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Nowadays, one of the main concerns in science and medicine is drug dissolution. Whether they were taken orally or intravenously, most drugs are dissolved before even reaching their targeted site. It mainly explains why it is necessary to administer a large dose to the patient.

The problem does not rely on the active ingredient but on the unfavorable body distribution. High cardiotoxic effect is one of the many side effects we can encounter due to drug dissolution. The heart muscle gets damaged (Fig. 1), and this leads to bad blood pumping.

The field of nanotechnology is trying today to find a way to distribute the drug without modifying it, such as loading it into a cargo. This could lead the drug directly to the target while controlling distribution and elimination. In oncology, many different kinds of nanoparticles are used in order to deliver drugs to the cancer sites, such as liposomes. Clinical research has shown that they are biocompatible with no toxic effect on the body. However, they have low cellular uptake, drug loading is also insufficient, and the drug can be released prematurely (1).

What is our goal?

Our goal is to find a way to synthesize particles, load, and deliver the drug efficiently without any leakage by the use of engineering. Here is how we are going to do it:

Use of extracellular vesicles in biotherapies

What are extracellular vesicles (EVs)?

EVs are lipid bilayer-delimited particles that are believed to be released from all types of cells . Unlike cells, they cannot replicate but they play a big role in communication. There are three main types of EVs: exosomes, microvesicles (Fig. 2), and apoptotic bodies. Their size varies between 20 nm and 10 µm, however, the majority has a size of 200 nm.

Why use EVs in biotherapies?

Evs (Fig. 2) are a promising therapeutic tool! They are used in regenerative medicine with stem cells and drug delivery. Not only they are a bio alternative to synthetic vectors, they also have targeting properties, are biocompatible, and are naturally stable in the blood.

EVs can carry a cargo, which is various biomolecules such as nucleic acids or proteins from their parent cell, and can provide them protection. One of the solutions to the problem of drug dissolution could be to use EVs to carry the drug to its final destination. Now, how could we integrate the drug inside the EVs?

In the last few years, many research projects have been dedicated to discovering how to use EVs for drug delivery (2). In order to do so, french researchers from the University of Paris made the fusion triggered by polyethylene glycol (PEG) of liposomes containing membrane and soluble cargoes, with EVs. Polyethene glycol is used in order to facilitate the fusion between the liposomes and the EVS. They also prevent liposomes from fusioning between them, due to their negative charge, and by making as well the reaction thermodynamically unfavourable.

For it to happen, we first need to synthesise the PEGylated liposomes while controlling meticulously their volumes and loading the drug inside. To do so, a chip can be used.

Synthesis of liposomes and drug loading: The micromixer chip

In the lab, a micromixer chip is a microfluidic device that allows rapid mixing, in our case, of two fluid streams.

In nanomedicine, the synthesis of particles is complex and needs to be well controlled for stability and good performance. Miniaturized flow chemistry is a key enabler in this area with the fabrication of microfluidic chips. What is convenient for chemistry in microfluidic, is that we reduce the volume of our particles, and we enhance the chemical process. More and more devices allow micromixing for nanoparticles, however, few have wide chemical compatibility.

Mixing is important in the formation of nanometric drugs. For liposomes, the size of the items will depend on how fast we mix them. With the kind of instruments we are developing today, we can go below the microsecond in terms of mixing which makes the items smaller and more efficient for their use.

Our project: The "Extracellular Vesicles Engineering on-chip"

For the next two months, we are going to combine all these notions into one project. We are going to design and fabricate passive and active micromixers, eventually using fluoropolymers. These micromixers are gonna be used in order to synthesize liposomes with the drug inside. Then we will fusion the loaded liposomes with PEG extracellular vesicles. Finally, we will characterize physicochemically the fluorescent hybrid EVs at the end to see the results of our experiments.