Tiny ‘Trojan horses’ kill brain cancer in mice
A recent experiment with mice suggests that nanoparticles loaded with “death genes” could be used to kill brain cancer cells that surgeons can’t reach.
The genes would be released from the tiny biodegradable particles to selectively kill off leftover tumor cells without damaging normal brain tissue.
“In our experiments, our nanoparticles successfully delivered a test gene to brain cancer cells in mice, where it was then turned on,” says Jordan Green, assistant professor of biomedical engineering and neurosurgery at Johns Hopkins University School of Medicine.
“We now have evidence that these tiny Trojan horses will also be able to carry genes that selectively induce death in cancer cells, while leaving healthy cells healthy.”
Green and colleagues focused on glioblastomas, the most lethal and aggressive form of brain cancer. With standard treatments of surgery, chemotherapy and radiation, the median survival time is only 14.6 months.
Improvement will only come with the ability to kill tumor cells resistant to standard treatments, says Alfredo Quiñones-Hinojosa, professor of neurosurgery and a member of the research team.
Death to oncospheres
Because nature protects the brain by making it difficult to reach its cells from the bloodstream, particles that could carry tumor-destroying DNA instructions directly to cancer cells during surgery are a good alternative.
Quiñones-Hinojosa and his team removed cancer cells from willing patients and grew them in the laboratory until they formed little spheres of cells, termed oncospheres, likely to be the most resistant to chemotherapy and radiation and capable of creating new tumors.
Quiñones-Hinojosa then worked with Green to find a vehicle for genes that would cause death in the oncospheres. Green’s laboratory specializes in producing round particles sized at nanoscale, measured in billionths of a meter.
The particles are made of biodegradable plastic whose properties can be optimized for different medical missions. By varying the atoms within the plastic, the team can make particles of different sizes, with different stabilities and affinities for water or oil.
For this study, Green’s team created dozens of different types of particles and tested their ability to carry and deliver a test sequence of DNA—specifically a gene for a red or green glowing protein—to the oncospheres.
By tracking the survival of cells that engulfed the particles and measuring the red or green light they emitted, the researchers determined which particles performed best, then tested that formulation in mice with human brain cancer derived from their patients.
They injected the particles directly into mice with a human brain cancer and into the brains of healthy mice for use as comparison. Surprisingly, healthy cells rarely produced the glowing proteins, even though the DNA-carrying particles were entering tumor cells and non-tumor cells in similar numbers.
They report the details in a paper published in ACS Nano.
“This is exactly what one would want to see, cancer specificity, but we are still researching the mechanism that allows this to occur,” says Green. “We hope our continued experiments will shed light on this so that we can apply what we learn to other scenarios.”
“It is exciting to have found a way to selectively target gene delivery to cancer cells,” says Quiñones-Hinojosa. “It’s a method that is much more feasible and safer for patients than traditional gene therapy, which uses modified viruses to carry out the treatment.”
The particles can be freeze-dried and stored for at least two years without losing effectiveness.
“Nanoparticles that remain stable for such a long time allow us to make up formulations well in advance and in large batches,” says Stephany Tzeng, a member of Green’s team. “This makes them easy to use consistently in experiments and surgeries; we add water to the particles, and they’re good to go.”
In a related study, published in the same journal, Green’s group also showed that a different particle formulation could effectively carry and deliver so-called siRNAs to brain cancer cells. siRNAs are very small molecules that carry genetic information to cells, but unlike DNA that can turn genes on, siRNA interferes with the production of particular proteins and can turn cancer genes off.
The National Institute of Biomedical Imaging and Bioengineering, the National Cancer Institute, and the Maryland Stem Cell Research Fund-TEDCO funded the research.
Source: Johns Hopkins University