RNAi, also known as "gene silencing," is a cellular mechanism that blocks the production of proteins, and has tantalized doctors as a potential medicine for a number of years now. However, by placing payloads of RNA in a polymer nanobot, scientists have finally shown that this technique can work against tumors in human patients.

Specially constructed molecules could potentially block the expression of genes critical to the reproduction of viruses and the spread of cancer. But until now, doctors had been unable to direct those molecules to the right cellular nuclei. Scientists from the California Institute of Technology solved this problem by placing the RNA molecules in a specialized polymer robot with a chemical sensor. When the environment of a cancerous cell triggered the chemical sensor, the robot releases the RNA.

The trial involved three people with melanomas who received the RNA-load nanoparticles intravenously four times, for 30 minutes, over three weeks. At the end of that time, samples taken from the melanomas showed both the presence of the RNA, and a reduction in tumor gene expression.

This technology still has a long way to go before it becomes a routine medical treatment. However, by targeting the epigenome, the expression of genes, as opposed to DNA itself, it has much more practical potential than genetic therapy. Plus, since RNAi can work against any transcription, RNAi nanobots could potentially disable both DNA viruses, like smallox, and RNA viruses, like SARS.

There's often a big difference between how a drug or method of delivery works in a lab and how successful it is in human trials. So, it's big news for researchers from the California Institute of Technology (CalTech) that they were able, for the first time, to successfully kill cancer cells in human patients using a new RNA interference (RNAi) therapy delivered via a special nanobot. This nanobot targets the messenger RNA (mRNA) to stop the production of protein in the cancer cell, thus starving the cancer from its source of survival.

Interfering RNAs are a new type of therapy that attack cancers
and other diseases at the genetic level; its discovery in 1998 won Andrew Fine and Craig Mello the 2006 Nobel Prize in Physiology or Medicine. But the Caltech researchers were the first to create the right nanobot to deliver the siRNAs and they were able to inject the drug-filled nanobots directly into the patients' bloodstreams.

This electron micrograph shows the presence of numerous siRNA-containing targeted nanoparticles both entering and within a tumor cell.: Credit: Caltech/Swaroop MishraThis electron micrograph shows the presence of numerous siRNA-containing targeted nanoparticles both entering and within a tumor cell.: Credit: Caltech/Swaroop Mishra



"There are many cancer targets that can be efficiently blocked in the laboratory using siRNA, but blocking them in the clinic has been elusive," says Antoni Ribas, associate professor of medicine and surgery at UCLA's Jonsson Comprehensive Cancer Center. "This is because many of these targets are not amenable to be blocked by traditionally designed anti-cancer drugs. This research provides the first evidence that what works in the lab could help patients in the future by the specific delivery of siRNA using targeted nanoparticles. We can start thinking about targeting the untargetable.”

There is now proof that a Nobel Prize-winning technology can deliver targeted therapy directly to cancer tumor cells, say a team of California Institute of Technology researchers led by Mark Davis, who published their findings in Nature. Their clinical trial showed that a specialized polymer nanoparticle injected into patients' bloodstreams did indeed carry a genetic off-switch message to cancer cells, rendering their proteins unable to replicate.

nanoparticle
The targeted nanoparticle used in the study and shown in this schematic is made of a unique polymer and can make its way to human tumor cells in a dose-dependent fashion. (Credit: Caltech/Derek Bartlett)

"The importance here is being able to model and target the protein," research team member Antoni Ribas, associate professor of medicine and surgery at the UCLA Jonsson Comprehensive Cancer Center, told TechNewsWorld.

Now that the nanotech-based method has been demonstrated, researchers can start working with it to develop therapies not only for cancers, but also for degenerative diseases such as Alzheimer's and metabolic disorders such as diabetes, study team member Yun Yen, associate director for translational research at the City of Hope Comprehensive Cancer Center, told TechNewsWorld.
Hidden Proteins

Researchers already knew that disabling cancer cells from replicating might hold the key to important advances in treatment. However, prior to this clinical trial, they had trouble targeting the specific proteins building the cells, which sometimes remain hidden in the folds of genetic strands.

This is where a discovery more than a decade old comes in. Nobel Prize winners Andrew Fire and Craig Mello found that shutting down cancer genes was easier when using RNA interference. This method uses double-stranded small interfering RNA chains (siRNAs) to cut the messenger RNA cancer cells use to repliate, rather than the RNA or DNA itself.

Researchers Fire and Craig made their discovery in worms, though, and before now, no one had shown that the siRNAs could be introduced into humans and make their way to targeted cancer cells.

Now, Davis, Ribas, and their team have the pictures to prove that they've used nanoparticles to deliver siRNAs directly to cancer cells and that the siRNAs have indeed interfered with the cancer cells' ability to multiply. Electronic microscopy has captured images of the nanoparticles around and even within the cancer cells.
Safety First

The research is part of a Phase I clinical trial of the new therapy, in which potential treatments are first checked for safety in human subjects. Fifteen patients overall were involved, Ribas told TechNewsWorld. All had cancer, although their tumors varied in type.

Only three of the patients had cancerous cells biopsied to demonstrate the efficacy of the nanoparticles and siRNA, noted Ribas.

These patients had melanoma, a skin cancer, and thus the cells were easier to reach for biopsy, he explained.

The next step is for researchers to enroll more patients and complete Phase II and III clinical trials, Ribas said.
Hitting the Bullseye

The cancer cell proteins targeted by the nanoparticle-delivered agent were indeed split at exactly the place the researchers intended, Davis said. This is the first time this mechanism has been demonstrated in humans, and its implications stretch to many forms of cancer and farther afield into other diseases.

nanoparticle
This electron micrograph shows the presence of numerous siRNA-containing targeted nanoparticles both entering and within a tumor cell. (Credit: Caltech/Swaroop Mishra)

"In principal," Davis said, "that means every protein now is druggable because its inhibition is accomplished by destroying the mRNA."

The problem for researchers up to now has been getting the interference chemicals into the cells themselves -- in this case, cancer cells. Davis' team has developed a unique polymer that can self-assemble into a nanoparticle that contains the siRNA. The team has shown that the nanoparticles reach cells in different concentrations based on different doses, which means that there are possibilities for tailoring dosages of disease-fighting siRNA on a disease-by-disease, or even patient-by-patient, basis.

Now that a delivery platform has been established, Yen said, researchers need not stop at delivering agents that interfere with cell growth. They can also develop ways to repair the cellular damage caused by aging.

"We also could deliver a gene to rejuvenate the cell," he said. "In this study, we already can see that we can inhibit a cell; what I'm saying is that we also can enhance it."

Look close. You may be staring at the end of cancer. Those tiny black dots are nanobots delivering a lethal blow to a cancerous cell, effectively killing it. The first trial on humans have been a success, with no side-effects:

It sneaks in, evades the immune system, delivers the siRNA, and the disassembled components exit out.

Those are the words of Mark Davis, head of the research team that created the nanobot anti-cancer army at the California Institute of Technology. According to a study to be published in Nature, Davis' team has discovered a clean, safe way to deliver RNAi sequences to cancerous cells. RNAi (Ribonucleic acid interference) is a technique that attacks specific genes in malign cells, disabling functions inside and killing them.

This Is the Future of the Fight Against Cancer

The 70-nanometer attack bots—made with two polymers and a protein that attaches to the cancerous cell's surface—carry a piece of RNA called small-interfering RNA (siRNA), which deactivates the production of a protein, starving the malign cell to death. Once it has delivered its lethal blow, the nanoparticle breaks down into tiny pieces that get eliminated by the body in the urine.

The most amazing thing is that you can send as many of these soldiers as you want, and they will keep attaching to the bad guys, killing them left, right, and center, and stopping tumors. According to Davis, "the more [they] put in, the more ends up where they are supposed to be, in tumour cells." While they will have to finish the trials to make sure that there are no side-effects whatsoever, the team is very happy with the successful results and it's excited about what's coming:

What's so exciting is that virtually any gene can be targeted now. Every protein now is druggable. My hope is to make tumours melt away while maintaining a high quality of life for the patients. We're moving another step closer to being able to do that now.