Nanoliposomes engineered to deliver therapeutic drugs that kill malignant cells

A new way to deliver cancer-fighting drugs using tiny particles made from lipids and chemotherapy drugs may have the power to knock out malignancies with a one-two punch. The strategy holds promise for patients with many different kinds of cancers.

“By combining ceramide with tamoxifen we've created a synergistic combination that we hope will effectively induce cell death in cancer models.”

In a collaboration between John Wayne Cancer Institute (JWCI), Penn State College of Medicine and the University of Connecticut, researchers are testing microscopic "nanoliposomes" engineered to deliver therapeutic drugs that can both kill malignant cells and cripple the cancer's ability to resist further attack.

For years, Myles C. Cabot, Ph.D., director of the Laboratory of Experimental Therapeutics at JWCI, has been studying ceramide, a waxy substance that occurs naturally in the body. Among its other biological roles, ceramide is part of a regulatory system that prevents cancer cells from growing and triggers cell death.

Dr. Cabot's work centers on a soluble, short-chain version called C6-ceramide which enters cancer cells more easily than long-chain molecules. C6-ceramide has been shown to kill malignant cells, but eventually, the cells acquire the ability to chemically convert ceramide into an inactive form, allowing the cancer to start growing again.

This phenomenon, called chemotherapy resistance, occurs with many anticancer drugs, and is a major cause of treatment failure. Unfortunately, when a cancer returns, treatment is typically more complex and less effective, and patient outcomes are poorer. Combinations of chemotherapy drugs are often used to overcome this resistance.

Now, Dr. Cabot's lab is testing nanoliposomes, particles with diameters measured in billionths of a meter, in a two-part anticancer system. With an exterior coat of C6-ceramide, each particle is like a tiny bubble that can encapsulate other drugs inside itself. The researchers will fill the bubbles with tamoxifen, a well-known anticancer drug that prevents the unwanted conversion of ceramide into its inactive form. As C6-ceramide is relatively soluble, it dissolves, releasing the tamoxifen. The combination should effectively increase ceramide's residence time, allowing it to kill the cancer without being deactivated.

The world's most-prescribed breast cancer agent, tamoxifen is also effective in fighting certain other cancers as well. Recent laboratory studies show that nanoformulations of C6-ceramide with tamoxifen effectively inhibit growth of colon and breast cancer cells and acute myelogenous leukemia (AML).

"We have already shown that C6-ceramide effectively retards growth of cancer cells," Dr. Cabot asserted. "By combining ceramide with tamoxifen we've created a synergistic combination that we hope will effectively induce cell death in cancer models."

The tamoxifen-filled C6-ceramide nanoliposomes are being tested in AML cells by Dr. Cabot's group. The next phase of research will include preclinical studies by Mark Kester, Ph.D., Professor of Pharmacology at Penn State College of Medicine, and Director of the Penn State Center for NanoMedicine and Materials. Similarly, the nanoliposomes will be tested on colon cancer cells at JWCI, then in preclinical models by University of Connecticut researcher Daniel W. Rosenberg, Ph.D.

"These nanoliposomes deliver a one-two punch, killing cancer cells while they prevent chemotherapy resistance," Dr. Cabot said. "We believe these will provide us with a new stealth weapon against cancer. It's exciting to think we may have a next-generation strategy that could be applied to many other malignancies, including blood cancers as well as solid tumors like breast, prostate and pancreatic cancer."

Dr. Cabot's work has attracted interest from Federal health agencies: The current project was awarded a supplemental grant from the National Institute of General Medicine. Dr. Kester is the inventor of the C6-ceramide nanoliposome, which is being licensed through Penn State Research Foundation.