Once a drug is injected systemically, can you steer it to where you want it under MRI guidance? Pierre Dupont, PhD, and colleagues saw this as an engineering problem. Solving it could enable concentrated drug delivery to, say, a deep tumor in the lungs while simultaneously taking images.
Labeling drugs with magnetized particles is the first step, allowing the MRI scanner’s magnetic pulses to propel them. The next step is to be able to actively steer the particles through a series of branching vessels to a desired location. But getting a scanner to both image and propel particles forcefully enough to overcome the force of the blood flow is easier said than done.
“We were always frustrated because the forces you can produce are limited by the magnetic gradients produced by the scanner,” says Dupont, head of the Pediatric Cardiac Bioengineering Lab at Boston Children’s Hospital. “Steering particles in the bloodstream is akin to whitewater rafting: You have limited paddling ability compared to the strength of the river, so you need to position yourself appropriately in the flow to follow your desired path.”
The lab previously developed a technique for propelling particles into tissue by creating the equivalent of a Gauss gun. This approach combined the MRI’s magnetic force with the force produced by collisions between the particles. But it relied on having already navigated the particles to the desired location inside the body.
“Navigation is the really hard part,” says Dupont. “In the existing approach, the MR scanner had to be programmed to alternate between imaging the particle and propelling it. This is really inefficient since whenever you are imaging, you are not propelling and vice versa. It’s like pushing a car up the hill and continuously stopping and starting. Half the time no one is doing anything.”
So Dupont and Ouajdi Felfoul, PhD, now at GE Healthcare, realized that they had to design a new way to program the scanner. “We looked at how imaging was being done,” says Dupont. “Then we said, ‘OK, can we design a pulse sequence that will image the particles at the same time it propels them?’
Hacking MRI for drug delivery
In Scientific Reports last week, they demonstrated their technique in a clinical-grade MR scanner. Through reprogramming, they harvested a much higher fraction of the scanner’s energy for propulsion purposes. This involved a few tricks:
- Rather than continuously image particles in 3-D, Dupont and Felfoul programmed the scanner to image only in the direction of propulsion, switching to full 3-D imaging only when needed. “This makes imaging faster, since imaging in three dimensions requires three times as much time,” explains Dupont.
- The engineers also adjusted the magnetic gradients that produce forces on the particles. Prior techniques had used small gradients that push in positive and negative directions, effectively cancelling each other out. Dupont’s team used larger imaging gradients that push solely in the desired direction.
- They programmed the scanner to image just the particle location, not the surrounding tissue, at rates of more than 100 times a second. This technique, called projection imaging, produces a different kind of MRI image, but one adequate for steering purposes.
“When steering in the bloodstream, you typically have a map of the vasculature from pre-operative images,” Dupont explains. “You don’t need to measure location in three dimensions, since the particles are constrained to move inside the blood vessels. All you really need to know is where a particle is along the vessel. When the particle approaches a branching point, you want to propel it toward the desired branch and know where it is with respect to the branching direction. This can also be measured in one dimension.”
Putting it to the test
With these changes in the algorithm, a clinical MR scanner can propel particles with much higher steering forces at a given imaging rate. Say the imaging rate is 58 times per second. With the old approach that alternated imaging with propelling, this imaging rate left no time to propel the particle. With the new method, the scanner can generate 90 percent of its maximal propulsive force.
In laboratory testing, the team successfully navigated a millimeter-scale particle through a branching vascular network:
The next frontier
Challenges remain. First, while millimeter-sized particles are suitable for navigating locations like the spinal canal, urinary system or ventricles of the brain, they’re too large for use in the bloodstream.
“For therapeutic purposes you want to be on the micron scale,” says Dupont. “This will pose challenges in coordinating the steering of groups of particles and in determining what concentrations of particles are needed for visualization.”
A related problem: How do you get the particles, once they reach their destination, to stay put and release their medications? For this, Dupont’s team has several solutions they plan to test.