Nanoparticles Could be Key to Improving Vaccine Delivery

Most vaccinations, including those for measles and Covid-19, require a number of injections before the receiver is deemed adequately protected. MIT researchers have created nanoparticles that can be tweaked to deliver their payload at different times, which might be used to produce "self-boosting" vaccines to make it easier to accomplish.

Researchers have described how these particles deteriorate over time and how they may be tweaked to release their contents at various times. The report also provides advice on how to prevent the contents from degrading while they are being held in reserve.

Researchers might create vaccinations that only need to be administered once and then "self-boost" at a predetermined time in the future using these particles, which resemble miniature coffee cups sealed with a cover. Similar to resorbable sutures, the particles can stay embedded in the skin until the vaccine is released before disintegrating.

According to the researchers, this method of vaccine administration may be especially helpful for providing childhood vaccines in areas where people don't frequently have access to medical care.

According to Ana Jaklenec, a research scientist at MIT's Koch Institute for Integrative Cancer Research, "this is a platform that can be generally applicable to various forms of vaccinations, including recombinant protein-based vaccines, DNA-based vaccines, and even RNA-based vaccines." We were able to develop formulations that address some of the instability that could be created over time by working on the mechanism of how the vaccines are delivered, which we reported in this publication.

According to the researchers, this strategy might be utilised to deliver a variety of additional therapies, such as cancer treatments, hormone therapy, and biologic medications.

Senior authors of the new study, which was published in Science Advances today, include Jaklenec and Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute. The paper's principal author is Morteza Sarmadi, a research specialist at the Koch Institute and recent MIT PhD graduate.

Release of drugs

The innovative microfabrication method the researchers used to create these hollow nanoparticles was initially introduced in a 2017 Science study. The particles are constructed from PLGA, a biocompatible polymer that has already received approval for use in implants, sutures, and prosthetic devices.

The scientists build arrays of silicon moulds that are used to form the PLGA cups and lids into cup-shaped particles. The researchers used a specially created, automated dispensing device to fill each cup with a medication or vaccine once the array of polymer cups had been made. The system is then mildly heated to cause the cup and lid to fuse together, locking the medicine inside, after the cups have been filled and the lids have been lined up and lowered onto each cup.

With the help of this method, known as SEAL (StampEd Assembly of polymer Layers), particles of any size or form can be created. Ilin Sadeghi, an MIT postdoc and the paper's lead author, developed a new variation of the process that enables easier and larger-scale manufacture of the particles. Their work was just published in the journal Small Methods.

The goal of the new Science Advances study was to better understand how the particles break down over time, what causes the particles to release their contents, and whether it could be feasible to make the medications or vaccinations that are carried inside the particles more stable.

In order to stabilise medications and vaccines and improve their kinetics, Jaklenec explains, "we sought to understand mechanistically what is happening."

The PLGA polymers that make up the particles are gradually cleaved by water, and after enough of these polymers have been broken down, the lid becomes extremely porous, according to their analyses of the release process. The cover splits, letting the contents stream out very quickly after these pores start to form.

We came to the conclusion that the key to this pulsatile release is quick pore development just before the release time point, according to Sarmadi. For a very long time, we don't notice any pores, and then all of a sudden, the system's porosity increases noticeably.

To their astonishment, the scientists discovered that particle size and shape had minimal impact on the kinetics of drug release. This distinguishes the particles from the majority of other kinds of drug delivery particles, whose size has a big impact on when the medication releases. Instead, due to variations in the composition of the polymer and the chemical groups connected to the ends of the polymers, the PLGA particles release their payload at various times.

According to Sarmadi, "we utilise the corresponding polymer if you want the particle to release after six months for a given use, or we use a different polymer if you want it to release after two days." This insight has applicability across a wide range.

The impact of pH shifts in the environment on the particles was also studied by the researchers. Lactic acid and glycolic acid are produced as byproducts of the breakdown of the PLGA polymers by water, which increases the acidity of the surrounding environment. The medications that are contained within the particles, which are often proteins or nucleic acids that are pH-sensitive, may be harmed as a result.

The researchers are currently investigating methods to reduce this rise in acidity in an effort to maximise the stability of the payload carried by the particles.

The researchers also created a computational model that can forecast how a specific particle will degrade in the body while taking into account a variety of design criteria to aid in future particle creation. The kind of PLGA particles that the researchers focused on in this study, as well as other kinds of microfabricated or 3D-printed particles or medical devices, might all be developed using this kind of model.

This method was previously employed by the research team to create a self-boosting polio vaccine, which is currently being evaluated in animals. The polio vaccination often needs to be administered in a course of two to four different shots.

"We think that by varying the composition, a cocktail of particles with various release timings might be generated in a safe, single-injection, self-boosting vaccination using these core shell particles. Such a single injection strategy has the potential to enhance cellular and humoral immune responses to the vaccination, as well as patient compliance "states Langer.

The treatment of conditions like cancer may benefit from this kind of drug delivery. In a 2020 Science Translational Medicine report, the researchers presented evidence that they could administer medications to cancerous mice models through the STING pathway, which stimulates immune responses in the vicinity of a tumour. The particles were injected into the tumours and over a period of months, they released multiple doses of the medication, which prevented metastasis and slowed tumour growth in the treated animals.