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8/30/2009 10:05:18 AM
Nanoparticle-Based Gene Therapy Technique Could Fight Late-Stage Tumors

Nanoparticle delivery of diphtheria toxin-encoding DNA that expresses selectively in ovarian cancer cells reduced the burden of ovarian tumors in mice, and researchers expect that this therapy could be tested in humans with advanced ovarian cancer within 18 to 24 months, according to a report in Cancer Research. If additional tests are successful, these finding could lead to a new treatment for ovarian cancer, which now causes more than 15,000 deaths each year in the United States. Because it is usually diagnosed at a relatively late stage, ovarian cancer is one of the most deadly forms of the disease.

The new treatment, developed by Janet A. Sawicki, Ph.D., of the Lankenau Institute for Medical Research, and Daniel Anderson, Ph.D., of the Massachusetts Institute of Technology (MIT), delivers a gene that produces the diphtheria toxin, which kills cells by disrupting their ability to manufacture proteins. The toxin is normally produced by the bacterium Corynebacterium diphtheriae. The nanoparticle used to delivery the toxin-encoding DNA was developed by MIT’s Robert Langer, Ph.D., co-principal investigator of the MIT-Harvard Center of Cancer Nanotechnology Excellence.

In preclinical studies, the investigators 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.

To further ensure tumor-focused effects, the nanoparticles were administered by injection into the peritoneal cavity, which encases abdominal organs such as the stomach, liver, spleen, ovaries, and uterus. Ovarian cancer is known to initially spread throughout the peritoneal cavity, and current therapeutic approaches in humans include direct injection into the peritoneal space, thereby targeting the therapy to the ovaries and nearby tissues where tumors may have spread.

The new nanoparticles are made with positively charged, biodegradable polymers known as poly(beta-amino esters). When mixed together, these polymers can spontaneously assemble with DNA to form nanoparticles. The polymer-DNA nanoparticle can deliver functional DNA when injected into or near the targeted tissue. For several years, the MIT-Lankenau team has been developing these nanoparticles as an alternative to viruses, which are associated with safety risks. In addition to ovarian cancer, these nanoparticles have demonstrated potential for treatment of a variety of diseases, including prostate cancer and viral infection. In future studies, the team plans to examine the effectiveness of nanoparticle-delivered diphtheria toxin genes in other types of cancer, including brain, lung, and liver cancers.

This work, which was supported in part by the National Cancer Institute, is detailed in the paper “Nanoparticle-delivered suicide gene therapy effectively reduces ovarian tumor burden in mice.” An abstract is available at the journal’s Web site.

View abstract

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