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In a "proof-of-concept" study, scientists at Johns Hopkins Medicine reported successfully delivering genetic code packets called nanoscale microRNAs to treat human brain tumors implanted in mice. The content of the super-small containers has been designed to target cancer stem cells, a kind of cellular "seed" that produces innumerable offspring and is an incessant barrier to rid the brain of malignant cells.
The results of their experiments were published online June 21 in Nano Letters.
"Brain cancer is one of the most well-known cancers in terms of genetic composition, but we have not yet developed a good treatment," says John Laterra, MD, Ph.D. .D., Professor of Neurology, Oncology and Neuroscience at the Johns Hopkins University School of Medicine and a researcher at the Kennedy Krieger Institute. "The resilience of cancer stem cells and the blood-brain barrier are major obstacles."
Blood entering the brain is filtered through a series of vessels that act as a protective barrier. According to Laterra, this blood-brain barrier blocks molecular drugs that could revolutionize brain cancer therapy by targeting cancer stem cells
"To modernize brain tumor treatments, we need tools and tools to methods, "explains Jordan Green, Ph.D., professor of biomedical engineering, ophthalmology, oncology, neurosurgery, materials science and engineering and d & # 39; Chemical and biomolecular engineering at the Johns Hopkins University School of Medicine. "We need the technology to deliver genetic drugs that are sensitive directly to tumors without damaging normal tissue."
Glioblastoma, the form of brain cancer that Senator John McCain is fighting in Arizona, is a good example. often requires repeated surgeries. Doctors remove brain tumor tissue that they can see, but the malignancy often comes back quickly, says Laterra. Most patients with glioblastoma live less than two years after diagnosis.
Scientists have long suspected that cancer stem cells are causing the return and spread of glioblastoma and other cancers. These stem cells give rise to other cancer cells and, if they escape the surgeon's knife, can lead to a whole new tumor.
Laterra and Green, members of the Johns Hopkins Kimmel Cancer Center, have designed an effective way of very small microRNA packets in established brain tumors. MicroRNAs target brain cancer stem cells to stop their ability to spread and support tumor growth.
Packages are made of biodegradable plastic similar to the material used for surgical sutures and which degrades over time. They are 1000 times smaller than the width of a human hair and typical of the size and shape of the natural components that cells use to communicate. When the cancer cells engulf the packets, they separate and release their microRNA "payload" specifically where the microRNAs must act in the cancer cells.
MicroRNAs specifically bind to messenger RNAs linked to two genes: HMGA1 and DNMT, which work together to regulate gene expression programs in cells
When microRNAs bind to these messenger RNAs, they block their protein production capabilities and disable programs that determine the characteristics of cancer cells. Without their stem properties, cancer cells are more differentiated, they lose their ability to spread tumors and they are more sensitive to radiation and drugs.
Johns Hopkins researchers implanted human glioblastoma cells in 18 mice. To mimic the clinical challenge of treating an existing tumor, scientists waited 45 days before treating the animals to make sure they had well-formed tumors. Half of the animals received nanoparticle infusions containing active microRNAs directly into their brain tumors, and the other half received nanoparticles containing inactive microRNAs. To isolate the effect of nanoparticles, scientists used mice that were multiplied without immune system T cells that target cancer cells.
Five of the nine mice receiving inactive microRNAs (controls) died within two months, and the rest of the control mice died within 90 days. Three of the nine mice receiving active microRNAs lasted up to 80 days, and six lived up to 133 days. These six were humanely euthanized, and the brains of isolated mice were examined for tumors.
All control mice had large tumors in their brains when they died. Four of the mice that received active microRNAs and lived up to 133 days had no tumors, and two had small tumors.
Green says that many genetic drugs are designed to target a gene. The type of nanoparticles that the Johns Hopkins team used in this study can encapsulate several types of microRNAs to target multiple gene networks
When brain cancer stem cells internalize the nanoparticle and move to a cell-free state Strains, doctors could exploit this condition, and give away radiation or other drugs to kill cells now vulnerable.
Green says scientific teams elsewhere are developing microRNA packets using lipid-based materials, and standard chemotherapy is provided in a liposome nanoparticle
Green and Laterra say the nanoparticles in their study are able to penetrate the whole tumor because the brains of rodents are small. Humans, with a larger brain, may need a pump and a catheter to channel the nanoparticles into the brain.
The Johns Hopkins team works to develop the development of its nanoparticles and to standardize their stability and quality.
The research team filed a patent application for some of the technology used in this research
In addition to Laterra and Green, the interdisciplinary team of Johns Hopkins scientists who played and contributed to this research. includes Hernando Lopez-Bertoni, Kristen Kozielski, Yuan Rui, Bachchu Lal, Hannah Vaughan, David Wilson, Nicole Mihelson and Charles Eberhart.
Funding for the study was provided by the American Brain Tumor Association, the ARCS Foundation, the National Science Foundation, the Bloomberg-Kimmel Institute for Cancer Immunotherapy, research to prevent blindness and the National Institutes of Health (R01NS073611, R01EB016721, F31CA196163 to R01CA195503)
SOURCE: Johns Hopkins University
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