Leaf Huang, PhD, began his studies at college majoring in physics, but he had a change of heart. Thirty-some years later, he spends his day making deliveries.

Leaf Huang, PhD Fred Eshelman Distinguished Professor and Division Chair Division of Molecular Pharmaceutics Research Interests Leaf Huang's Laboratory of Drug Targeting conducts research on liposomes and immunoliposomes for drug delivery. Current activities are focused on the development of nonviral vectors for gene (including oligonucleotides) therapy, and receptor-mediated drug and vaccine targeting using self-assembled nanoparticles. The technologies are tested for therapy of cancer and other diseases in animal models.

No, you won’t see Huang standing at your door with a pizza in his hands; rather, he delivers cancer treatment to the cells that need it. Huang, the chair of the Division of Molecular Pharmaceutics at the UNC School of Pharmacy, is using his three-plus decades of research experience to design new methods of drug delivery that could make gene therapy an effective weapon in the fight against cancer.

Still Using Physics
Huang first began investigating drug delivery during his postdoctoral training at the Carnegie Institution of Washington. In the years since then, he has become a leader in drug delivery and gene therapy research, publishing more than 280 peer-reviewed articles and more than 100 invited reviews and book chapters. He also has co-edited two books.

Before coming to UNC-Chapel Hill, Huang was the Joseph Koslow Professor of Pharmaceutical Sciences at the University of Pittsburgh, where he directed the Center for Pharmacogenetics. The center, established in 1999, helped the University of Pittsburgh move from twenty-ninth to sixth among schools of pharmacy in funding from the National Institutes of Health. Since bringing his Laboratory for Drug Targeting with him to Chapel Hill in 2005, Huang has helped the UNC School of Pharmacy rise from fourteenth to eighth in NIH funding.

Huang’s road to success, however, wasn’t always a straight path. While physics was his first program of study at National Taiwan University, he later decided his interests lay in biology. However, the curriculum did not allow him to change his major. For that reason, he had trouble getting accepted into a graduate program in biology in the United States. Finally, he found a place in the biophysics program at Michigan State.

“I was always interested in biology, so for a time I thought I chose the wrong major,” Huang says. “But looking back, I don't regret the choice. Physics provides very good general science training. With that kind of background, it was very natural for me to get into biology because biology nowadays is a quantitative science.

“We still do biophysics in my laboratory. For example, one of the formulations that we are making requires a high-pressure, high-temperature chamber. We designed that chamber. We still use physics in our work. It was definitely not a waste.”

It’s All in the Delivery

Huang is using his drug-delivery experience to make gene-therapy treatment for cancer safer and more efficient. His lab is working on therapeutic treatments for lung cancer and lung metathesis of melanoma, as well as a vaccine for cervical cancer.

Cancer is characterized by unregulated cell growth caused by damage to the genes that control cell division. Gene therapy takes several approaches to treating cancer, but the common process involves delivering specifically designed genes into cells and incorporating them into the cells’ genetic structure to achieve the desired effect by silencing or expressing certain genes.

Huang says that while designing the genes to treat cancer is relatively simple, getting them to the right cells is tricky. In fact, the need for more efficient and precise delivery methods is one of the major issues preventing gene therapy from becoming a common treatment for disease.

“These molecules are very big, so they need to cross the cell membrane to get inside the cell to be functional,” Huang says. “The second challenge is that they are unstable, so you have to protect them during delivery.”

Currently, the most common technique of drug delivery uses viral vectors. Scientists replace the disease-causing genes in a virus with genes designed to achieve a specific effect. When the modified virus infiltrates body cells and incorporates its genetic materials into those of the cells, the designed genes become part of the cells’ DNA and produce the desired effect.

However, this method could cause harmful side effects, due in part to the fact that viruses are pathogenic and could infect healthy cells as well as cancer cells. Some researchers, including Huang, are studying an alternative: using liposomes—spherical vesicles that have a membrane composed of a lipid bilayer—to carry genes to the cells.

A Novel Vector

Huang’s lab has produced a novel nonviral vector called LPD nanoparticles, which is consisted of lipid, polycations (molecules with multiple positive charges), and DNA. This vector has been used in a clinical trial to treat children with Canavan’s disease.

To solve the problem of delivering the genes to the right cells, anisamide ligands are attached to the surface of the LPD nanoparticles. These molecules bind to specific receptors that are only found on the surface of many human lung cancer cells. Huang’s research has shown this method to be effective in directing the LPD nanoparticles to their targets.

When mixed in the right amounts and the right order, the ingredients in LPD automatically form nanoparticles with DNA encapsulated inside. The DNA in turn acts as a carrier for siRNA, a much smaller molecule that does the actual work in silencing genes.

“siRNA uses a natural mechanism in eukaryotic cells that the cells use to silence a gene,” Huang says. “What we have done is to design the siRNA and then deliver it into the cell. The siRNA joins the cellular silencing function and silences the target gene.

“We try to silence those genes that are important to the growth of cancer cells. If we succeed in silencing those genes, the cancer can’t grow any more.”

One of the genes that Huang is targeting produces vascular endothelial growth factor, a protein produced by tumor cells. VEGF spurs the growth of blood vessels from surrounding tissues to a tumor, providing the tumor cells with nutrients.

“We use siRNA delivered to the tumor cells to cut off the VEGF,” Huang says. “We try to silence the VEGF gene. If silenced, the tumors cannot send signals to attract the vessels, and they basically starve to death.”