HSC RESEARCHERS INVESTIGATE NOVEL DRUG DELIVERY SYSTEM

February 1, 2003

Researchers at UNT Health Science Center are investigating a more effective way to deliver anticancer medication to tumors.

Andras Lacko, PhD, professor of molecular biology and immunology, and Walter McConathy, PhD, associate professor of internal medicine, are investigating whether reconstituted high density lipoproteins (rHDL) can be used to transport anticancer medication directly to tumors.

Reconstituted HDL is a combination of anticancer medication and natural components found in HDL, typically referred to as the carrier of â??good cholesterol.â? Fatty materials called lipids and a protein called apolipoprtein (A1) are taken from HDL and reassembled with anticancer medication into rHDL, which the researchers expect will act as a transport vehicle, delivering the medication directly to cancerous cells through a process called receptor binding, Dr. McConathy said.

Cancer cells contain pathways into the cell, called SRB-1 receptors, that recognize and interact with A1, the main protein in rHDL. Drs. McConathy and Lacko have shown in cellular models that the anticancer medication contained in rHDL is likely taken up via the cancer cellâ??s SRB-1 receptors. â??The core of the rHDL contains the cargo, or anticancer medication, and the cancer cellâ??s receptors on the cell surface represent the dock where the cargo is unloaded,â? Dr. Lacko said. â??The HDL particle is then released into the blood to resume its normal functions.â?

Drs. McConathy and Lacko suggest that the pathway through SRB-1 would also help combat a patientâ??s resistance to anticancer drugs. â??Resistance to anticancer drugs is a big problem, similar to antibiotic resistance,â? Dr. Lacko said. Cancer cells pump the medication back out of the cell to defend themselves against the anticancer drugs, he explained.

Since the type of contact with the surface of a cancer cell affects whether it will resist the medication, resistance may be reduced if contact with the wall of a cancer cell is altered. They theorize that using SRB-1 as a different pathway into the cell may bypass the usual mechanisms that pump drugs out of cancerous cells.â??By using the SRB-1 pathway to deliver medicine to a tumor, we may be able to improve the effectiveness of anticancer drugs,â? Dr. McConathy said. They plan to focus on this possible benefit in future research.

Another benefit of rHDL is that it facilitates the solubility, or dissolvability, of cancer drugs, Dr. Lacko said. Solubility is important because most cancer drugs are administered intravenously. In most current preparations, substances called solubilizers must be mixed with the cancer medication to liquefy it before it can be injected into the bloodstream. Solubilizers are often toxic, leading to many of the unpleasant side effects of chemotherapy, Dr. McConathy said.

rHDL contains lipoprotein, a large complex molecule of lipids and proteins that naturally carries substances that are not ordinarily soluble, such as cholesterol or fat, Dr. Lacko said. The researchers theorize that because the anticancer medication would be carried by the lipoprotein in the rHDL complex, it would already be in a form that could navigate through the body without the need for solubilizers.

Drs. McConathy and Lacko have also shown in cellular models using the anticancer drug taxol that the rHDL complex is stable. â??It can stay in the body longer in the rHDL complex, compared to the conventional methods of delivering cancer medication.â?

While the use of rHDL as a drug delivery mechanism is still in its early, developmental stages, Drs. McConathy and Lacko believe it shows great promise. â??We believe this project has a practical application for patient care and a clear path to utilization,â? Dr. Lacko said. â??Hopefully, this will progress quickly to a point where it can help patients.â?

Most cancer research takes 10 years or longer to reach that point, but Dr. Lacko hopes to see clinical trials of the rHDL delivery system in less than five years.â??We hope this will have general applicability in treating cancer, but itâ??s hard to imagine there wonâ??t be at least one or two types of tumors that will be very sensitive to this improved rHDL therapy,â? Dr. McConathy said.

Drs. McConathy and Lacko have been involved in lipoprotein research for more than 25 years and have applied for a patent on the rHDL drug delivery technology. In 2001, they launched Lipomedics Ltd. Co., a private venture that licensed the rights to the rHDL technology through the health science center.They began their partnership in cancer research through their membership in the health science centerâ??s Institute for Cancer Research. The ICR encourages collaboration between researchers with different specializations and helps translate laboratory findings into clinical studies among patients, according to Kenneth Brunson, PhD, director of the institute.

Their research is funded primarily by the Breast Cancer Research Program at the Department of Defense and the Institute for Cancer Research. The James Winterringer Memorial Fund for Prostate Cancer Research also provided a donation that allowed them to purchase much needed laboratory equipment. For information on how to help Drs. Lacko and McConathy in the war against cancer, call 817-735-2113.

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