A Penn State College of Medicine study shows for the first time in an animal model that ceramide, a naturally occurring substance that prevents the growth of cells, can be administered through the blood stream to target and kill cancer cells.

"Ceramide is the substance that accumulates in cancer tissues and helps to kill cancer cells when patients undergo chemotherapy and radiation," said Mark Kester, professor of pharmacology, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center. "By boosting the amount of ceramide through an injection in the bloodstream, our study in mice suggests that we can provide a stronger cancer-killing therapy without additional side effects."

This study, titled "Systemic Delivery of Liposomal Short-Chain Ceramide Limits Solid Tumor Growth in Murine Models of Breast Adenocarcinoma," was published in the May issue of Clinical Cancer Research, a journal of the American Association for Cancer Research.

Administering extra ceramide is not as easy as it seems. Injected directly into the bloodstream, ceramide is toxic. But Kester applied knowledge gained from previous laboratory studies in nanotechnology and encapsulated the ceramide in tiny bundles called liposomes.

"The major problem with ceramide is that it is a lipid and therefore is not soluble in the systemic circulation," Kester said. "Packaging ceramide in our nano liposome capsules allows them to travel through the bloodstream without causing toxicity and release the ceramide in the tumor."

Although the mechanism remains unknown, ceramide is inherently attracted to tumor cells. The liposome-encased ceramide travels through the bloodstream to the tumor where it enters the tumor cells through the tumor's leaky vasculature. The ceramide disrupts the mitochondria, which act as the energy producer for the cell. This causes apoptosis, or cell death. The ceramide also reduces the vascular network that feeds the tumor. In this study in mice, the ceramide bundles targeted and destroyed only breast cancer cells, sparing the surrounding healthy tissue.

Kester and his team first tested the ceramide-filled liposomes in a culture of breast cancer cells. The administration of ceramide reduced by more than 50 percent the number of breast cancer cells.
Additional cell culture studies showed that ceramide accumulated in the mitochondria of the breast cancer cells supporting earlier laboratory studies that ceramide interferes with the structure of the cell and causes tumor death.

In a mouse model of breast tumors, the team administered liposome-encased ceramide every other day via intravenous injection.
After 21 days, the mice treated with the liposome-encased ceramide had a six-fold lower tumor volume than the mice treated with "empty"
liposomes.

The weight of animals treated with ceramide did not vary significantly from the mice treated with empty liposomes signifying that the ceramide was not toxic (weight would have been lower with toxicity). When the tumors were examined, those treated with ceramide showed a 20-fold increase in cellular apoptosis and a 40 percent decrease in cellular proliferation, or growth, compared to the control group.

"Although we've shown that ceramide has an effect on breast tumor cells in mice, breast cancer cells in humans may eventually resist the treatment, suggesting that ceramide should be used in combination with more traditional cancer treatments as a treatment booster,"
Kester said. "Our next step is to explore how additional chemotherapeutic agents could be incorporated into the liposomes for a more lasting effect."

Other study team members were: Thomas C. Stover, Ph.D., Arati Sharma, Ph.D., Department of Pharmacology, and Gavin P. Robertson, Ph.D., Departments of Pharmacology, Pathology, and Dermatology, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center. All research methods were approved by the Animal Care and Use Committee of Penn State College of Medicine. This study was supported by a grant from the National Institutes of Health.

Contact: Amy Buehler Stranges abuehlerstranges@psu.edu