Most vaccines, from measles to COVID-19, require a series of multiple shots before the recipient is considered to be fully vaccinated. To make that easier to achieve, MIT researchers have developed microparticles that can be tuned to deliver their payload at different time points, and which could be used to create what the scientists describe as “self-boosting vaccines.”

Using these particles, which resemble tiny coffee cups sealed with a lid, researchers could design vaccines that would need to be given just once, and would then “self-boost” at a specified point in the future. The particles can remain under the skin until the vaccine is released and then break down, just like resorbable sutures. The same strategy could also feasibly be used to deliver a range of other therapeutics, including cancer drugs, hormone therapy, and biologic drugs.

In their development, reported in Science Advances, the researchers described how these particles degrade over time, and how they can be tuned to release their contents at different time points. The study also offers insights into how the microparticle contents can be protected from losing stability before they are released.

“This is a platform that can be broadly applicable to all types of vaccines, including recombinant protein-based vaccines, DNA-based vaccines, even RNA-based vaccines,” said Ana Jaklenec, PhD, a research scientist at MIT’s Koch Institute for Integrative Cancer Research. “Understanding the process of how the vaccines are released, which is what we described in this paper, has allowed us to work on formulations that address some of the instability that could be induced over time.”

This type of vaccine delivery could be particularly useful for administering childhood vaccinations in regions where people don’t have frequent access to medical care, the researchers say.

Jaklenec and Robert Langer, PhD, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, are senior authors of the new study, which is titled, “Experimental and computational understanding of pulsatile release mechanism from biodegradable core-shell microparticles.” First author is Morteza Sarmadi, PhD, a research specialist at the Koch Institute.

Next-generation therapeutics require advanced drug delivery platforms with precise control over morphology and release kinetics, the authors wrote. “Biodegradable core-shell microparticles represent a promising class of biomaterials with applications that can improve efficacy and adherence, which is particularly important for patients in a developing world.” Such applications might include single-injection vaccine delivery, transdermal vaccine delivery, cancer immunotherapy and pH-dependent oral drug delivery, “… all of which are otherwise infeasible with traditional drug delivery systems,” the team noted. “Controlled drug delivery technologies can particularly aid in the treatment of diseases that require multiple shots by improving patient adherence.”

The researchers first described their new microfabrication technique for making these hollow microparticles in 2017. The particles are made from poly(lactic-co-glycolic acid), (PLGA), a biocompatible polymer that has already been approved for use in medical devices such as implants, sutures, and prosthetic devices.

To create cup-shaped particles, the researchers create arrays of silicon molds that are used to shape the PLGA cups and lids. Once the array of polymer cups has been formed, the researchers then employ a custom-built, automated dispensing system to fill each cup with a drug or vaccine. After the cups are filled, the lids are aligned and lowered onto each cup, and the system is heated slightly until the cup and lid fuse together, sealing the drug inside.

This technique, called SEAL (StampEd Assembly of polymer Layers), can be used to produce particles of any shape or size. In a recently published paper, Ilin Sadeghi, PhD, an MIT postdoc, and others created a new version of the technique that allows for simplified and larger-scale manufacturing of the particles. The authors further suggested, “These 3D core-shell microparticles demonstrate a delayed pulsatile profile, which can be programmed from a few days up to several months. These microparticles’ unique tunability, in terms of release time point, morphology, and compatibility with biologics and hydrophilic small molecules, provides a wide range of opportunities for pulsatile drug delivery.”

In the newly reported study in Science Advances, the researchers wanted to learn more about how the particles degrade over time, what causes the particles to release their contents, and whether it might be possible to enhance the stability of the drugs or vaccines carried within the particles. “We wanted to understand mechanistically what’s happening, and how that information can be used to help stabilize drugs and vaccines and optimize their kinetics,” Jaklenec said.

The authors further commented, “To provide insights into the pulsatile release mechanism from biodegradable core-shell microparticles, we performed a comprehensive study using various experimental and computational tools. Specifically, we focused on particles with a 3D microstructure that can be microfabricated or 3D printed thanks to a multilayer microfabrication technique termed StampEd Assembly of polymer Layers (SEAL).” Their studies of the release mechanism revealed that the PLGA polymers that make up the particles are gradually cleaved by water, and when enough of the polymers have broken down, the lid becomes very porous. Very soon after these pores appear, the lid breaks apart, spilling out the contents.

“We realized that sudden pore formation prior to the release time point is the key that leads to this pulsatile release,” Sarmadi said. “We see no pores for a long period of time, and then all of a sudden we see a significant increase in the porosity of the system.”

The investigators then set out to analyze how a variety of design parameters, including the size and shape of the particles and the composition of the polymers used to make them, affect the timing of drug release. “In this work, various tools from experimental and computational approaches were integrated to study the complex mechanism of degradation in biodegradable core-shell microparticles,” they wrote.

To their surprise, they found that particle size and shape had little effect on drug release kinetics. This sets the particles apart from most other types of drug delivery particles, for which size plays a significant role in the timing of drug release. Instead, the PLGA particles were shown to release their payload at different times based on differences in the composition of the polymer and the chemical groups attached the ends of the polymers.

“Uniquely, the delayed pulsatile release profile was preserved across all 25 different designs of microparticles studied,” the investigators stated. “Size independence of release time point from particle geometry (within ±2 days in vitro), within the range studied, provides an advantage over existing drug delivery systems such as hydrogels and microspheres.” In fact the studies showed that pore formation and deformation in the microparticle cap were the two parameters that controlled the release kinetics. “Since the release profile is independent of particle geometry within the range studied (100- to 500-μm particles), this approach can be applicable to a wide range of core-shell particle designs,” the scientists added.

Sarmadi further noted, “If you want the particle to release after six months for a certain application, we use the corresponding polymer, or if we want it to release after two days, we use another polymer. A broad range of applications can benefit from this observation.”

The researchers suggested that their study was the first to use multiple experimental and computational tools to study pulsatile release kinetics from biodegradeable microparticles. “Results of this study not only can provide insights into the mechanism of pulsatile release but also can enhance general understanding of degradable biomaterials such as Poly(L-lactide), (PLLA). Furthermore, they can aid in the design and fabrication of next-generation biomaterials and drug delivery systems for a broad range of drug delivery applications including self-boosting vaccines.”

The researchers also investigated how changes in environmental pH affect the particles. When water breaks down the PLGA polymers, the by-products include lactic acid and glycolic acid, which make the overall environment more acidic. This can damage the drugs carried within the particles, which are usually proteins or nucleic acids that are sensitive to pH.

In an ongoing study, the researchers are working on ways to counteract this increase in acidity, which they hope will improve the stability of the payload carried within the particles. To help with future particle design, the researchers also developed a computational model that can take many different design parameters into account and predict how a particular particle will degrade in the body. This type of model could be used to guide the development of the type of PLGA particles that the researchers focused on in this study, or other types of microfabricated or 3D-printed particles or medical devices.

The research team has already used this strategy to design a self-boosting polio vaccine, which is now being tested in animals. Usually, the polio vaccine has to be given as a series of two to four separate injections.

“We believe these core shell particles have the potential to create a safe, single-injection, self-boosting vaccine in which a cocktail of particles with different release times can be created by changing the composition,” Langer said. “Such a single injection approach has the potential to not only improve patient compliance but also increase cellular and humoral immune responses to the vaccine.”

Drug delivery using the same approach could also be useful for treating diseases such as cancer. The researchers previously showed that they could deliver drugs that stimulate the STING pathway, which promotes immune responses in the environment surrounding a tumor, in several mouse models of cancer. After being injected into tumors, the particles delivered several doses of the drug over several months, which inhibited tumor growth and reduced metastasis in the treated animals.

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