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High-density lipoproteins (HDL) haul excess cholesterol to the liver for disposal, but new research suggests so-called 'good cholesterol' can also act as a special delivery vehicle that can help destroy tumors. According to research published in the journal Neoplasia, synthetic HDL nanoparticles loaded with small interfering RNA (siRNA) can silence cancer-promoting genes selectively, shrinking or destroying ovarian cancer tumors in mice. The team that carried out this study was led by Anil Sood of The University of Texas MD Anderson Cancer Center and Andras Lacko of the University of North Texas Health Science Center.
"RNA interference has great therapeutic potential, but delivering it to cancer cells has been problematic," said Dr. Sood, who is the co-principal investigator of the Texas Center for Cancer Nanomedicine - one of nine Centers of Cancer Nanotechnology Excellence funded by the National Cancer Institute. "Combining siRNA with HDL provides an efficient way to get these molecules to their targets," said Sood.
Based on these results, the investigators are starting the process that they hope will lead to human clinical trials.
"If we can knock out 70, 80 or 90 percent of tumors without drug accumulation in normal tissues in mice, it is likely that many cancer patients could benefit from this new type of treatment in the long run," Dr. Lacko said.
Previous studies have shown that cancer cells attract and scavenge HDL by producing high levels of its receptor, SR-B1. As cancer cells take in HDL, they grow and proliferate. The only other site in the body that makes SR-B1 receptor is the liver. This selectivity for cancer cells protects normal, healthy cells from side effects.
Earlier attempts to deliver siRNA by liposomes and other nanoparticles have been hampered by toxicity and other concerns, including drug stability.
"If siRNA is not in a nanoparticle, it gets broken down and excreted before it can be effective," Dr. Sood said. "HDL is completely biocompatible and is a safety improvement over other types of nanoparticles."
The team developed a more stable synthetic version of HDL called rHDL.
Using rHDL as a delivery method has other advantages as well. rHDL has not shown to cause immunologic responses, helping to minimize potential side effects, Dr. Lacko explained, and it exhibits longer time in circulation than other drug formulations or lipoproteins. Also, because SR-B1 is found in the liver, an rHDL vehicle may help block and treat metastasis to that organ.
In their studies, the researchers first confirmed the distribution of SR-B1 and the uptake of rHDL nanoparticles in mice injected with cancer cells. They found that siRNA was distributed evenly in about 80 percent of a treated tumor. As expected, the nanoparticles accumulated in the liver with minimal or no delivery to the brain, heart, lung, kidney or spleen. Safety studies showed uptake in the liver did not cause adverse effects.
Using two siRNAs, one tailored to shut down the gene STAT3, and one to shut down the FAK gene, the investigators aimed to attack treatment-resistant ovarian cancer tumors. STAT3 and FAK are important to cancer growth, progression, and metastasis; however, they also play important roles in normal tissue so targeting precision is vital. The siRNA/rHDL formulation alone reduced the size and number of tumors by 60 to 80 percent. Combinations with chemotherapy caused reductions above 90 percent.
Conventional approaches to target STAT3 have met limited success, Dr. Sood said. FAK, which is over expressed in colorectal, breast, ovarian, thyroid and prostate cancers is particularly activate in ovarian cancer that overactivity is one reason for the poor survival rate for ovarian cancer. While previous attempts have targeted FAK with liposomal nanoparticles or small molecule inhibitors, these methods are not tumor-specific and are more likely to harm normal cells, the scientists noted.
"In order to help expedite the study's progress to a clinical setting, we have identified 12 genes as biomarkers for response to STAT3-targeted therapy," Sood said. "Next, we'll work with the National Cancer Institute Nanoparticle Characterization Lab to develop a formulation of the HDL/siRNA nanoparticle for human use."
About The National Cancer Institute (NCI)
To help meet the goal of reducing the burden of cancer, the National Cancer Institute (NCI), part of the National Institutes of Health, is engaged in efforts to harness the power of nanotechnology to radically change the way we diagnose, treat and prevent cancer.
The NCI Alliance for Nanotechnology in Cancer is a comprehensive, systematized initiative encompassing the public and private sectors, designed to accelerate the application of the best capabilities of nanotechnology to cancer.
Currently, scientists are limited in their ability to turn promising molecular discoveries into benefits for cancer patients. Nanotechnology can provide the technical power and tools that will enable those developing new diagnostics, therapeutics, and preventives to keep pace with today’s explosion in knowledge.
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