>> From the Library of Congress in Washington, D.C.
[ Silence ]
>> Welcome everyone.
Today's lecture was organized by the Science,
Technology & Business Division.
I'm Tomoko Steen.
I'm a research specialist here at the Library of Congress
at the Division of Science, Technology & Business.
Today's lecture is on cancer nanotechnology.
And nanotechnology is a frontier now, and the House is also working
on the new bill on nanotechnology.
And those who are working on it sent me apology not being able
to join today.
But today's speaker is one of the pioneers in the field.
And he has been actually working very actively
at the Johns Hopkins University, Professor Robert Ivkov.
He is actually based at the Department of Radiation Oncology
and the Molecular Radiation Science
at Johns Hopkins University's School of Medicine.
And also he has a joint appointment at the Engineering Department
at Johns Hopkins as well.
And he is a visiting researcher
at NIST [inaudible] for everyone I hope.
And he has been doing a lot
of research collaboration at the NIST as well.
And his Ph.D. is from the University of Maryland, College Park.
His masters is from the University of Toronto.
And his most recent project started from 2000,
and he is not only a researcher but inventor on this special technology.
So without further ado please join me to welcome Professor Ivkov.
[ Applause ]
[ Pause ]
>> So this can serve as a sound check.
Thank you very much, Tomoko for the invitation.
And it's a real pleasure and an honor
for me to present to you today.
I think I accidentally --
[ Pause ]
Okay, it's just a little slow like some of us early in the morning.
So to begin with I'd like to just lay the groundwork to sort
of prepare you for some of the themes that I'd
like to try to bring across to you.
And when Tomoko was communicating with me about this topic
and to give a presentation initially I thought, oh, well I'll just talk
about cancer magnets and nanotechnology and all this stuff.
And then when I started working on it I realize it's going
to be a little bit more challenging to bring this
across to a broad audience.
So some of the themes that I'd like to bring across to you are
that real innovation, real technology development,
real advances particularly
in challenging problems take a long time.
They also require multidisciplinary approaches.
And not just saying the words of multidisciplinary
but truly cooperation and having experts
who really are not just expert in one particular area
but who have some expertise in a number of areas.
And there's another one that actually comes to mind as well.
And that is there's really nothing new under the sun.
Many of these ideas are not new to us.
They're old.
We've been practicing.
As humans we've been practicing nanotechnology for over 1,000 years.
But what we do as humans is we tend to reinvent,
we tend to not necessarily trace a circle in innovation but a spiral.
Every time we come back around to the same topic we've got new
information, we've got new technologies, new methods,
and this brings about advancement.
And so with that as the prelude, and forgive some of the quality
of these slides because I'm actually pulling these graphical images
from documents and information because I wanted
to really just display the information in the sources.
So these are age-adjusted overall cancer death rate --
sorry, overall death rate from a number of different diseases.
And what one can see is that compared
to other diseases the overall age-adjusted death rate from cancer
for the years 1958 to 2010 has changed very little.
A note here is that this is on a logarithmic scale
so even a two-fold change will just appear as a little slight dip.
But having said that one should be impressed I think by the fact
that many other diseases have had marked decreases
in the overall death rate.
And that's an interesting fact.
Notice particularly cardiovascular disease.
We're approaching, we're approaching essentially a declining
cardiovascular death rate and a flat cancer- related mortality rate
so that now we're probably, if these trends continue, we might start
to see that cardiovascular death may not be the number one cause
of death.
Interestingly one can also dig into this and look
to see Alzheimer's-related death is increasing dramatically.
So is this really a dismal figure?
Well, actually if one takes a closer look, a closer examination
of cancer death by organ or by particular anatomical site,
and on the top we have for men, and on the bottom graph is for women,
you do see that there are actually significant decreases.
Note this is not a log scale, this is a linear scale,
so any change is going to be magnified.
But there is actually some change in the direction that we would
like to see, whereas the death rate is declining.
Lung cancer for both men and women, for men it's a dramatic decline,
but the reason is men were smoking earlier than women were,
and that cessation of smoking has caught hold
in the male population more so than it has in the female.
And so that's contributing to the decline.
But notice prostate cancer.
What I'd also like to highlight, I put the bar up here,
this is roughly around 1971.
1971 was a watershed year where President Nixon signed
into law major reform and funding
for cancer-related research driven primarily by patient advocacy.
And I think this is an important point.
And whenever I talk with people or even friends, family members and so
on it's like why aren't you doing more about cancer?
Well, actually as it turns out the war
on cancer I would argue is having its effect, but notice it's 10
to 20 years out from the time that is was begun.
So to really have a meaningful impact
on this disease it does require sustained commitment.
It's not a simple disease.
So why do we have such a difficulty with cancer?
Well, one way of looking at it is cancer is not a single disease.
It's roughly 300 diseases.
But more to the point from my point of view,
again remember I'm a physical chemist.
I'm not a biologist, I'm not an epidemiologist,
so I really am always a little bit nervous when I'm putting graphs
like this up on the board.
Cancer is a genetic disease, it's an autoimmune disease,
it's an epigenetic disease.
If one thinks about it breast cancer,
prostate cancer death does not come from the local disease.
So men do not die from locally advanced prostate cancer,
typically not.
Women do not generally die from locally advanced breast cancer.
You tend to die, these people tend to die from the metastatic disease.
And think about this for a moment.
What does it take for a prostate or a breast cell to migrate
from its environment, take up residence in the liver,
brain or bone, and actually restructure its environment
and take over?
This is not something that is a simple quick fix little turn
on a switch or turn off a switch kind of a problem.
So it does require sustained commitment
and a multidisciplinary approach from all fields of science.
So now switching to nanotechnology.
The concept of nanotechnology
and more specifically the National Nanotechnology Initiative
which began in 2000 when it was signed into I guess a law
if you will by President Clinton, if one starts to dig
around for the history of this many times you often end up here.
Richard Reynman gave a relative famous lecture
in the American Physical Society meeting in 1959,
and it was titled There's Plenty of Room at the Bottom,
meaning there is a great deal of opportunity
in science on the low length scale.
So nanotechnology as it is currently defined
by the National Nanotechnology Initiative is that it is the science
and engineering and technology or practice of controlling matter,
using matters on length scales of 1 to 100 nanometers.
We have been doing nanotechnology for over 1,000 years.
Stained glass windows in the cathedrals in Europe are essentially
that way because of nanotechnology.
So when I was preparing for this talk I asked colleagues
at Johns Hopkins who are part
of the Cancer Center Nanotechnology Excellence,
one of these is the radiology professor Martin Pomper
who is also a collaborator on several projects.
One example of nanotechnology enabled cancer diagnostic imaging is
through the use of this.
And I won't go into the name of it and so on,
but essentially it is a nanoparticle that has been labeled
with a very specific molecule that binds to a particular receptor
on prostate cancer cells.
It's a prostate specific membrane antigen.
I'll show you some other slides of some work that I'm doing
with some other collaborators
on this a little bit later in the presentation.
But prostate specific membrane antigen is one of those markers
or it's a protein that tends to be up regulated or expressed
in great quantity when prostate cancer metastasizes.
Not very often found in high levels necessarily.
I mean sometimes it is, but it's not always consistently found
at really high levels in the primary disease.
But when prostate cancer metastasizes it tends
to be overexpressed in abundance.
So what they did was they attached a nanoparticle,
and then they used this particular isotope of fluorine [phonetic]
and this PSMA molecule to initiate a study
in imagine a patient who has prostate cancer.
And what one sees is that with a regular CT bone scan one doesn't see
the cancer.
But hopefully the lighting is sufficient that you can actually see
that they were able to find tiny lesions in the bone
that were not apparent by traditional scans.
So one example of nanotechnology enabled imaging
for diagnosis of cancer.
One reason why one might say that the breast cancer rate
and prostate cancer rate might be declining is better screening
methods, earlier detection.
So I like hunting around for pictures on the web
when I'm starting to prepare talks, and this one caught my eye.
Initially I chuckled and I was going to discard it.
But then I thought, no, wait, wait, there's something interesting here.
First I would like you to look down here.
This red bar is representative, for example,
to scale the width of a human hair.
What we are talking about is manipulating matter
and making machines that are on the same sort of a scale like relative
to the human hair, like that.
So when I looked at this I thought, oh yeah, that's something
from Star Trek and started laughing and was going to throw it out.
But then I sat back and I thought, wait a minute,
it's an interesting thing about the length scale here.
Because if you think this is farfetched look at this.
The size scale that we are talking
about here is the size scale of a virus.
And viruses are actually extremely sophisticated machines
that do exactly this.
They respond to their environment, they know exactly
when to release their genetic material.
They have all this complex signaling that goes
on to do what they are going to do,
otherwise they wouldn't have survived.
So anybody who works in this field knows that the size scale
that we're talking about, we might even say it glibly, the size scale
that we're talking of nanoparticles is really on the order
of the size scale of a virus.
But I don't think we have spent enough time thinking
about the full implications or the logical conclusions of this.
So one of the themes that I'd like to bring out here is to say
that many of this might actually be possible if we begin to think
about nanotechnology in the right context.
And I think that's actually something we haven't
in the nanotechnology community haven't really begun to do yet.
So the virus does a lot of things that we think is science fiction
if we think about engineering materials.
But by studying the virus I think we can begin to accomplish some
of the goals that we set out to accomplish in healthcare.
So why is this so important?
Why is the size so important?
So nanomaterials I think are very unique or very special
in part because of their size.
And this is a general statement,
this is not necessarily only applicable to biology or medicine.
But when materials are taken
down to a very small size scale then the surface area becomes a much
greater proportion of the total amount
of material one is dealing with.
And now the surface properties become significantly enhanced
compared to the other bulk properties of the material.
So electronic properties, magnetic properties,
even quantum effects can become significant and play a role.
So we can use this to our advantage.
Anisotropy, in other words something that is not equal.
So we've got anisotropies in shape.
We can have elongated particles, we can have various types of square
or rectangular particles.
The shape of the particle actually has a significant effect
in medical applications.
And if you doubt that look at the virus.
So we have other anisotropies
that become important in surface chemistry.
This I think is in one sense one
of the reasons why nanotechnology enabled products are facing some
technological hurdles is because we have not yet figured out exactly how
to control that chemistry or what we need to do.
Because viruses have already figured that out, and that's one
of the themes I want to bring out in this talk, and I'll use examples
from research to emphasize that.
So it turns out that the chemistry,
the chemistry of the surface the physical chemical properties
actually determine how this material is going to interact with your body.
Because if your body thinks it's seeing a virus it is going
to treat it like a virus.
And so here is just a cartoon,
but this I think makes the point very nicely.
These are particles that I've developed and worked
on several years ago, and these were antibody targeted,
anti-cancer particles that have magnetic iron oxide crystals
that we could actually initiate heating
with an external magnetic field to do therapy.
So I'm giving you a little bit
of the foreshadowing of the talk, the topic.
These particles are about 40 nanometers in diameter.
And there is a discussion, there has been an ongoing discussion
in the nanotechnology and nanotechnology in cancer
and that is targeting doesn't work.
And there are some sides who say targeting does work,
and then targeting doesn't work and so on, back and forth.
So the only thing I would have to say to that is
if targeting does not work then why would natural selection have given
viruses their ligans [phonetic] that are very specific
to certain receptors on itself.
So viruses are very much targeted.
So it must work, we just simply haven't figured out how to do it.
That's my hypothesis.
Another interesting thing
that I believe has real medical implications is
that when we bring the size scale of our objects down to the really,
really small regime, the nanometer size regime,
a lot of these surface properties
and their interaction forces become significantly enhanced
and they tend to cluster.
So this is another set of particles.
These are magnetic iron oxide crystals
that have developed while at Johns Hopkins.
We call them just the JHU particles because I'm not creative enough
to spend time to think about a clever marketing name.
So JHU nanoparticles.
But here's H1N1 virus.
They tend to do the same thing.
They form these fractal aggregates.
I wonder if much of what the H1N1
or other flu viruses can accomplish comes
about because they form these clusters.
It's a question.
So one aspect or one issue that one has to consider is
that if we inject these nanoparticles
into a person's blood the body is going to treat this like a virus.
So what does the body do?
Well, we've developed innate and adaptive immune systems
to do exactly this, to address,
to protect us against pathogens, protozoans and viruses.
So what happens?
So the first step is opsonization.
It's a process, opsonization where blood proteins
and other immunologic factors essentially bind to that particle,
to that virus, to that protozoan to create a surface
that can be recognized by different parts of the immune system.
So there is the opsonization to create a corona
that now has these flags for various parts of your immune system,
let's say macrophages, white blood cells, other subcomponents
of your immune system to essentially take these particles or viruses
out of your bloodstream, sequester them into these lysosomes
and then hit them with enzymes and acid to just destroy them.
That's how your immune system in a nutshell works.
So should we be surprised that nanoparticles are not going
to experience the same fate?
I'm going to switch gears just for one second to show you that a lot
of this stuff really isn't just cartoons and science fiction.
So here is an example with the collaborator, Dr. Shawn Lupold
in urology, we took an anti PSMA antibody, we attached it to the --
you know the bioprobe, we attached it to the particle,
and this is just in cell culture.
This is not in an animal model.
This is a human prostate cancer cell that expresses the PSMA protein.
And then we just took electron micrographs to see what's happening.
And so we exposed the cells to the particles with the antibody,
and then we rinsed several times and then took these samples
to do electron microscopy.
And what you see is exactly what the cartoon was showing.
That when these particles are -- there is an environment around here
that is laden with these antigens, with these PSMA proteins,
that the particles now are going to congregate
and aggregate in these large clusters.
And that's what you see here.
And what happens when the cell sees this the cell is going to start
to internalize these particles.
And if one uses these guys as sort of a Trojan horse
to deliver therapy that's precisely what you want to have happen.
So the question is can we do this specifically for the cancer cells
or our target therapy target
and somehow avoid doing it with the immune system.
So there's another aspect or another part of tumor physiology
that is important if one looks in the nanotechnology of cancer
and nanotechnology field.
People make a big deal out of this EPR effect,
enhanced permeability and retention.
And basically it means this.
The vascular structure in the tumor is chaotic.
Tumors are abhorrently growing tissues.
They have all these growth factors, hormones,
all kinds of stuff going on.
And so the blood vessel supply is chaotic and very leaky.
So this gives us an opportunity to deliver material specifically
to the tumor and avoid too much retention
in other parts of the body.
So why even care about that?
Well, it turns out that the size of these vessels or the pores
in these vessels is actually somewhat fixed
or there's a range of sizes.
And it turns out furthermore that that size is kind of advantageous
for this nanometer, 10 to 100 nanometer length scale.
And here's an example, and this is something that I just pulled out.
It's been published.
But this is an example of a mouse being injected
with a small molecule dye, and it has tumors, but you notice
that the dye goes everywhere.
It's the red dye.
And then the mouse was injected with a nanoparticle,
a fluorescent nanoparticle that was labeled with this dye,
and you notice that there is accumulation in specific sites,
and these are the sites of the tumor.
So as a general concept this is one area that a great deal
of research has been focused on.
And one of the people who has been doing a fair amount of research
in this area is Justice Haynes [phonetic] who is also part
of the Cancer Center
in Nanotechnology Excellence at Johns Hopkins.
He's been researching developing nanoparticles to deliver drug
to brain tumors, essentially glioblastoma multiforme.
And so if you can see this is an image obtained from sections
from a mouse brain that was injected with nanoparticles.
The red here are nanoparticles
that have not had an enhanced coating designed
to minimize interactions with the proteins of the tissue.
And the green particles you notice these spread much better throughout
the tumor tissue because these particles have been coated in a way
to minimize this interaction with the blood proteins
or the biological system.
In other words, he's trying to make the particles have a little bit more
of a stealth character and be able to slip through
or move around undetected.
And so when they injected these particles into mice
that were bearing human brain tumor xenografts,
so they actually implanted human brain tumors into the brains
of mice, what we look at here is a measure
of the tumor size or tumor growth.
And so with no treatment you can see
that the tumors essentially grow unchecked.
When the tumors were injected or the mice were injected with paclitaxel,
PTX, paclitaxel is an anti-cancer drug,
then there was some effect on the tumor growth.
And when the mice were injected
with the particle containing the paclitaxel
that didn't have this specialized coating, well, you can see that some
of the drug is being delivered.
But when they added this special coating the paclitaxel delivery
to the tumor was much more efficient.
It was spread out through the tumor much better,
and so more of the cancer cells are killed thereby affecting more
of the tumor growth.
So that's a nice application
of nanotechnology which is drug delivery.
Now I'm going to move onto the next part which is heat.
Why would we even consider heat?
So coming back to the theme heat as a therapeutic agent
for cancer has been known for over 2,000 years.
Not new. The trouble is applying heat specifically
to cancer is really challenging because heat doesn't care
if it's bone tissue or liver or cancer.
So does it work?
And to just convince you that heat therapy does actually work very
nicely, it tends not to work so well when it's used by itself,
but when it's combined with radiation
or chemotherapy what it does is it enhances the effectiveness
of existing or commonly used therapy.
So here's an example.
These are clinical trial data in human patients with cervical cancer.
This is actually becoming standard of care in Europe.
Notice, and this is a survival curve,
so we're looking here years after treatment.
So this is survival progression and what fraction
of the initial population survived.
So we start with 100 percent or 1 which is all of the people
who were treated, and you notice that the ones
who only received radiation therapy, let's see if I can see this,
about 12 years out maybe about 20 percent of them are still alive.
But when they combined heat with radiation they doubled
that survival, 40 percent.
So it's a step in the right direction.
We haven't cured cancer, but it is a step in the right direction.
So the concept that I've been working on for
over ten years now is this concept
of thermally enhanced therapy for metastatic disease.
And it basically goes like this in this cartoon.
Develop a nanoparticle that has this magnetic core that can generate heat
when it's exposed to an alternating magnetic field, has an antibody
or some other cancer specific ligan, it gets injected,
evades a lot of the immune processes, immune surveillance
in the blood, and is able to be taken up
and retained specifically by the tumors.
And then the person goes into a device
that would be very similar to an MRI machine.
And now you specifically deposit heat into the cancer tumors
or in the context of chemotherapy or radiation
to enhance control of metastatic disease.
And remember metastatic disease is the most lethal part
for many of these cancers.
Not all. So just a little bit about what I'm talking
about when I'm talking about static or alternating magnetic fields.
Static magnetic fields are time invariant.
In other words, the magnetic poles don't change with time.
Time varying or alternating magnetic fields the poles do change
with time in a periodic fashion.
These static magnetic fields are very useful
for many medical applications,
and one of them is magnetic resonance imaging, MRI.
Alternating magnetic fields, on the other hand,
are useful for therapeutic application that might involve heat
or actually being able to use them to activate some nanomachine
because you can actually send signals using these alternating
magnetic fields.
And to just give you a little bit more of a flavor
on this the property of magnetics that we look
at is a property called hysteresis,
and many of you might know this experience from when you were kids.
I know I loved this experiment.
If you go to bed at night and you take a nail
that is essentially just not magnetic, put it on a magnetic.
In the morning when you wake up you take that nail
up you can pick up other nails with it.
That property is ferromagnetism, and that's the property
that when you take initially a magnetic substance
that has zero magnetization, put it in the presence of a magnetic field,
and then you take that field away there's memory, remnants.
That's the same property that if I put that material
into an oscillating magnetic field causes it to release
or lose power in the form of heat.
And I can generate intense heat from magnetic materials.
Very often people come into my lab, I'll take a screwdriver,
put it in the magnetic field coil, and it goes from room temperature
to about 3,000 degrees Celsius in one second.
It's red hot.
So that's a very effective, very efficient way of depositing energy.
There is another mechanism, it's induction heating.
Any electrically inducting material will generate some heat
through induced eddy currents.
And so we have to be careful on the safety patient, safety side,
we have to be careful about this
because tissues will heat nonspecifically in the presence
of an alternating magnetic field.
So if it was as easy as just sticking a bunch of magnets
into a person and putting that person
into a magnetic field coil we'd all go home, we'd be done.
But it's not quite so simple.
And just to give you an idea, one of the things that we do
in my lab is we do work very hard to build these magnetic field coils,
magnetic field devices that give us very homogeneous fields in the area
that we want because the nanoparticles are going
to heat based on the power of the magnetic field.
And I'll show you some temperatures in mouse tumors
that we've generated by controlling the heat.
Therapy is going to be dependent on how well you can control the heat.
So we need to have very good control over those magnetic fields.
And then to just show you some examples.
One example these are the JHU particles,
and then here are some examples of particles
that are put into a magnetic field.
And the change in temperature can be very rapid.
This particle here heats very well.
Within about five, ten seconds we've increased the temperature
in the sample by 20 degrees C. So you can literally ablate regions
of a tumor or kill cancer cells very nicely if one can do that very well.
So I have to put a little bit here from NIST.
One of the things that I do is really work with people,
with scientists at NIST to study the magnetic properties
of the nanostructured materials.
And for this I used the NIST Center
for Neutron Research among other things.
It's a great facility.
We are able to use the neutrons to study the magnetic properties
and the magnetic structure of these nanoparticles.
And I use that information to tune the chemistry
of the magnetic nanoparticles to get exactly the kind
of heating properties that I want for therapeutic applications.
And this is just a slide to show you some example
of the type of data one gets.
And if one does the really hard work to figure
out what it all means one can actually look
to see what the particles really look like
and understand why they generate the heat that they do.
Whereas other particles might not be as effective.
So using that information here's a type of particle
that you can buy commercially, it's commercially available.
It doesn't heat very well.
Here is a particle that I developed a few years ago.
These heat very nicely, but you notice that I need
to put more power on these guys.
And so I run the risk of actually overheating tissue.
These are now commercial available and are
in clinical trial at Dartmouth.
And these are the particles that I've developed while
at Johns Hopkins to essentially dial back the magnetic property
so that I get heating, not necessarily as intense,
but I can get more heating at lower power.
And so what does this all mean when we start
to actually inject these into models of cancer?
So here's my bioprobe again, my magnetic nanoparticles.
These is the part that actually generates the heat.
This is the business end.
The rest of it is really just to avoid detection by the immune system
and also achieve preferential retention in the cancer tumor.
So I do a lot of this engineering and chemistry
to just get the particles there.
So mice bearing human breast tumors were injected with these particles.
So the antibody is just a chimeric L6 antibody, ChL-6 antibody
that is specific to a protein that is produced by these tumors.
So the purple or the blue bars are -- and these are the tumors.
So what we did was we injected this material,
and three days later we harvested the tumors in other organs,
and we looked to see how much of the material was in those tissues.
And if we look at just the antibody we get about 18 percent
of the injected dose by mass is in the tumor.
When we look at our functional antibody labeled nanoparticle we
actually didn't do too badly.
We have a fair amount of material in the tumor.
And then as a test or a control we inactivated the antibody
in other samples, and we injected those and look what happens.
When the antibody isn't working very well then the particles don't stay
in the tumor.
And they end up liver and spleen mostly.
Liver and the spleen are these organs that function as part
of the reticular endothelial system, part of the immune system
where a lot of this material that macrophages
that are all constantly surveilling will gobble up and deposit.
So these materials, many of these nanotechnology products,
if one isn't very careful one actually ends up having --
as soon as they're injected they end up in the liver and the spleen.
They don't have a chance to get to the target.
So one of the things that we have to work very hard to do is
to actually achieve a long enough circulation time in the blood
so that these guys have a chance to get to the tumor
through the enhanced permeability effect.
And then by using that antibody or that other molecule
that specifically binds to a marker on the cancer cell keeps it there.
So when we do all of that and we apply our heat what happens?
So these are tumor growth data.
And these are tumors where the mice only have the bioprobes injected.
These were mice that were exposed only to the magnetic field.
And then these were mice that only had --
actually that had no treatment at all.
And so you see that these are controls and nothing happens.
When we exposed the mice
after injecting the nanoparticles two days later we put them
into the magnetic field
and we initiate the therapy we generate heat inside the tumor
and we kill tumor cells.
What's interesting about this is that we can dial
in how much therapy we want.
So here was at one power setting and here was at another power setting.
So we actually inflicted enough damage to these tumors
to delay their growth significantly.
And then we took electron micrographs and we actually see
that mice whose tumors were exposed
to the alternating magnetic field actually had destruction
in the tumor.
Another example of this similar thing -- I'm sorry.
[ Pause ]
I don't know which button I pushed but clearly --
so very quickly this is coming back to the PSMA antibody.
So here is an interesting model.
We grow two tumors on the mouse.
One tumor is PSMA negative, the other tumor is PSMA positive.
That's actually kind of a cool system to use because now
if we inject our particles, if they're really working they're going
to go to one tumor and not the other.
Yup, that's exactly what we saw.
Antibody labeled particles, PSMA positive tumor,
here's the PSMA negative tumor.
Particles without the antibody not much difference in either tumor.
And then we did some MRI contrast, so you're looking
at a sagittal view of the mouse.
These iron oxide nanoparticles they're what's called a T-2
contrast agent.
So when you put them in an MRI,
when they are present the image gets darker.
So here's a tumor without the particles, and it's brighter
than the one that has the particles.
So, pancreas cancer, lethal disease.
Diagnosis is usually --
the prognosis is usually pretty much a death sentence,
five percent chance of survival.
One of the problems is that it's asymptomatic
until time of diagnosis.
And time of diagnosis there's usually some pain or something.
And when it is diagnosed it's locally advanced.
There's a very large tumor that is often inoperable.
And the interesting thing is it's kind
of resistant to radiation therapy.
And, in fact, the radiation oncologists cannot give it a high
enough dose without actually causing excessive damage
to the sensitive tissues nearby.
So we decided to test our approach in a mouse model of pancreas cancer
where we actually have large and small tumors.
And the sizes of these tumors are controlled.
And, of course, this is a mouse model so everything is much smaller.
But we noticed that with radiation, this is a 5 Gy dose,
a particular dose of radiation.
Indeed the larger tumor is more resistant than the smaller tumor.
Just to give you an example
of how well we can control the heat we can control the heat
to a prescribed thermal dose.
We injected the nanoparticles.
In this case we injected them directly into the tumor.
And by modulating the power we can control the tumor temperature
to a very specific value.
Doing that we find that, okay, yeah,
we actually do better with the larger tumors.
So compared to radiation alone it's an interesting effect.
Where radiation fails we actually succeed.
So larger tumors are actually better for us.
So this is an ongoing study.
And I'll just show you the last little bit here from this study
where we combine the radiation with the nanoparticle hypothermia.
These are just the small tumors.
But notice that even for the small tumor when we combined radiation
with heat we get a very significant delay in the tumor growth.
So we really do cause an effect.
So with all of this seeming so promising, and I'm just going
to wind down with this, with all of this seeming
so promising what do we need to do
to translate more of this into the clinic?
So the benefits I think from the science are really quite clear
if we can engineer the particles well.
We can potentially address metastatic cancer.
So what's the challenge?
The challenge is this.
It's a regulatory risk.
It's a new technology.
It's undefined.
There's no really good experience with how
to actually put this through the system.
So there are chemical, manufacturing and controls
that need to be addressed.
There's toxicity assessment.
And then there's also the question of how is this going to actually go
through the regulatory process.
Because what I've showed you, particularly these antibody
or these other molecule conjugated nanoparticles, you have a biologic,
you have an injectable drug, the nanoparticle,
and then you have a device.
So it's very complicated.
It's a great technology, it's a great idea,
but it's extremely complicated.
What does that mean?
Well, it means it's really going to take a lot of work, a lot of money
and a lot of time to get it into the clinic.
And just as a reference, for small molecule drugs
for which there is a well defined path it takes just
to get the first clinical trial it takes about $20 million and five
to ten years and most of them fail.
So that's just to give you an idea.
And this is why there needs to be a sustained commitment
to address such big problems.
So one of the strategies
that I think could potentially work is we want
to develop a realistic path to the clinic,
so we want to address some clinical unmet need
by a simplified version of this.
So that simplified our chemistry, that simplifies our toxicity and all
of our regulatory concerns.
Mode of administration should be local.
What diseases, what cancer indications can be benefitted
by a local mode of administration?
And for those I would argue liver, pancreas and brain.
And I didn't highlight it then, but if one looks
at the cancer death rate, pancreas flat,
liver actually starting to go up.
So it takes a fair amount, actually a lot of work.
Cancer is a very complex set of diseases
that involves the immune dysfunction, immune disregulation.
It involves genomic, genetic instability.
It involves epigenetic instabilities.
I think nanotechnology because it is actually in the size range
of something that we have been naturally selected to deal with,
that offers us an opportunity to with the right control to be able
to take advantage of things, tools that we develop, of what we learn
to really specifically home in on certain diseases,
and even to modulate or reverse certain diseases, other diseases.
So the potential exists.
The potential also exists to enhance current or existing therapy.
And at least in the case of magnetic nanoparticle hypothermia
with the right engineering and with the right tools,
the right collaborations with scientists
at federal research institutions we are able to develop particles
that produce very specific heat doses to be able
to cause the damage that we need.
And with that, I will end and I'll leave the slide of acknowledgments.
Because a lot of this work over the years has taken a great deal
of effort, many students, many very fine collaborators at Johns Hopkins,
at NIST and other institutions.
And with that I'd like to thank you for your attention.
[ Applause ]
>> Do you have any questions?
>> You've been working on this for ten years.
>> Yeah, over ten years.
>> When you said about the challenges and the time lines
and the money and the [inaudible] where do you think this is at from
where you are now in the time line, are you guys five to ten years
out from that path that you're on?
>> So the current path that I'm on I'm developing the strategy
that I laid out was let's say the untargeted version
where we locally administer the particles.
I would argue that we've developed the particles --
before I answer just let me give you sort of the background
or the rationale thinking like a typical physical chemist.
We have a significant amount of data in mice, rats and even rabbit models
of liver cancer, pancreas cancer, breast cancer, prostate cancer.
So we're fairly confident that there is good, therapeutic potential
to move this into the clinic.
Our manufacturing is reproducible.
In fact, these particles were developed not specifically
in my laboratory but in collaboration with a company, again,
because I anticipate just from really developing this
from the ground up with scalability, manufacturing controls
and all of that built in.
So I would feel very confident saying with the right money
that version for, say, pancreas cancer could be
in a clinical trial in two to three years.
Yes?
>> I'm curious about the fate of the particles
after you've [inaudible] them in the model animals [inaudible].
Are they destroyed?
Do they migrate to other cells?
Are the ligans vulnerable to [inaudible] degradation?
>> That's a very excellent question actually.
So what happens during the heating process this is an area of research,
one of the people on here, my current post doc,
Aneil Ataluri [phonetic], he's a mechanical engineer,
and this is one area of interest
for him is modeling what actually happens during an immediately
post heating.
There's a complex series of physiological and mechanical changes
that occur in the tumor during heating.
Tissue expands and becomes much more pliable.
Increased blood flow comes in.
And also there is concomitantly tissue destruction.
So the particle distribution inside the tumor will become modified,
okay?
So now depending on the type of damage and the extent
of damage the process of, quote, healing,
resolution of the damage has a further impact on what happens
to the particles because now you have various components
of the immune system, macrophages and so on coming in to clean
up the debris and the mess.
They may take up the particles.
And so sometimes what one finds is that the particles just stay
where they are if you destroyed enough tissue
that nothing really gets in there.
Or they may actually migrate, the particles get moved
out to some other periphery or some other zone nearby or get transported
to the draining lymph nodes and then eventually end up in the liver.
So my guess would be that,
because I've never actually done this experiment,
but my guess would be an extremely successful therapy
that eradicates the tumor would probably result
in the particles ending up in the liver and the spleen
because that's their ultimate fate anyway.
Yes?
[ Inaudible Audience Question ]
>> Have you compared the impact of radiation and chemotherapy
in the rats in comparison to what you do in the [inaudible]?
>> So let me ask you the question or repeat the question just
to make sure that I understand it.
Have I compared the effects of radiation plus chemotherapy
in an animal model with the nanoparticle heating,
is that correct?
>> Yes, it is.
>> So from which perspective, toxicity or --
[ Inaudible Audience Question ]
So the answer is yes but not completely all the way there yet.
So in much of the work that we've been doing one of the things
that we do for the effectiveness is we do look to compare
between the nanoparticle hypothermia radiation, I have not done chemo,
I haven't done as much, actually I have done no chemo or models
with chemotherapeutic agents.
But radiation compared with the nanoparticle hypothermia
and then in combination.
And typically what we see the nanoparticle hypothermia is usually
not as effective as the radiation
or it's comparable to effect of radiation.
But when it's combined there seems to be an enhanced effectiveness.
And one of the other interesting things that we see is that because
of that we can actually potentially use a lower dose of radiation
to minimize the toxicity from those therapies.
And what we also see is that we don't have overlapping toxicities.
Now, we haven't pushed the limits, at least on the nanoparticles to see
where the toxicities lie.
But at least as far as the heating as long
as we're controlling the heat dose we don't have toxicities
that overlap.
In other words we're not making the problem worse.
What we do see instead is that radiation has specific toxicities
when we hit a high enough dose.
The heat therapy also has specific toxicities
when we hit a high enough dose.
But they're not the same.
And because we can combine them and use a lower dose
to be more effective we actually don't see the same type
of toxicity and toxic effect.
And that's really the significant benefit and the significant hope.
A radiation oncologist friend of mine and collaborator who deals
with pancreas cancer, he looked at our data recently
because post doc just recently presented this at a weekly meeting
in the department, he said this is the most exciting thing I've
ever seen.
Because his big challenge is he
as a radiation oncologist cannot deliver a high enough dose
to the pancreas tumor without causing damage to the duodenum
and other very sensitive structures that are right nearby.
So, yes, that's a very good question.
And that's exactly where we take our research is to really look
to see how to effectively combine these two to get the same
or better effects but with a much lower dose.
>> Well, I think you should [inaudible] chemotherapy,
and the reason why I say that is because I'm a [inaudible] and I sit
in [inaudible] National Cancer Institute as an advocate.
And in some of the clinical trial questions, because I'm coming
from the patient standpoint, some of the clinical trials have proven
in many areas that chemotherapy long term, and the reason why I can say
that is because I'm a four time cancer survivor of now 28 years,
and I went through the 70s and 80s with chemotherapy and radiation.
And I've had long-term effects [inaudible].
And I think if you start looking at your research going in the direction
of preparing the toxicity and long terms of chemotherapy as that part
and then your nano [inaudible] in doing that comparison study I think
that may be more of a [inaudible] to get something for [inaudible].
>> Would you like to co-write my next proposal?
[Laughter] I completely agree with you.
And absolutely this is a discussion
that we always have internally in my research group.
The fact is that for every added therapeutic modality one has
to include not just an additional cohort of animals,
but it actually takes three or four more
because you need all of the controls.
So absolutely agree.
But a trimodal therapeutic study would require a really sizeable
study population of many different cohorts,
and that's where I actually run into the challenge.
It takes more resources to do that.
So if you want to join me in writing a grant proposal I'm all for it.
>> There was a study [inaudible] many years ago back in 1977,
and I think that if you came back and looked at survivors,
if you asked to plug in the survivor [inaudible] and see the long effects
of that, then that may be a bidding piece for you because of the fact
that a lot of survivors [inaudible] who are still living [inaudible].
But the point being is that in
that case you would see chemotherapy is much better now than it was.
But the fact that the long- term effects sometimes
if you do [inaudible] the survivors there are a lot of things
out there that affect you.
>> Completely agree.
In fact, I would just add to that, I didn't highlight it,
but I don't know if any of you have noticed the leukemia rate is
going up.
That's one of the effects of chemotherapies.
It's absolutely 100 percent correct.
I would love to do that.
Okay.
>> I have two questions for you.
One, you mentioned something about Dartmouth.
What is the name of that study or how do I find out about it?
>> So the PI on that is Professor Jack Hoopes.
He has been doing a canine clinical trial for oral sarcoma.
>> Okay.
>> I'm not sure how much of that --
I'm pretty certain he hasn't published anything yet.
So it is a legitimate clinical trial only the patients are not humans,
they're actually dogs.
So spontaneous tumors.
I'd be happy to put you in touch
and if you're really interested to follow that up.
>> And how do I find out more information about what you're doing?
I saw a couple things were unpublished.
>> I can give you my card.
>> Okay.
>> Very simple, happy to talk.
>> Than you for making complex things as simple as possible today.
A laymen's question [inaudible].
This sounds to intriguing.
At the same time I wonder if the animal experiments can do --
do they live long enough, for example to get an idea
of the rate clearance of these nanoparticles through the liver
and spleen out of the system?
Do you have an idea how long they remain,
and do you conceptually see any potential problems.
As you mentioned some of those tend to stay in situ
if they effectively destroy a tumor.
Jumping ahead so obviously I'm asking you to think possibilities.
Do you think there would ever potentially problem given the heavy
[inaudible] usage for someone having a tumor clear,
going through this kind of equipment,
and having these particles reheat and [inaudible].
>> Ah. So I think there are two questions there.
So to answer the second question, let's go to that second question,
I'm not sure but I can guess that it's probably not going
to be a significant issue
because eventually these particles are degraded
so that the magnetic properties are decomposed.
The iron retention in humans is actually fairly long lived.
But the particles depend very much
on this very specific magnetic anisotropy energy which depends
on the structure and so on.
So macrophages they're just going to pound away on them.
So long term I would expect there to be a problem, number one.
Now, to your first question I smile because, first of all,
to answer it the answer is, no, we don't go long enough.
But here's what I think we haven't really clued in on.
I wonder if the animal models we're using are actually even appropriate.
Because what I showed you are data
from human tumor xenografts in mice models, okay?
So what that means is we implanted human cancer cells
to grow human tumors in mice.
The only way you can do that is
if you use an immune compromised strain of mouse.
If the nanoparticles are like a virus then its interaction
with that immune system has absolutely no bearing
on what you would expect to see in a human.
That's one of the areas that I'm really thinking.
And I've been writing proposals on this and they don't get funded
because people don't think it's important I guess, I don't know.
But I think it's actually important that we need
to take a re-examination of the nanotechnology
and the models we're using particularly for cancer
and bring some parody for how we align or what kinds
of models we use for which studies.
A very good question.
You probably didn't expect that long of an answer.
>> You reference 300 different types of cancers most
of whose etiologies we don't even know or understand.
Most of whose histologies we can't even differentiate.
And consequently when you talk
about metastatic cancer you haven't really talked
about when it has moved from the prostate, say, to the lymph nodes.
I have small cell right now and it's moved to the lymph nodes.
And essentially we're going to be playing whack them all on it.
And I don't see how the ferrous oxide particles are going
to be trained to go do the lymph nodes after they're in the prostate.
>> So there are -- I'm very sorry to hear about that.
So there are two different strategies
or two different approaches that I admittedly kind of mixed up.
So one is to address disseminated disease,
and the other is locally advanced disease.
Locally advanced disease involves image guided, if you will,
but image guided interventional therapy
where the nanoparticles could be directly injected
into the tumor and then we heat it.
Okay. I didn't focus on this
because that would be a whole different talk.
But I believe, and there are significant amounts of data coming
out now in the past two years showing that heat,
heating of tumors has a profound effect on the immune system
to modulate the immune system to re-engage it for cancer therapy.
And that's I think an interesting and an exciting proposal,
but that would require that the heat therapy
and also radiation would have to be done in the context
of vaccination, cancer vaccination.
And people are doing exactly those kinds of clinical trials right now.
So to answer that question specifically that would be the way
that I would approach addressing disseminated disease probably
in the best possible way.
Hit the main tumor or hit one of the tumors
and re-engage the immune system, reverse the energy
of the CDA positive T-cells if you will to now then home in
and start hunting down the other tumors.
On the other hand I also showed some work that we've been doing
with molecularly labeled ligan labeled nanoparticles
that are specific to particular markers, antigens or other proteins
on a cancer cell surface.
It turns out that in many cases the primary tumor when metastasis
or dissemination occurs it's a particular subclone
of the original tumor.
So it tends to be that the metastatic sites are less
heterogeneous than is the original tumor.
So it turns out if you find that correct marker I think,
I don't know, find that correct marker, label the particles
with that correct marker, systemically deliver,
intravenous delivery and, again,
with all of the other caveats having been discussed hopefully long enough
circulation time and a good specific binding to those cells.
So two different strategies.
>> Thank you.
>> You're welcome.
>> Maybe you can talk to him after this.
But please join me in thanking Professor Ivkov.
[Applause]
>> Thank you for your attention.
>> This has been a presentation of the Library of Congress.
Visit us at loc.gov.