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It’s A Small, Small World

Medicine’s next frontier is a world unto its own — how the nanomedical revolution makes a universe of us all.

In 1966, when UC San Diego was little more than a patchwork of Quonset huts and former military barracks, theaters across America premiered the science fiction movie Fantastic Voyage. In it, a submarine and its crew are shrunk to microscopic size and injected into the body of a scientist suffering from an inoperable blood clot in his brain. The mission: repair the blood clot and save his life.

The concept was truly fantastic for the time; so much so that any researcher peering into a microscope at then-UC La Jolla may have justly relegated it to science fiction forever. How could they have known that decades later, researchers would strive to master that fantastic frontier—to save not only one life, but impact the lives of millions?

 

Rocket to the Stomach

The lab of Joseph Wang, a nanoengineering professor at UC San Diego’s Jacobs School of Engineering, is the first stop on UC San Diego’s own fantastic voyage. There, you’ll find a team creating tube-shaped micromotors—smaller than the width of a human hair—that could one day be used to efficiently deliver drugs to specific locations in the body, or even perform surgeries and conduct biopsies on hard-to-reach tumors. Wang recently teamed up with Liangfang Zhang, a nanoengineering professor affiliated with the cross-disciplinary Institute of Engineering in Medicine, to demonstrate how micromotors could be deployed inside a mouse’s stomach and deliver cargo to the stomach wall. “This is the first example of loading and releasing a cargo in vivo,” says Wang. “We thought it was the logical extension of the work we have done, to see if these motors might be able to swim in stomach acid.”

Not only are they able to swim in stomach acid, the acid is a major factor in their ability to swim at all. Made primarily of zinc, these tubular micromotors react with stomach acid to generate a stream of hydrogen bubbles that propel the motors like miniature rockets. This propulsive burst allows the motors to swim around and lodge themselves and their cargo firmly in the stomach wall. As a bonus feature, the zinc micromotors are biodegradable—they gradually dissolve in stomach acid, disappearing within a few days with no toxic traces left behind.

As part of their experiment, Wang, Zhang and their cohorts tested the ability of micromotors to deliver a cargo of gold nanoparticles to the stomach wall of mice. The mice ingested tiny drops of solution containing hundreds of these gold-loaded micromotors, which became active as soon as they hit the stomach acid and propelled themselves toward the stomach wall. Remarkably, the researchers found that more than three times as many gold nanoparticles ended up in the stomachs of mice when delivered by the micromotors, compared to when the gold nanoparticles alone were ingested normally.

The experiment shows the promise of micromotors to safely and efficiently deliver cargo in living animals, a prospect that could one day revolutionize drug delivery. Yet there is much to be explored before that day comes—elements like navigation capabilities and more precise targeting will be crucial.

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BIG IDEAS, TINY DEVICES Nanoengineering professors Liangfang Zhang (above) and Joseph Wang (below) have teamed up to explore the potential of micromotors to deliver medicine in the body.

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NanoGraphicMultitasking Microfish

Wang is also working with UC San Diego nanoengineering professor Shaochen Chen, an innovator in 3-D printing technology, to develop “microfish”—microscopic fish-shaped robots. Similar to Wang’s tubular micromotors, these microfish swim via a chemically powered reaction, yet can also be steered with magnets. “We incorporated a traditional micromotor into a nature-inspired design, such as a fish shape, to create a ‘smart microswimmer’ that can do multiple tasks in solution,” says Chen.

By combining Wang’s expertise in micromachines and Chen’s 3-D printing technology, researchers were able to print hundreds of multitasking microfish within seconds. The microfish were printed with tiny pieces of platinum in their tails, which react with hydrogen peroxide to serve as external fuel. When the fish then were released in a hydrogen peroxide solution, the tails produced a stream of oxygen bubbles as propellant, while tiny magnetic iron oxide particles printed into the heads of the fish allowed researchers to guide the fish with magnets.

Researchers also printed unique nanoparticles throughout the bodies of the microfish to detect and absorb poisonous toxins. In their experiments, researchers showed that the microfish could efficiently detoxify a solution contaminated with a poison found in bee venom. When the nanoparticles bind with toxin molecules, they even glow red in color, making the fish also useful as toxin sensors.

MICROFISH MAKER Nanoengineering professor Shaochen Chen, a leader in 3-D printing, uses nature-inspired design to create tiny microfish that can be steered with magnets.
MICROFISH MAKER Nanoengineering professor Shaochen Chen, a leader in 3-D printing, uses nature-inspired design to create tiny microfish that can be steered with magnets.

The versatility of these microfish may hold great potential in and out of the body, but they are still at the proof of concept stage. Wang and Chen forecast several years before they can be used for medical applications. As a step toward this goal, researchers are planning to build microfish that are powered by more in vivo-friendly fuels, such as water or enzymes.

 

Drugs on Target

When it comes to nanomedicine, one of the main goals is targeted drug delivery—directing drugs to only diseased sites, rather than spreading the drugs to healthy areas throughout the body. This is especially important for diseases like cancer and severe bacterial infections, “which are typically treated with very toxic drugs,” says Brian Luk, M.S. ’14, a bioengineering graduate student in Zhang’s nanomedicine lab. “You don’t want these types of drugs being distributed all over your body, just to the problem areas.”

Luk, who was named one of the 2016 Siebel Scholars at UC San Diego, works with Zhang to develop new nanoparticles to treat not only cancer and bacterial infections, but a variety of autoimmune and cardiovascular diseases. In a particularly “fantastic” research study, the team created nanoparticles disguised as human platelets so that they might better navigate through a human body.

The nanoparticles are essentially tiny spheres, packed with drugs and covered with the cell membranes of real human platelets. This coating naturally protects the nanoparticles from being recognized as foreign agents and from being attacked by the body’s immune system. The platelet membranes also have a natural preference to bind to damaged blood vessels and pathogens such as MRSA bacteria, making them not only useful as a cloaking device, but also as a homing device for problem areas.

Tests on rodents have been remarkably positive. In one experiment, researchers packed the nanoparticles with drugs to treat blood vessel injuries and injected them into rats with damaged arteries. The drugs primarily ended up on the artery wounds and healed them. Likewise, antibiotic-filled nanoparticles were injected into MRSA-infected mice and found their way right to the infected organs. Researchers found that they were able to use just one-sixth of the clinical dose of antibiotics to kill off the infection.

“With our platform, we are basically concentrating the antibiotics on the MRSA infection so we can introduce less total drug into the body while still maintaining the drug’s efficacy,” says Luk. “We’re using extremely small particles to help us find innovative strategies to address pressing health issues around the world.”

Just another way the smallest things can make the biggest difference.