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Nanotech delivery system shows its mettle against ovarian cancer in mice
CAMBRIDGE, Mass.—Attempting both to curb the threat of ovarian cancer and to provide perhaps the first effective therapy for advanced ovarian cancer, researchers with the Massachusetts Institute of Technology (MIT) and the Lankenau Institute for Medical Research (LIMR) in Wynnewood, Pa., have reported that a nanoparticle delivery system carrying a "killer gene" has effectively suppressed ovarian tumor growth in mice.
In the United States alone, ovarian cancer causes more than 15,000 deaths annually and ranks as the fifth-leading cause of cancer-related death in women as well as the leading cause of death from gynecologic cancers. Much of this because the disease is generally diagnosed at a relatively late stage, and effective therapies are available neither for late-stage disease victims nor for those with cancer recurrence, note MIT and Lankenau researchers.
The research findings were published in the Aug. 1 issue of the journal Cancer Research, and address how the nanotech method delivers a gene that produces the diphtheria toxin, which kills cells by disrupting their ability to manufacture proteins. After some additional preclinical studies have been undertaken, human trials are expected within a year or two, says Daniel Anderson, research associate in the David H. Koch Institute for Integrative Cancer Research at MIT and a senior author of the paper.
"Unlike chemotherapy, which can destroy both cancer and healthy cells and lead to many adverse effects, this new therapy specifically targets cancer cells and leaves the healthy cells alone," affirms Dr. Janet Sawicki, a professor at LIMR who lead the LIMR researchers in this work. "Our hope is to begin doing clinical trials in patients in the next 18 to 24 months and then potentially tailor this therapy to treat different solid tumor types including pancreatic, prostate and cervical cancers."
Anderson and others from MIT, including professor Robert Langer, along with the LIMR team, found that the gene-therapy treatment was equally as effective, and in some cases more effective, than the traditional chemotherapy combination of cisplatin and paclitaxel. Furthermore, it did not have the toxic side effects of chemotherapy because the gene is engineered to be overexpressed in ovarian cells but is inactive in other cell types.
The researchers went an extra step to keep the therapy tumor-focused by administering the nanoparticles via injection into the peritoneal cavity of the mice. This cavity encases abdominal organs such as the stomach, liver, spleen, ovaries and uterus, and ovarian cancer is known to initially spread throughout the peritoneal cavity. The new nanoparticles were made with positively charged, biodegradable polymers that, when mixed together, can spontaneously assemble with DNA to form nanoparticles. The polymer-DNA nanoparticle can deliver functional DNA when injected into or near the targeted tissue. Reportedly, there is no clinical precedent for the use of this C32-117 poly(beta-amino ester) polymer as a delivery vehicle.
The researchers also note in their paper that, given the rapid shutdown of protein synthesis following uptake and expression of diphtheria toxin-encoding (DT-A) DNA, it is likely that cells will show no resistance to the nanotherapy, meaning that it may be possible to administer DT-A nanotherapy over an extended period of time to suppress tumor growth, and perhaps even reduce tumor burden.
"Currently, ovarian cancer patients are treated with chemotherapeutics following surgical debulking. Further studies…will be aimed at assessing the therapeutic efficacy of DT-A nanotherapy as an adjuvant therapy to surgical debulking," the researchers wrote.
The MIT-Lankenau team has been working on this method for several years now because they wanted an alternative to viral delivery methods, which they felt were associated with too many safety risks. In addition to ovarian and other types of cancer, these nanoparticles have demonstrated potential for treating viral infections as well, the researchers note.
Future studies already in the planning stages by the MIT-Lankenau team are expected to examine the effectiveness of nanoparticle-delivered diphtheria toxin genes in other types of cancer, including brain, lung and liver cancers.