Tech + Engineering

07
May

Nanoparticles: The Next Big Thing in Medicine

DNA. The very acronym calls to mind the molecule’s exquisite structure, a linear double helix. Our understanding of DNA and its orbiting strands has thrown back the curtains on many diseases—cancer, infections, cardiovascular ailments, and neurodegenerative disorders among them. But there’s far more to DNA than that. Now, chemists and nanotechnologists are repackaging and chemically modifying DNA and its sister nucleic acid, RNA, in myriad new forms, tacking them on to nanoparticles in a quest to unlock new breakthroughs, especially in the health sciences.

Gold nanoparticles with DNA
Chemists and nanotechnologists have been studding gold nanoparticles, like these, with nucleic acids in their search for better medical diagnostics and treatments.

And they’ve been succeeding. One field where nucleic acids have been particularly useful and promising is in medical diagnostics, or tests that clinicians use to determine the nature of a disease or disorder. By deconstructing the double helix, scientists have been using single strands of DNA as new probes for disease, allowing doctors to accurately diagnose a patient and save countless lives.

Such tests are typically carried out on a chip called a microarray, which contains hundreds, even thousands of these probes, each searching for a different disease marker in a sample from a patient. Such genomic screening tools are revolutionizing the field of medical diagnostics by allowing hospitals and doctors to rapidly determine the inherent genetic makeup of a patient and the various organisms with which the patient may be infected.

Timely Tests

Take sepsis, for example, an infection of the blood. When a doctor suspects a patient has sepsis, they immediately order a battery of antibiotics. That’s because sepsis can kill swiftly—patients often cannot survive the three days typically required to confirm the infection. In cases where sepsis is confirmed, antibiotics can be an appropriately prescribed life-saver. But if sepsis is not at fault, the course of antibiotics won’t do any good and may, in aggregate with other such cases, contribute to resistance.

New tests using single-stranded DNA, though, can alter the calculus of that equation. Instead of waiting three days to confirm sepsis, diagnostics based upon gold nanoparticles studded with DNA can confirm or rule out the infection in about two hours. Moreover, they can identify the specific bacteria with which the patient is infected, allowing the doctor to prescribe the proper antibiotics and only the ones that are necessary. A company I founded, Nanosphere, has brought these tests to market.

Staphylococcus aureus
Cells of Staphylococcus aureus, the cause of many infections, are seen here under 50,000x magnification. New tests can confirm deadly systemic infections, known as sepsis, far faster than existing ones.

However, there are many more possibilities if one can carry large amounts of nucleic acids like DNA or RNA into living cells. It could help us to better understand how cells work, give us new ways to track disease and, perhaps more importantly, provide new treatments for diseases with a known genetic basis. The trick is getting the nucleic acids inside the cells, though. Linear nucleic acids like DNA and RNA do not easily enter cells on their own. That’s because the cell’s membrane is composed of a negatively-charged wall of lipids meant to keep foreign nucleic acids out so they don’t interfere with the cell’s normal operation.

Infiltrating the Cell

One solution is to hook DNA and RNA strands to large, positively-charged polymers, or molecules made of repeating components. The polymer’s positive charge allows it to slip past the cell’s outer defenses. Unfortunately, these polymeric materials are often toxic and, despite their promise, are still limited in terms of where in the body they can carry DNA or RNA-based therapeutics. The vast majority of drugs under development that are based upon these polymer structures target diseases of the liver because that’s where they naturally accumulate—one of the liver’s roles is to filter the blood stream of foreign chemicals.

Fortunately, there’s another option. Instead of attaching DNA and RNA to potentially toxic polymers, we can link them to nanoparticles, including the one I developed which led to the founding of Nanosphere. I call theses structures spherical nucleic acids, or SNAs. When single- or double-stranded DNA or RNA is arranged into a high-density form on the surface of a spherical nanoparticle, the nucleic acids take on new properties, including the ability to enter cells without help from a polymer. These structures can do this by engaging scavenger proteins on the surface of cells, which uniquely recognize SNAs and facilitate endocytosis, a process by which cells engulf molecules.

Spherical nucleic acid
Gold nanoparticles and linear nucleic acids combine to form spherical nucleic acids, which have unique properties.

Being able to insert SNAs into cells has opened up a whole new world for researchers. For example, we can associate an SNA with a short complementary sequence of DNA modified with a fluorophore, or a chemical that provides a fluorescent signal. When this binds to a specific sequence of messenger RNA—a type of nucleotide that codes for certain proteins—the short sequence with the fluorophore is released, lighting up the cell. Diseased cells produce different amounts and types of messenger RNAs, so these flares provide what is currently the only way to track messenger RNA levels in live cells. With these flares, we can locate cancer cells, for example, or concentrate stem cells within a sample or study how potential pharmaceuticals affect the inner workings of cells.

Most promising, though, are the potential of SNAs in new therapies. SNAs can be designed to target a disease through gene regulation more effectively than the polymer-based materials. They can enter cells and flip genetic switches, causing a cancer cell to die, for instance. A similar action in a different circumstance could correct a misbehaving cell that’s producing too much of one protein.

SNAs can also cross barriers, like the skin, that linear nucleic acids typically cannot penetrate, opening the door for the development of many new pharmaceuticals. These new treatments could address psoriasis or melanoma, speed wound healing, or soften scar tissue. SNAs can also cross the blood-brain barrier, something not easily done by most molecules or particles.

This could open new avenues for tackling debilitating diseases like glioblastoma multiforme (a type of brain cancer), Alzheimer’s, and Parkinson’s. They are even being evaluated as a new class of broad-spectrum antibiotics and as a treatment for traumatic brain injury. SNAs can distribute therapeutics to nearly any tissue in the body, carrying large payloads of genetic material that target many forms of cancer with unique genetic signatures. Because of these unusual structure-dependent properties, SNAs have a chance to transform the field of gene regulation therapy and change the future course of drug development. They could positively impact tens of millions of people who suffer from diseases with known genetic links.