With several molecularly targeted drugs now available and many others in development, the days may be numbered for conventional chemotherapy drugs, which were developed primarily for their ability to kill rapidly proliferating cells. However, one research group is well on the way to developing a new way to target the delivery of standard chemotherapy drugs, one that may fully harness their potency while reducing their toxicity.

"These new agents are designed to target tumors for better treatment of cancer," says Dr. John W. Park, who leads the team of researchers from the University of California, San Francisco (UCSF), funded by NCI's Specialized Programs of Research Excellence (SPORE), which developed this technology. "Oncologists have many chemotherapy drugs that are very good at killing cells - we just need a way of directing them specifically to cancer cells in order to cut back on their side effects."

To accomplish this goal, tens of thousands of chemotherapy drug molecules are loaded into synthetic nanoparticles called liposomes, which have a knack for penetrating cells. Researchers then take multiple copies of portions of antibodies that specifically recognize receptors highly expressed by cancer cells and attach them to the liposomes' perimeter. Antibody fragments for this approach include those discovered using phage antibody library technology developed by Dr. James D. Marks, another member of the UCSF Breast SPORE team. The end product is a novel targeted nanoparticle they call an immunoliposome.

"A liposome is a type of nanoparticle that can be created when lipids are mixed with water," explains Dr. Stephen Creekmore, chief of NCI's Biological Resources Branch. Liposomes have a fatty exterior that holds their contents and may help them slip into cells, but they have no inherent ability to target specific cells. "But, by combining these particles with antibodies, the goal is to target chemotherapeutic agents more specifically to tumors," he says.

So far, Dr. Park's team has focused on aiming these immunoliposomes at two receptors: HER2, which is often overexpressed in breast cancer, and EGFR, which is overexpressed in many cancers including lung, colorectal, brain, pancreatic, ovarian, breast, and prostate tumors. Both receptors are involved in cell growth and development, and have been in the crosshairs of other heralded molecularly targeted agents, including trastuzumab (Herceptin), cetuximab (Erbitux), gefitinib (Iressa) and erlotinib (Tarceva). The scientists have succeeded in loading several chemotherapy drugs, including doxorubicin, vinorelbine, epirubicin, topotecan, and irinotecan, into the immunoliposomes.

In studies with cancer cells in culture and tumor models in mice, the immunoliposomes demonstrated a remarkable affinity for cancer cells, with minimal release of their contents into the bloodstream. This precise targeting has generated the results the team had hoped for: increased effectiveness and reduced toxicity compared with conventionally administered chemotherapy.

"In essence, instead of just dumping the chemotherapy drugs into the bloodstream for dissemination, the immunoliposome serves as a protective package with a way to target the delivery of its contents," notes Dr. Creekmore. The team collaborated with NCI's Biological Resources Branch for initial manufacturing of large-scale quantities of immunoliposomes for use in preclinical testing.

"Though it might seem like a straightforward process to conjugate the antibodies onto the liposomes, our biopharmaceutical development program at NCI-Frederick worked with Dr. Park's group to iron out several wrinkles in the manufacturing process to make consistent clinical-grade materials," Dr. Creekmore says. Details of this research have been recently published online in Biotechnology Progress. "Once we demonstrated that it could be feasibly done, the approach could be realistically evaluated by commercial companies that were interested in moving forward with the clinical trials."

Dr. Park's team is collaborating with Hermes Biosciences and Johnson & Johnson to manufacture and test their immunoliposomes in clinical trials.

"The toxicology testing of immunoliposomes loaded with doxorubicin is nearing completion. We eagerly anticipate moving this agent ahead through clinical trials," says Dr. Park. "We believe that this approach is flexible and can be used with new nanoparticle-based or liposomal drugs as well as different antibodies."

"Meanwhile, if clinical trials can demonstrate efficacy of the doxorubicin-laden immunoliposomes, we might see them on the market a few years from now," says Dr. Creekmore.

By Sunil Jani