha said.
The delivery of microscopic gold nanorods to the tumor is accomplished by direct injection or via a pump developed by Ellis Meng, Ph.D., at the USC Viterbi School of Engineering.
The pump, an inch in diameter for use in mice, will be slightly larger for humans, Sinha said. The pump, made of silicone, can be programmed to deliver the gold nanorods to the tumor once or twice a day.
Uttam Sinha, M.D.
“This eliminates the need for patients to return to the clinic for injections,” said Sinha. “This is an active remote controlled pump. There are not many pumps like this on the market today.”
In the mouse experiments, gold nanorods were used to deliver a small interfering RNA (siRNA) molecule to head and neck tumors. This siRNA molecule blocks the production of a protein known as sphingosine kinase 1 (SphK1). Previous work by the USC team had shown that this protein prevents radiation-damaged cells from undergoing apoptosis, the cell death program triggered in healthy cells when they age or experience major damage.
RNA interference, which uses siRNAs to reduce the production of specific proteins, has shown promise for treating cancer and other diseases, but these molecules are readily degraded in the blood stream. To overcome this problem, the SUNY-Buffalo team, an early pioneer in the cancer nanotechnology field and an original member of the National Cancer Institute's Alliance for Nanotechnology in Cancer
, has developed biocompatible gold nanorods that can protect siRNAs from degradation and deliver them to tumors.
Working together, the two groups created a gold nanorod-siRNA construct that targets SphK1. When injected directly into head and neck tumors growing in mice prior to radiation therapy, this formulation boosted the efficacy of radiation therapy by over 50 percent. Moreover, this boost in efficacy was seen using greatly reduced doses of radiation. Animals that were treated with the nanoparticle formulation showed no ill effects from the drug. The investigators are now developing a new formulation that could be used to sensitize tumors for which direct injection of drug is not feasible.
The next step is clinical trials to test the efficacy of injections and the pump in humans, Sinha said.
The research was supported by the National Cancer Institute and the Whittier Foundation.