Fatty spheres loaded with siRNA shrink ovarian cancer tumors in preclinical trial
Nanoparticles slip through blood vessel pores to attack tumor
(HOUSTON) -- A molecular "off" switch packaged in a tiny sphere penetrates deeply into ovarian cancer tumor cells, stifling a troublesome protein and drastically reducing the size of tumors, researchers at The University of Texas M. D. Anderson Cancer Center report in the Aug. 15 edition of Clinical Cancer Research.
The mouse model experiment, featured on the cover of the journal, demonstrates a potent delivery system for short interfering RNA (siRNA) to attack cancer, says senior author Anil Sood, M.D., associate professor in the Departments of Gynecologic Oncology and Cancer Biology at M. D. Anderson.
"Short interfering RNA is a great technology we can use to silence genes, shutting down production of harmful proteins," Sood says. "It works well in the lab, but the question has been how to get it into tumors." Short pieces of RNA don't make it to a tumor without being injected directly, and injection methods used in the lab are not practical for clinical use.
The research team took siRNA that targets a protein that helps ovarian cancer cells survive and spread and rolled it into a liposome -- a lipid ball so small that its dimensions are measured in nanometers (billionths of a meter).
Getting the siRNA inside tumor cells is important, Sood said, because the targeted protein, focal adhesion kinase (FAK), is inside the cell, rather than on the cell surface where most proteins targeted by cancer drugs are found. "Targets like FAK, which are difficult to target with a drug, can be attacked with this liposomal siRNA approach, which penetrates deeply into the tumor," Sood said.
Mice infected with three human ovarian cancer cell lines derived from women with advanced cancer were treated for 3-5 weeks. They received liposomes that contained either the FAK siRNA, a control siRNA, or were empty. Some mice received siRNA liposomes plus the chemotherapy docetaxel.
Mice receiving the FAK-silencing liposome had reductions in mean tumor weight ranging from 44 to 72 percent compared with mice in the control groups. Combining the FAK-silencing liposome with docetaxel boosted tumor weight reduction to the 94-98 percent range.
These results also held up in experiments with ovarian cancer cell lines resistant to docetaxel and to the chemotherapy drug cisplatin.
The FAK-silencing liposome and the liposome with chemotherapy also reduced the incidence of cancer by between 20 and 50 percent in all tested cancer lines.
In addition to its anti-tumor effect, the researchers found that the therapeutic liposome attacked the tumor's blood supply, especially when combined with chemotherapy. By inducing cell suicide (apoptosis) among blood vessel cells, the treatment steeply reduced the number of small blood vessels feeding the tumor, cut the percentage of proliferating tumor cells and increased cell suicide among cancer cells.
Sood and Professor of Molecular Therapeutics Gabriel Lopez-Berestein, M.D., an expert in liposomal therapeutics, cite at least two factors for the success of the anti-FAK liposome.
"This particle is so small, it has no problem getting through the tumor's vasculature and into the tumor," Lopez-Berestein says. The FAK-targeting liposome ranges between 65 and 125 nanometers in diameter. Blood vessels that serve tumors are more porous than normal blood vessels, with pores of 100 to 780 nanometers wide. Normal blood vessel pores are 2 nanometers or less in diameter.
Second, the liposome -- a commercially available version known as DOPC -- has no electrical charge. Its neutrality provides an advantage over positively or negatively charged liposomes when it comes to binding with and penetrating cells.
The next step for the FAK siRNA-DOPC liposome is toxicity testing. "So far it appears to be very well-tolerated," Sood says. "We hope to develop this approach for clinical use in the future."
In addition to ovarian cancer, FAK is overexpressed in colon, breast, thyroid, and head and neck cancers.
Co-authors with Sood and Lopez-Berestein are first author Jyotsnabaran Halder, Ph.D., Aparna Kamat, M.D., Charles Landen, M.D., Liz Han, M.D., Yvonne Lin, William Merritt, Nicholas Jennings, Robert Coleman, M.D., David Gershenson, M.D., and Rosemarie Schmandt, Ph.D., all of the Department of Gynecologic Oncology at M. D. Anderson; Arturo Chavez-Reyes of the Department of Experimental Therapeutics at M. D. Anderson; and Susan Lutgendorf, Ph.D., and Steven Cole, Ph.D., of the Department of Medical Hematology Oncology at UCLA.
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