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Getting Straight to the Site of Disease

Nanomedicine is going to battle against brain disease in Iraq veterans.

In today’s finest medical pavilions, where therapies are touted as cutting edge, the treatment of breast cancer still involves going under the knife. With luck, the tumor can be cut out without sacrificing the whole breast. For the unlucky, a lot of tissue must be removed in order to get rid of the malignant cells.

As advanced as modern medicine is, it’s often not possible to get at a diseased area without affecting the entire body. Surgery and radiation kill good cells along with bad, and chemotherapy and antibiotics infiltrate the whole body, producing unwanted side effects on normal organs. Even when we want to direct a drug to influence one part of the body, modern medicine still can’t transport a drug precisely to the diseased area or make sure that the drug releases its dose exactly where we want it to. For this reason, treatments today are still blunt weapons.

The promise of nanomedicine is to completely revolutionize treatment by transporting the medicine directly to the diseased site without compromising the rest of the body. The key in nanomedicine is the transport feature, which is also its greatest challenge.

The body has developed partitions to protect itself and its critical organs. The central nervous system, for example, is one of the best-defended sites in the body. It is encased in bone and has its own circulatory system. The “blood-brain barrier” makes that circulation impermeable to larger antibiotic molecules, which makes it difficult to treat central nervous system infections.

Treatments today are still blunt weapons.

Veterans who are currently coming home from Iraq and Afghanistan, where injuries to the head make up 20 percent of battlefield wounds, are challenging the medical community to deal with this problem.  Many of the wounded go on to develop meningitis or abscesses—destructive brain lesions that can, even if successfully treated, result in permanent neurological problems.

Innovators in medical research are working on new techniques to transport medication through the body’s network of blood vessels that can precisely target the diseased cells, or—in the case of infections—intruders like bacteria and viruses. The rapidly evolving science of nanotechnology has provided us with novel techniques to achieve this goal in the form of tiny nanoparticles that can be injected into the blood stream, where they will locate an objective and accomplish a mission.

A nanoparticle that is designed to treat a disease inside the brain must be small enough to cross the blood-brain barrier, yet big enough to carry and hold on to a therapeutic payload throughout the journey. It has to elude the antibodies of the immune system that seek to destroy all things foreign in the body. It has to pass through the walls of the brain’s blood vessels. And, at the conclusion of its journey, it must penetrate the walls of the bacterium and disable or destroy it.

The government’s Defense Advanced Research Projects Agency (DARPA) is known to invest in cutting-edge projects with a high potential payoff if the funded research is successful. Today’s Internet and the global positioning system (GPS), for example, are the result of work initially funded by DARPA. The agency is currently investing in nanomedicine in the form of nanoparticle therapeutic platforms, to treat military-relevant diseases and get sick soldiers back on their feet as quickly as possible.

Veterans who are currently coming home from Iraq and Afghanistan, where injuries to the head make up 20 percent of battlefield wounds, are challenging the medical community to deal with this problem.

We’ve been hearing about nanomedicine for many years, and the media has heralded its power many times over. As with various other technologies, hype preceded the real, often obstacle-ridden, work necessary to achieve success. But we are now seeing nanoparticles in real medical diagnoses and treatments. Some truly novel nanoparticle treatments, like those envisioned by DARPA, are now in human trials and showing positive results.

In May 2013, DARPA awarded $6 million to a team to develop therapeutic nanoparticles for the treatment of traumatic brain injuries and associated infections. The work will represent a collaboration of experts from three institutions that will tackle different aspects of nanomedicine—building the particle, creating the mechanisms to guide that particle through the body to its target, and developing the payload to activate the cure. 

A group of material chemists from the University of California, San Diego (UCSD) is specializing in engineering the design of nanoparticles. Their job is to construct a particle big enough to hold its cargo and yet small enough to pass through cell membranes.  Nanoparticles are made out of biological materials, like proteins and nucleic acids that can be created in the lab, and elements, like gold, the baser iron, or even silicon, a readily-available element that assimilates easily with human tissue—it is actually critical to bone and connective tissue health—and has the added bonus of being biodegradable.

As these particles have to pass through many barriers, their size and shape are also critical. The particle being designed by the UCSD team is around 100 nanometers in size—several thousand times smaller than a human cell and made out of silicon. The advantage of using silicon is that it is a common, crystalline material, and scientists have developed techniques to create uniform holes, or pores, in the crystal by exposure to acid—think dental cavity—or an electrical current. These particles are referred to as mesoporous silicon nanoparticles (MSNP’s).

The pores in the particle may be loaded, variously, with drugs designed to release within the target cell or with nucleic acids (DNA or RNA) for gene therapy. It is even possible to create molecular ‘nanogates’ to act as doors and prevent release of the entrapped cargo until it is exactly where it needs to be to do its work most efficiently. After the UCSD team designs the best nanoparticle container to hold the medicine and allow it to pass through the immune system undetected, the next step is cellular engineering—figuring out how the nanoparticle will breach the walls of the target cell. The outer coat of the particle will be interacting with other cells in the blood and must be able to elude the immune system.

Most cells have distinctive surface proteins, like product logos or lapel pins that distinguish one from another—this is how the immune system distinguishes friend from foe. The surface proteins are­­­ embedded in a lipid membrane and are used by the nanoparticle to identify the target cell. When the two come into contact, the particle’s “targeting” protein interacts with the targeted cell’s surface. This is the critical moment in which the diseased cell decides whether to allow the particle to bind to it. It requires the proteins to be a specific match.

The creation of the targeting protein will fall under the direction of the Sanford-Burnham research group at the University of California, Santa Barbara, which has previously identified the markers on the protein surfaces of brain tumors and blood clots. For the DARPA project, they will try to find discrete surface characteristics on the bacteria that infect the brain so the nanoparticles can home in on and attach to only those targets. Once attached, the particles will be absorbed into the bacteria and release a peculiar form of RNA that nature has already designed to control normal cell function, but that humans have just begun to co-opt for therapeutic purposes.

It is even possible to create molecular ‘nanogates’ to act as doors and prevent release of the entrapped cargo until it is exactly where it needs to be.

The messenger of the cell, RNA regulates the expression of genes, meaning that it can turn them off. Scientists first discovered RNA-based gene silencing in plants—purple petunias to be precise. They turned the flowers partially white by silencing the gene that produced the purple color. The same mechanism was later found to operate in primitive roundworms. The latter work ultimately resulted in a Nobel Prize for two Americans1 and identified this particular type of RNA as short interfering RNA (siRNA) or silencing RNA. The siRNA binds to the target cell’s RNA and disables it. 

Thanks to the research of these Nobel laureates, we now know that gene silencing is part of normal cell function. There are siRNAs in every cell, selectively turning off certain protein manufacturing functions, be it the cell of an animal or plant, human or manatee, bacteria or even virus. The key for scientists now is to understand how to manipulate it.

Early work in this area showed that merely injecting “naked siRNA,” into the bloodstream wouldn’t work for the treatment of human disease. The molecular structure of siRNA makes it vulnerable to normal “housekeeping” enzymes designed to quickly break down random circulating bits of nucleic acid; this system prevents naked circulating siRNA from getting into a target cell. But more recent research has showed that when it’s tucked into a silicon mesopore vehicle, siRNA can be protected from scavenging immune cells and circulating nucleases—the enzymes that break down old DNA and RNA—until it has done its job.

A team from MIT will handle the final step in eliminating the culprits in brain infections by designing siRNAs that can disable those bacteria. A siRNA has been developed, for example, that inhibits—or interferes with—bacterial expression of coagulase, an enzyme produced by Staphylococcus bacteria that clots off the blood supply to infected tissue.

The treatment envisaged by the DARPA team will likely be a dose of particles held in a liquid suspension and injected into the body. The particles will then be transported passively in the blood, floating from the veins, through the heart, into the arteries, and eventually to the capillaries of the brain, where they’ll bind to surface proteins on the bacteria of the brain infection. They’ll then swarm the defenses of the objective organism, and penetrate and disable the machinery within. The job completed, the particles will then be disassembled by housekeeping cells and the component parts—bits of silicon and nucleic acids—recycled or excreted.

There are clinical trials already underway for nanoparticle approaches to the treatment of cancer, obesity, and viral infections. As we gain greater understanding of the genetic underpinnings of diseases, we can act with increasing precision. We might target the overactive fat cells in obesity, the tumor cells in cancer, the virus in hepatitis, or the bacteria in traumatic brain infections. While we may never eliminate the damage done by a bullet passing through a limb or a brain, we’re coming closer to a future where there is no longer any need for surgery, radiation, chemotherapy, or antibiotics—a future where we can reach the diseased cells directly.


William Hanson, M.D., is the author of The Edge of Medicine. He is Professor of Anesthesia and Critical Care and the Chief Medical Information Officer at the University of Pennsylvania School of Medicine. His research has been featured in national and international publications, including Popular ScienceU.S. News & World Report, and he has been a guest on NPR’s Fresh Air as well as on Discovery Channel television documentaries.

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