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Nanoparticle Therapy: Promising New Directions in Ovarian Cancer Treatment

Imagine a cancer treatment made from particles so small, they fit through the pores in capillary walls and can be readily engulfed by cells.

Focus article photo

Conejo-Garcia's research team includes from left to right, Juan Cubillos-Ruiz, Uciane Scarlett, Melanie Rutkowski, Jose Conejo-Garcia and Yoland Nesbeth.

Called nanoparticles because they are less than 100 nanometers in size, these ultrafine particles are about the size of a virus. Yet they are able to do things that simple molecules cannot because they are typically made of two or more molecules assembled to perform specific tasks.

One team of Norris Cotton Cancer Center researchers led by Jose Conejo-Garcia, MD, PhD, has developed just such a nanoparticle, one that is proving to be effective in treating tumors of late-stage ovarian cancer in both mice and cultured human cells.

Conejo-Garcia, an immunologist who is originally from Spain and who previously did research on ovarian cancer at the University of Pennsylvania, came to Dartmouth for "the excellent environment for working in tumor immunology." Here, his team has been able to collaborate with a variety of immunology researchers approaching ovarian cancer from different angles. "Our overarching goal is to translate what we learn in various preclinical models to a clinical setting," says Conejo-Garcia. His team also has been collaborating with Cancer Center researchers working on breast cancer, as well as engineers from Dartmouth's Thayer School studying methods for making nanoparticles.

Taking on a Tough Foe

The team's target, ovarian cancer, has been a frustratingly difficult disease for researchers. Ovarian cancer is a "silent disease," almost always starting as a tiny lump of cells in the ovary. By the time symptoms emerge it usually has already spread throughout the peritoneal cavity.

"The story with ovarian cancer is almost always the same," says Conejo-Garcia. "Initially the treatment consists of surgical debulking plus chemotherapy. Patients respond, but then after some months or years, the disease comes back, arising from chemo-resistant cells that have survived the initial treatment." Unfortunately, as of yet there is no simple test to detect early-stage ovarian cancer, though researchers are working on identifying biomarkers for that purpose.

The nanoparticles developed by Conejo-Garcia and his team don't target ovarian cancer cells. Instead, they target other cells within the tumor "microenvironment"—the collection of cells in and around a tumor. "If you look at a typical section of a tumor under the microscope, in many cases much of the space is occupied by cells that are not tumor cells," says Conejo-Garcia. Cancer cells often trick the cells around them into growing blood vessels, lending structural support, or even defending against harmful substances.

The nanoparticles developed by Conejo-Garcia and his team target dendritic cells, a type of immune cell. Normally, dendritic cells collect pieces of pathogens such as viruses and bacteria and present these pieces to T-cells, which then recognize and attack the pathogens. Unfortunately, this mechanism usually fails with ovarian cancer cells, which typically corrupt surrounding dendritic cells. These corrupted cells stop signaling T-cells, and even help the tumor to grow. Conejo-Garcia's nanoparticles consist of a piece of "shortinterfering RNA," or siRNA, encapsulated in a polymer. The nanoparticles are injected into the peritoneal cavity of ovarian cancer-bearing mice, where they are quickly engulfed by the corrupted dendritic cells protecting the cancer cells. The siRNA and the polymer in the nanoparticles activate these dendritic cells, turning them into cells that can stimulate T-cells to create an immune response against the tumor.

The team's nanoparticles have increased survival in mice with advanced ovarian cancer. The particles also have been tested on human ovarian cancer cells in culture, and shown similar changes to the dendritic cells.

The Promise of Nanoparticles

Results like these have researchers excited, and hoping for swift adoption. "Nanoparticle treatments are very new, so I think implementing them clinically will take a while," says Juan Cubillos-Ruiz, a graduate student working with Conejo-Garcia, "but I also think they're very promising. In the future maybe they'll complement classical approaches like chemotherapy and surgery."

The National Cancer Institute (NCI) also sees great promise in nanoparticle therapies. ConejoGarcia's research, along with that of collaborating teams at the Cancer Center, was funded by an NCI Nanotechnology Group Award. With his group's findings, Conejo-Garcia hopes that the Cancer Center will be designated as the newest of several NCI Excellency in Nanotechnology Centers around the country.

In the meantime, Conejo-Garcia and his team are starting experiments with different types of nanoparticles. This time, they're working with several Dartmouth teams to create nanoparticles with iron cores in place of the siRNA. Again, the particles will target cells in the tumor microenvironment. Once the iron-core particles have infiltrated the tumor, the tumor (or, in a clinical setting, the entire patient) would be placed inside a coil producing a rapidly vibrating magnetic field, similar to an MRI machine. The vibration of the magnetic field would make the iron in the nanoparticles vibrate, generating heat. "Hopefully we'll be able to send these [iron] particles to the tumor, then apply the magnetic field and literally fry the tumor without damaging surrounding tissues," says Conejo-Garcia.

Nanoparticle research may sound like science fiction at times, but at its heart it is motivated by the same principles that guide all research at Norris Cotton Cancer Center. "I decided to work on cancer research during one of my first rotations as a resident, the first time I saw a kid with leukemia," says Conejo-Garcia. "Knowing what I do can be translated to help somebody makes me certain I made the right decision."

October 10, 2009