On average, patients with chronic illnesses follow their prescribed treatments about 50 percent of the time. That’s a problem. If drugs aren’t taken regularly, on time, and in the right doses, the treatment may not work, and the person’s condition can worsen.
The issue isn’t that people are unwilling to take their prescriptions. It’s that some drugs, like HIV medications, require unwavering commitment. And essential medicines, like insulin, can be brutally expensive. Plus, the Covid pandemic illustrated the difficulties of delivering perishable follow-up vaccine shots to regions with no cold chain. “Are we really squeezing all the utility out of those drugs and vaccines?” asks Kevin McHugh, a bioengineer at Rice University. “The answer is, in general, no. And sometimes we’re missing out on a lot.”
For example, the injectable drug bevacizumab can be used to treat macular degeneration, a leading cause of blindness. But even though it’s effective, dosing adherence is notoriously low. “People hate getting injections into their eyes,” McHugh says. “And I don’t blame them at all—that’s terrible.”
McHugh’s lab is in the drug delivery business. The goal is to give patients what they want—less hassle—while also giving them what they need: consistent dosing. The lab’s answer is an injection of drug-delivering microparticles that release their contents in timed delays that can span days or even weeks. “We’re trying to engineer these delivery systems to work in the real world, as opposed to in this idealized version of the world,” McHugh says.
In the June issue of Advanced Materials, McHugh’s team described how their system works. It starts with an injection containing hundreds of tiny microplastic particles, each encapsulating a small dose of a drug. These miniscule capsules are made of the polymer PLGA, which our bodies break down safely. By adjusting the molecular weight of the polymer used for each capsule, the scientists can control how fast they erode and release medication. In this study, the team demonstrated a single shot containing four groups of microparticles that released their contents at 10, 15, 17, and 36 days after injection.
“Having long-acting delivery strategies is a great unmet need,” says SriniVas Sadda, an ophthalmologist with UCLA and the Doheny Eye Institute who was not involved in the study. The patients Sadda sees are elderly. They are often dependent on family members for transportation and may skip appointments because of other health problems. “Maybe they’ve fallen and broke their hip and they end up not coming in,” he says. “Missed visits can be a big problem because you miss treatment and the disease could get worse. And it’s not always possible to recover.”
It’s hard to have delicate control over the levels of a drug in your body, in part because most medications operate like sledgehammers. Pop an ibuprofen or an antidepressant, and those levels will spike as the drug quickly passes through your gastrointestinal tract. Extended release pills prolong a drug’s effect but still taper off from a peak. And you can’t simply front-load a steep dose to delay the next one, since some drugs, like insulin, have a narrow “therapeutic window” between being helpful and dangerous.
Ironically, new and more advanced kinds of drugs have only made this problem more daunting. In 2021, seven of the 10 best-selling drugs in the United States were biologics, a class that includes proteins, hormones, and gene therapies. Biologics are more finicky than small molecules like ibuprofen, and rarely work orally. But they’re effective. “The potency and the specificity provided by protein drugs like antibodies is so great,” McHugh says. “Now the question would be how to make them last for long.”
During a postdoctoral fellowship at MIT about six years ago, McHugh experimented with manipulating polymers to encase drugs. His team invented a type of microparticle that encapsulated a drug using PLGA because the polymer has been used clinically in FDA-approved treatments since 1989. It was clear that changing the polymer’s molecular weight would delay its degradation—and the drug’s release—but the technique was expensive and hard to scale up. And some of the most important applications, like for vaccines, need to be extremely low-cost. “If we’re trying to develop and deliver vaccines in low- and middle-income countries, maybe these technologies have to cost a couple of pennies,” he says. “How do we make a billion of these?”
So when McHugh started his own lab at Rice, his team put his original process under the microscope. His previous method entailed casting a microscopic PLGA “bucket” to fill with a drug, then adding a flat “lid” of the polymer. They’d line the bucket and lid up under a specialized microscope, smush them together, and heat them to form a seal. Too many steps, McHugh thought.
He asked Tyler Graf, the PhD candidate leading the project, whether they could instead dip the unsealed particles—en masse—into a melted pool of PLGA. Intrigued, Graf tried. No dice. The individual buckets couldn’t form clean seals because the PLGA wouldn’t break off from the pool. Long strings of the polymer dragged out, like cheese pulling off of pizza. “That’s obviously not feasible because that’s extra material that can’t fit through a needle,” says McHugh.
Graf wondered what would happen if they nixed that step entirely. He took a glass slide dotted with barely visible unsealed buckets and flipped it face down above a hot plate. The top of each bucket pinched in and sealed off. “We got a little bit lucky,” McHugh says. “That was the first place where we were thinking this is really going to be something exciting here.”
Today they use lab robots to fill the capsules, and they are working to automate the entire process, which they call Pulsed, for Particles Uniformly Liquified and Sealed to Encapsulate Drugs. McHugh believes that this automation cuts costs and makes the tech scalable. Thanks to minor tweaks to the capsule recipe, the Pulsed particles rupture with distinct, predictable delays, ranging from days to over a month.
For their recent study, their team wanted to know how quickly these capsules would degrade in a living animal, so they compared the timing in test tubes to that in mice. In one trial, they loaded the microparticles with tiny fluorescent molecules in lieu of medicine. With the mice, they injected a small volume of the capsules beneath the animals’ skin, then they tracked the fluorescence as the molecules diffused outward. With the test tubes, they kept the capsules in a saline solution at body temperature and checked to see when the fluorescent molecules spilled into the solution. In all cases, the timing matched. This means that timing predictions based on lab experiments will likely hold up well in living bodies.
They also tested whether the microparticles can carry biologics without spoiling them. They tested one—bevacizumab, the antibody that treats macular degeneration and some cancers—by loading the drug into microparticles along with a cocktail of stabilizing chemicals. Eighteen days later, the drug remained over 90 percent active.
The team envisions designing a library of these particles that can mimic different dosing schedules: daily, weekly, monthly, or something in between, depending on the patient. For example, while they haven’t yet tested their system with Covid vaccines, the capsules described in the new study could match the timing needed for them: two doses given at three- or four-week intervals.
“It’s really an important direction for the future of controlled and sustained drug delivery,” says Kibret Mequanint, a biomedical engineer with the University of Western Ontario, who was not involved in the work. However, he points out, the current particles are not ideal for drugs that require doses multiple times per day—they don’t dissolve fast enough.
Compared to other injectables or slow-release oral pills, the microparticle results are “very exciting,” says Rahima Benhabbour, a polymer chemist at the University of North Carolina who is not involved with McHugh’s team. “The main takeaway here is the stability of the biologics. I really liked that,” she says.
Benhabbour’s team uses PLGA to create implants that release drugs at a slow and steady rate, with no initial burst. (Drug levels from injections typically spike before tapering down.) That’s essential for HIV pre-exposure prophylaxis, or PrEP, which requires a person to maintain a certain concentration of the drug in their bloodstream at all times to be protected. Her team published a paper in February reporting that, based on tests in macaques, their implants could maintain those PrEP concentrations in people for over five months.
Benhabbour cautions that it’s unclear how many microparticles could be squeezed into one injection. The maximum volume for subcutaneous injections for humans (like those given to McHugh’s mice) is 1.5 milliliters. That’s not guaranteed to be enough space for multiple doses, especially drugs like PrEP that require a lot of medication per dose. “The only question I have is: Can they deliver enough?” she says.
It’ll be hard to pack a syringe with a year’s supply of a weak drug that requires daily dosing, McHugh admits. But a potent drug that only needs monthly dosing into a small area, like an eye, would fit more easily.
Sadda, the ophthalmologist, notes that some macular degeneration patients can already get by on one injection of bevacizumab per month, or even less. “I would imagine that for this to be successful, you’d have to get at least a three-month period—and probably longer,” he says.
Work is underway to extend that drug-release period. The shortest release the Rice team has engineered to date is 12 hours, and the longest is 36 days. “We want to have a library that [spans] every day for six months,” McHugh says. “That would be a dream.” He suspects they could even program a delay of a year or more with types of PLGA that degrade more slowly.
The team also plans to make the microparticles compatible with more drugs. The bevacizumab stayed active through its journey inside the capsules because the team crafted a specific recipe to stabilize it. But that took a lot of trial and error. So McHugh wants to find what chemicals or polymers might stabilize a broad swath of proteins, from immunotherapies to vaccines. “If we can find that, then we can just fill whatever we want inside and not spend a lot of time on the formulation that stabilizes it,” he says.
As they sort out the engineering details, they are still searching for other conditions that might benefit from a tool like this. “If all you’re getting is one injection into your arm every month and a half instead of one injection every month, that’s not a big difference,” McHugh says. A big difference, to him, would be using this technology to treat hard-to-reach tumors—by squeezing multiple doses into a single shot that reaches tissues like the brain, pancreas, or liver. He says it could also be used to help hard-to-reach patients by simplifying vaccine regimens for people in remote regions. “It’s all about what you are changing,” he says.