So, can you explain the principle and the advantages of using targeted delivery?
The principle is to propose an alternative to traditional drug delivery.
Traditionally, you encapsulate a very toxic anticancer drug,
and the risk is that the drug leaks out at undesirable places.
With in-situ chemistry, rather than encapsulating a toxic compound,
we encapsulate two precursors of the drug that have a low, or even zero, toxicity.
And in the end, we deliver non-toxic compounds, so that the risk in case of a leak is minimal
since toxicity itself is reduced.
Then, we combine these compounds directly in the tumor
to create the therapeutic molecule.
Can you tell us how you applied this general principle of in-situ chemistry
in your own research on cancer treatments?
In every delivery problem, one must define a capsule, an encapsulation process,
and an external stimulus that breaks the capsule open.
In our case, the external stimulus is ultrasounds,
the same ultrasounds that are used for sonography in hospitals.
Then, our capsule is a "double emulsion".
A double emulsion is simply like a double vinaigrette:
we encapsulated nanodroplets of water
into microdroplets of perfluorocarbon, that travel in water.
Perfluorocarbon is a very peculiar molecule,
akin to the coating of non-stick frying pans.
One of its properties is that it does not mix with water nor with oil.
In fact, in our double emulsion, it enables us to isolate
the nanodroplets from the outside of the microdroplets.
In our study, we encapsulated one of the precursors,
let's call it A, inside of the droplets,
and outside of the droplets, the second precursor, B, moves freely.
With ultrasounds, we can break the droplets open,
and bring the two precursors together,
so that A and B can react with each other.
How do you encapsulate these compounds in your double emulsion?
The encapsulation is performed in two steps.
During a first step, we prepare a nanoemulsion:
an emulsion of nanodroplets of water, in perfluorocarbon.
And then, during the second step, you prepare an emulsion of this first emulsion, right?
Yes, exactly! But this time we use a new procedure,
this time we don't use a mechanical or energetic procedure, like ultrasounds:
instead we use microfluidics.
More precisely, we use the system that's on the screen here:
it is composed of 30 parallel channels,
that split the first emulsion into micrometric droplets.
The channels are the small twisted things, right?
Yes, that's it! In black, you see the nanometric emulsion,
that first arrives in these twisted channels,
that are very narrow and lead to a large pool.
When the emulsion reaches the step,
it breaks up at regular intervals,
forming the small dark droplets that you see here.
Here the zoom is not strong enough to see the nanoemulsion inside of the droplets,
but if you zoom in, like in that video,
where the contrast is inverted so that droplets are this time white,
this time you can see the nanodroplets inside of the microdroplets.
This is a typical double emulsion structure.
Your double emulsion is now ready,
you have droplets inside of droplets
that you can put into a microfluidic device,
now the second part of the experiment is the interaction with ultrasounds.
So, why would sending ultrasounds onto this double emulsion
ensure that the reaction partners meet?
Here, ultrasounds are used as an external stimulus
to break up the capsules, in this case the double emulsion.
That's why we first chose to use perfluorocarbon
to separate the nanodroplets from the water outside:
perfluorocarbon is actually very sensitive to ultrasounds.
In particular, if you focus an ultrasonic wave on a place
where you have perfluorocarbon, it vaporizes,
meaning that it goes from the liquid phase to the gas phase.
This happens very fast, and it's enough to break up the structure,
thus freeing the compound that was inside.
So, with an imaging device, you can localize a specific spot,
select the position of the tumor,
bring the reaction partners A and B together by breaking the capsule,
and the anticancer drug is formed only in the tumor.
So you only use one ultrasonic device to image and treat the tumor;
you combine two of its uses.
Yes, it's one of the main advantages of this technology:
we use the same ultrasonic imaging device
first to image the tumor, then to treat it.
You just described a very ambitious project, that sounds very promising!
Did you develop this medical application right away,
or did you start with a simpler, model experiment?
Can you tell us about this?
Yes, you're right, in this kind of research we start very far off the application
so we can slowly get closer to it.
We started by working on a model,
to check that we were able to control both where and when this chemical reaction happened.
And what is your model reaction,
what quantity did you measure to make sure that it worked?
For this model reaction,
we mostly needed to be able to visualize the reaction with a microscope.
The only way to do that was to use a reaction that produced fluorescence.
We've been through all the different elements of your experiment,
now let's sum up the whole experiment.
First, we prepare droplets that contain a compound, A.
Outside of these droplets, we place a second compound, B.
We inject this mix into a microfluidic device,
this channel is placed at the spot where the ultrasounds are the most intense.
Due to the focusing, the ultrasounds vaporize the perfluorocarbon,
so that compound A is freed, and can meet compound B.
Then, what happens in our model experiment
is that we see an increase in light intensity, very fast and very intensely,
meaning that compounds A and B actually met, reacted with each other
and formed a fluorescent chemical product.
You've shown that your model experiment works,
what are the next steps now?
Obviously, in the future we would like to apply this concept in a more realistic setting,
and produce anticancer drugs in situ.
That's what we're doing right now.
A few months ago, we started an in vitro study: a study with actual cells,
to check whether we are able to make an anticancer drug
directly on the cells and induce cell death.
And then, if that works, and it seems to be the case,
the next step is small animals, mice or rats,
to show that this concept works one level closer to our end goal.
Then, what might be even more interesting
would be to use chemicals that are too toxic to be commercially available,
as with our strategy the toxicity is decreased dramatically.
Indeed, we can use precursors with a much lower toxicity,
then encapsulate them in microdroplets,
and in the end, we might be able to use all the molecules
that were discarded because of their toxicity.
Now, to wrap up this video, I think you have something for us?
Yes, I chose this picture with perfluorocarbon microdroplets.
This is the cornerstone of this project,
it all relies on encapsulation, so it seemed like a good summary!
Thanks a lot! We will be very glad to add it
to our blackboard, back in the studio.
Thank you for taking part in the Lutetium Project!
Thank you!
