December 10, 2024 • 28 mins
In this episode Dr. Adewuya is joined by Dr. Heike Daldrup-Link, a Professor of Radiology at Stanford University. Our conversation explores the fascinating intersection of nanotechnology and clinical medicine, particularly its transformative role in medical imaging and its significance for pediatric oncology. We discuss how nanoparticles function within the body for imaging purposes, highlighting their advantages over traditional imaging agents. Our discussion covers the advancements in precision medicine in cancer imaging, including the reduced side effects associated with safer imaging modalities. Additionally, we will examine the ethical considerations of utilizing nanoparticles in children, explore ongoing clinical trials, and discuss potential long-term health effects on pediatric patients.
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:00):
(upbeat music)
- Welcome to "Stanford Medcast,"
the podcast from Stanford CME
that brings you the latest insights
from the world's leadingphysicians and scientists.
If you're joining us for the first time,
be sure to subscribe on Apple Podcast,
Amazon Music, Spotify, or YouTube
(00:21):
to stay updated with our newest episodes.
I am your host, Dr. Ruth Adeuwya.
Today I will be chattingwith Dr. Heike Daldrup-Link.
Dr. Heike Daldrup-Link isa Professor of Radiology
and Pediatrics at StanfordUniversity School of Medicine,
where she leads groundbreaking research
in pediatric oncology imaging.
As a leading physician scientist,
(00:42):
Dr. Daldrup-Link is renownedfor her pioneering work
in applying nanotechnology
to enhance diagnostic imaging techniques
for children with cancer.
Her research focuses ondeveloping innovative,
non-invasive imaging agentsthat improve cancer detection
and reduce the need for radiation,
making cancer diagnosticssafer for young children.
(01:04):
Through her work at Stanford,
she combines her expertise inmolecular imaging, radiology,
and oncology to push the boundaries
of how clinicians diagnose, monitor,
and treat pediatric cancers.
Over the past 10 years,Dr. Daldrup-Link's team
has received 77 honors and awards
for innovative cellular imaging research.
(01:25):
Thank you so much, Dr. Daldrup-Link,
for chatting with me today on the podcast.
- Thank you so much for having me.
- I'm excited to chat withyou about this emerging tech,
nanotechnology, and itsutilization in clinical medicine.
For listeners who are lessfamiliar with what this is,
can you talk about what is nanotechnology
in the context of medical imaging?
(01:47):
And what makes it particularly exciting
for pediatric oncology?
- Nanotechnology in general
describes extremely smallmaterials and devices,
in the order of one to 100 nanometers.
In the context of medical imaging,
we mostly talk about new contrast agents,
(02:07):
which are a little largerthan the usual molecules
that we use as contrastagents in the clinic nowadays.
We can use them for improvingmedical imaging diagnosis
and we can also use themas so-called theranostics,
combined diagnostic and therapeutic drugs.
(02:27):
- That's a new term to me. Theranostics.
When you talk about these nanoparticles,
can you explain how theywork within the body
for imaging purposes?
And how they do differ fromtraditional imaging agents?
- There are differenttypes of nanoparticles.
And our group specifically works
with iron oxide nanoparticles.
(02:48):
These nanoparticles contain iron,
which we can detect with an MRI scanner.
They provide a signal on our images.
When we inject theseiron oxide nanoparticles,
because they are relatively large,
they stay in blood vesselsfor a relatively long time,
(03:08):
and that allows us
to generate very high resolutionvascular imaging studies.
Over time, these nanoparticlesaccumulate in various organs.
We can target them so thatthey find a specific organ
where we want them to accumulate.
For example, in tumors,they slowly accumulate
(03:29):
through a process wherethey penetrate the vessels
and then accumulate in the tumor tissue.
We can better image vessels.
We can target certainorgans within the bodies,
and we can also specifically image tumors.
- This is quite interesting.
If I'm hearing you correctly,
it's the property of these molecules
that make them beneficial in oncology
(03:50):
because they bind to the tumor cells.
What are the thingsthat you can appreciate
because of this binding?
- We have non-targeted nanoparticles,
and these are actually more commonly used.
They just behave differentlyto standard contrast agents
because of their large size.
Initially they stay in the black pool
that allows us to imagevessels with very high detail.
(04:14):
Then they leak across tumormicrovessels, into tumors,
and there they arephagocytosed by immune cells.
That allows us conclusions aboutthe immune cell composition
in the tumor.
Now, we can also decoratethe nanoparticles
with antibodies or any other target
(04:35):
that cancer cells can recognize,
which then specificallyallows the nanoparticles
to accumulate in the tumor tissue.
That applies specificallyto the theranostics.
We have some nanoparticles
that we attach to therapeutic drugs.
We can attach them witha linker that is cleaved
(04:57):
by specific enzymes that are only present
in the tumor tissue and not anywhere else.
That then leads to therapeutic drugs
that have very little or no side effects,
and that are only activatedin the tumor tissue.
When the nanoparticlereaches the tumor tissue,
the cargo is cleaved bythe enzyme that is there.
(05:18):
The therapeutic drug isonly released in the tumor,
and not anywhere else.
- It's a tremendous opportunityfor personalized medicine
in terms of allowing cliniciansto identify the tumors
and treat them in ahighly specific manner,
and ultimately improvingpatient outcomes in such a way
that might not be seen throughconventional treatment.
(05:41):
If we talk specifically about
how are we improving theprecision of cancer imaging,
especially for younger patients,
who may be more vulnerable to radiation
and invasive procedures?
- I think we have to differentiatewhat we have available
in the clinic right now,
and then what is in thepipeline of research.
If we look at what we have right now,
(06:03):
these are the non-targeted nanoparticle.
We specifically use an iron oxide compound
that is FDA approvedas an iron supplement.
We use this iron supplement off-label
as a contrast agent for MRI.
In MRI, you might have heard about
(06:24):
the gadolinium-based contrast agents.
There are some concerns becausegadolinium is a heavy metal
and it can deposit in certainorgans including in the brain.
And so there's some concernabout long-term retention
of gadolinium in certain patients.
Using an iron supplement,from a safety perspective,
(06:46):
the iron is incorporated into the body's
reticuloendothelialsystem, in liver, spleen,
and bone marrow, it is metabolized there,
and completely eliminated over time.
Any agent can have a sideeffect, so these nanoparticles
can sometimes lead to allergic reactions.
I think it's very difficult
to say there's theultimate safe procedure.
(07:10):
Any procedure or anydrug has pros and cons.
With regards to the nanoparticles,
the big pro is that it canbe completely metabolized.
We can use it in patientswith renal insufficiency,
for whom immune contrast agents
or urinated contrast agents are a problem
because the kidneys cannot eliminate them.
But we can make a personalizedplan for the patient
(07:32):
to choose the best optionfor their specific condition.
- I appreciate your comment about safety.
It's this check and balance ofwhat would be slightly safer.
I'm curious about whetheryou have seen this reduction
in side effects, compared toconventional imaging methods.
- I have seen different side effects.
(07:53):
For the current clinical contrastagents that we have there,
iodine-based contrast agents,these are for CT imaging,
which involves radiation exposure.
The urinated contrast agentsare usually given in patients
who have an intactfunction of their kidney,
because these contrast agents
are eliminated through the kidney.
(08:14):
In patients who have a problemwith their kidney function,
nanoparticles will be a great alternative
because they are taken up byliver, spleen and bone marrow
and then metabolized there.
They are not eliminatedthrough the kidneys.
It's similar for thegadolinium-based contrast agents.
For MRI, there's a problem if the patient
(08:35):
has renal insufficiency, because again,
these standard clinical contrast agents
are eliminated through the kidney.
If the kidney doesn't function,
then they are not properly excreted,
and that then can cause problems.
All of these contrast agentscan lead to allergic reactions.
The nanoparticles overall statistically
(08:57):
can have a little higherfrequency of allergic reactions
compared to the gadolinium chelates,
and approximately the same
or similar risk of allergic reactions
to urinated contrast agents.
We specifically check ourpatients for any history
of allergic reactions.
We make a personalized decision
(09:18):
and avoid it if a patient has any history
of severe allergic reactions.
- Can you expound on whatyou typically see there,
when you talk about allergicreactions to the nanoparticles?
- There are a numberof different reactions.
These iron oxide nanoparticles have a
carboxymethyl dextran coatthat is a dextran derivative.
(09:40):
A lot of people haveallergies against dextran.
We look for such history.
If that is present, we knowthat the true allergic reaction
against these nanoparticles
is essentially a dextran allergy.
There are new research efforts ongoing
to develop new nanoparticlesthat have a different coat
(10:00):
to have a much risk of allergic reactions.
In addition to thistrue allergic reaction,
iron supplements can cause something
that we call a pseudoallergy.
It presents with similar symptoms,
but it's not a true allergy,but a complementary action.
And that happens when these nanoparticles
(10:23):
are injected into thebloodstream too fast.
If we deliver the nanoparticlestoo fast to the bloodstream,
then complement factors inthe blood can be activated
and that can lead to anallergy-like reaction.
To minimize that effect,
the FDA actually has issueda strong recommendation
(10:44):
that nanoparticles have to be infused
over at least 20 minutes,
so the body has the advantage
to capture these nanoparticlesand transport them properly.
We also have these protocolsin place in our clinic.
I have not seen any, so far,
any allergy-like reaction in our patients.
(11:06):
We had one patient who had alight form of allergic reaction
and that was properly treated,
and didn't lead to any major short-term,
or long-term problems.
- It's clear that nanotechnology
holds this immense potentialfor advancing patient care,
but adopting it in aresponsible way also means
(11:28):
addressing some of these sideeffects that you've mentioned.
The ongoing researchthat you and your team,
and I think countless others are doing,
are obviously some of those crucial steps
to maximize the benefits of nanotechnology
while really ensuring thatthere is safety around it.
I wanna take a step back
and ask you how you cameto focus on nanotechnology
(11:50):
within pediatric oncology imaging.
- I took quite a journey, asyou might hear from my accent.
I'm originally from Germany, actually,
and I went to medical school in Germany.
While I was there,
the first MRI contrastagents were developed.
Gadolinium-DTPA is thefirst MRI contrast agent,
(12:12):
was patented in 1981,
and then the first human patient received
this gadolinium-based contrastagent in Berlin in 1983.
And shortly after that,
the first human volunteerreceived the drug in Berlin
in 1983 because it was developed there,
(12:32):
and then actually thefirst patient underwent
an gadolinium-enhancedimaging study in 1983
at the Hammersmith Hospital in London.
And from there, actually,
research centers aroundthe world, including UCSF,
were involved in the development
of this gadolinium-based contrast agents,
which ultimately broughtme to San Francisco.
(12:55):
In the process,
since I was involved invery early developments
of MRI contrast agents, I alsogot involved in development
of nanoparticle-based alternatives.
So through my careerI was involved in many
phase one to phase three clinical trials
(13:16):
for MRI contrast agents,
including gadolinium-basedcontrast agents.
I believe I was involvedin clinical trials
for every nanoparticle for MRIs
that was ever used in the clinic.
I got a very good foundationwith two nanoparticle studies.
(13:37):
I'm really thrilled toshare that knowledge now
in institution like Stanford,
which has immense resourcesto advance this field.
- Your journey is incredible.
It's almost like you follow the journey
of imaging from Germany,
and you're continuing to develop it,
and that's just incredible.
(13:57):
As someone who has this deep history
into the evolution of imaging,
I'm curious if you couldshare a recent case or a study
where nanotechnology hasreally played a pivotal role
in the diagnosing ormonitoring of pediatric cancer.
- Currently in the clinic,
we start with the moresimple applications.
(14:19):
Applications range from vascular imaging,
delineating tumors better,
and also imaging specific immunecells in the tumor tissue.
The most common applicationis vascular imaging.
We inject the nanoparticles,
they stay in the blood pool much longer
than the current small molecular probes.
(14:42):
Therefore, we can see thevessels to much greater detail
than with standard contrast agents.
We use this technique on a regular basis
for planning of a liver transplant.
Patients who have liver tumorsthat involve the entire liver
and who need a liver transplant.
In order to plan the surgery,
we need to know wherethe vessels are exactly,
(15:04):
and in young children, thesevessels and their branches
can be really small.
Using the nanoparticlescan help us immensely
to see the anatomy that canhelp with surgery planning
and with an improved andmore efficient process
for a liver transplant.
We can use nanoparticlesto better see tumors
(15:24):
that can help to guide biopsies,
or help us to follow these tumors
before and after treatment.
Get more experiment for whichwe examine very few patients,
imaging immune cells in the tumor tissue.
We have nanoparticles that are taken up
by tumor-associated macrophages,
immune cells in the tumor tissue,
(15:44):
and some immunotherapieswith nanoparticles,
we can see this activation of immune cells
in the tumor tissue, and theseimmune cells essentially,
they fight the cancer cells.
- Your response really highlights
some of these promising developments
in pediatric oncology imaging
when it relates to detectionand treatment planning.
(16:07):
I think one of the thingsthat I heard from you is how,
by the improved imaging ofvascular structures in tumors,
it could play the key role,
especially in the pediatric population
where these networks are so complex
that it really provides this opportunity
to shift towards this less destructive
and more targeted interventions
and really enhancing diagnosis precision,
(16:29):
which is just so exciting.
One of the things that you mentioned
is that you have someapplications in clinic,
but you have these experimental things
that are still being researched.
What does the pathway look like
for integrating these innovations
that are experimentalinto clinical practice?
- The nanoparticles that we currently use,
fortunately are FDA approvedas an iron supplement
(16:52):
for the treatment of anemia.
A lot of safety data already available
for these kind of nanoparticles.
And for my specificexperimental applications,
I applied for an IND with the FDA,
an Investigational New Drug application.
This is from anadministrative point of view,
(17:13):
a little more straightforward if the drug
is already FDA approved, sowe apply for off-label use
of an already FDA-approved agent.
And I have to say currently,
these iron supplementsare approved for adults,
and so the off-label useis number one for imaging,
and number two for applicationsin the pediatric population.
(17:36):
Other nanoparticles that arecurrently in development,
they have to go throughthe entire IND process,
so they start with phase zero,phase one clinical trials,
with dose-escalating studieswhere we check the safety
and toxicity of the agents,starting with very low doses,
and then slowly increasing
(17:58):
until we find the lowest possible dose
that leads to a signal on our MR images,
and then from there, wehave to apply to the FDA
for subsequent studies.
Those clinical trials for new agents
are often driven by companies,
because they are veryadministrative and time
(18:18):
and cost-intensive,
and usually only companieshave the resources to do that.
There is at least one company currently
that is very active in this field
to advance new nanoparticleswith this improved coating
that I mentioned earlier.
They just completed aphase two clinical trial
in adult patients with liver tumors.
(18:39):
This will be an agent that willbe specifically FDA-approved
as a contrast agent.
We wouldn't use it off-label anymore,
but the purpose of this agent would be
that it's a contrast agent,
and so we have high hopes for that agent
because that would makeit much easier to use
than through an off-label use.
(19:00):
- With this technologybeing relatively new,
are there any ethical considerations
around using nanoparticles in children?
And how do you approach these concerns?
- With my experimental studies,
we do that through an IRB protocol,
an ethical committeereviewed what we want to do
and they provided input,
(19:21):
and then ultimately approve the study.
We have a consent form.
We meet with parents and the patient
and try to explain as best as possible
what the advantages and disadvantages are
of a nanoparticle-based study.
Then the patient sign an informed consent.
I do believe that it's very important
(19:41):
to explain in muchdetail the pros and cons
of the potential advantagesand potential risks
of nanoparticle-baseddiagnostics and therapies
so that patients and parentscan make an informed decision.
At Stanford, when we have children
who can understand the procedure,
we do obtain a consent from the parents
(20:05):
because they make the decision,
and we also obtain what iscalled an assent from the child.
The parents decide andthe child also decides,
if say, want to participate or not.
- I think that's incredible
that there's this processof transparent communication
with the patients
and for pediatricpopulation with the parent
(20:26):
and the actual child to make sure
that they're fully informedof the implications
of the interventions thatthey will be going through.
I meant to ask you this earlier.
Are there any negativeimpacts on the clinicians
in any way of adopting nanotechnology
or utilizing nanotechnologyin medical spaces?
(20:46):
- Yeah, of course.
For any new technology, initially,
the whole workflow is much longer
because we have the consent procedure.
On the clinical side,
it's really important todefine which questions
can we answer with the technology at hand
and which questions requirethis new technology.
(21:11):
Oftentimes when you havea new tool at your hand,
you want to use it for everything.
In medicine, it's reallyimportant to think this through
very carefully, and defineareas where this can be helpful,
and areas maybe wherethe standard technology
is good enough.
- Here's spot on about the fact
that there seems to bea specialized nature
of nanotechnology,
(21:33):
and this would require anupskilling for clinicians
to understand when and howto administer therapy safely.
Can you talk a little bit
about the accessibilityissues surrounding this?
- I'm a physician scientist,
so I do not know the actualcosts that come out in the end.
Currently for our clinical trials
(21:55):
that my group is conducting,
those are funded by theNational Cancer Institute,
and so the National CancerInstitute funds the entire study,
so there are no costs to the patient.
Once these technologies getinto the clinic, of course,
then eventually thepatient would be billed.
(22:15):
I do believe there is arisk with new technologies
which can be more expensive,
that has downstreamimplications for the cost,
both for the insurance andperhaps also for the patient.
- I appreciate your perspective,
and fully realize thatthis is a little bit
outside of your wheelhouse,
but I think that perspectiveis important for our listeners
to understand the costof new technologies.
(22:37):
We're fortunate, we said at Stanford,
and some of our patients will have access
to these technologies, but over time,
how will these new technologiesactually be available
in other areas?
- For patients who are interested
to participate in a clinical trial,
any clinical trial fora medical condition,
they can go online on ClinicalTrials.gov,
(23:02):
and that is a website by theNational Institute of Health
that lists all clinical trialseverywhere in the country.
There, patients can find clinical trials,
which most of the time coverall the costs for a treatment
and these clinical trialsare open to everyone.
From there, make an informed decision.
(23:23):
This is a resource thatis open to everyone.
I would highly recommend thatinterested listeners here
might want to check it out,
because I think it's a fantastic resource.
- I think that's an excellent point,
and a good resource to be aware of.
When we talked aboutyour specific research,
which uses an iron supplementthat is already FDA approved,
(23:45):
there's a clearer pathwayin terms of understanding
the long-term health effects.
Can you talk a little bit about others
that don't have that same situation?
Can you foresee any potentiallong-term health effects
of nanoparticles in pediatric patients?
- With current research,
there's a lot of emphasis on generating
(24:07):
a good image contrast with nanoparticles,
focusing on achievingaccumulation of nanoparticles
in certain tumors.
There is often not as much emphasis
on the metabolism of these drugs.
I think this is really crucial,even in an early phase,
because nanoparticle would not be viable
(24:29):
if it wouldn't get metabolizedand eliminated from the body.
We have to make sure thatwithin a certain time period,
these nanoparticles arecompletely metabolized
and eliminated.
Sometimes nanoparticlesor other contrast agents
can accumulate in certain tissues.
(24:50):
If they're not metabolized there,
then they can cause an immune response
or an inflammatory reaction.
That can then lead to tissue problems.
This has been described forthe gadolinium chelates,
for example, in patientswith renal insufficiency.
The gadolinium can bedeposited in the skin,
and then cause a skin sclerosis,
(25:12):
thickening and hardening of the skin,
which certainly we want to avoid.
Some nanoparticles are so small
that they can actually be eliminated.
If that is the case, then theymight appear in wastewater
and could have an environmental impact.
So that is a very important issue as well
(25:34):
that we have to be aware of.
- Nanotechnology does offer this potential
to enhance precision in tumor detection,
and that we can leverageit to visualize vasculature
and help clinicians delivermore personalized care,
but also the realization thatthere's still more research
(25:54):
to be done in terms of themetabolism specifically,
but also the impact environment.
To wrap up our conversation,
to someone who's been partof this imaging journey
for a long time,
what do you hope will bethe biggest breakthroughs
in pediatric oncology imagingin the next five to 10 years?
- One big part,
(26:14):
artificial intelligenceapplications currently,
so that's everywhere.
That's a huge area of development.
We are fortunate to work
with a very talented computerscientist in our team.
And some tiny little aspect
where the nanoparticles can come in here
is that they provide a verysteady contrast enhancement
(26:37):
over time.
We don't have as muchvariation in the images,
compared to a contrast agent
that provides a short peak enhancement
and then decreasing enhancement of tissues
so that every imagelooks a little different.
So that can help withcomputer post-processing also,
application of theranostics.
The underlying idea isthat if I can already see
(27:00):
where a drug is going,
and I see that it accumulatesin the tumor tissue,
why not use it as acarrier or Trojan horse
to shot drug into the tumor tissue?
And that would also allow me to monitor
the efficacy of certain therapies.
I believe that theranosticsis a big new area.
(27:23):
Another big area arecancer immunotherapies.
Here we images are trying to develop more
and more sophisticated approaches
that we can image different populations
of immune cells in the body.
The nanoparticles canalso help us with that,
as can many other imagingtechniques as well.
- Really exciting work thatis happening in this field
(27:45):
and exciting to seethe promise of a future
that leverages this technology.
Thank you so much forchatting with me today.
- Thank you. It was a great pleasure.
- This episode was broughtto you by Stanford CME.
To claim CME forlistening to this episode,
click on the Claim CME Link below,
or visit Medcast.Stanford.edu.
(28:06):
Check back for new episodes by subscribing
to "Stanford Medcast" whereveryou listen to podcasts.
(bright music)
(upbeat music)
- Welcome to "Stanford Medcast,"
the podcast from Stanford CME
that brings you the latest insights
from the world's leadingphysicians and scientists.
If you're joining us for the first time,
be sure to subscribe on Apple Podcast,
Amazon Music, Spotify, or YouTube
(00:21):
to stay updated with our newest episodes.
I am your host, Dr. Ruth Adeuwya.
Today I will be chattingwith Dr. Heike Daldrup-Link.
Dr. Heike Daldrup-Link isa Professor of Radiology
and Pediatrics at StanfordUniversity School of Medicine,
where she leads groundbreaking research
in pediatric oncology imaging.
As a leading physician scientist,
(00:42):
Dr. Daldrup-Link is renownedfor her pioneering work
in applying nanotechnology
to enhance diagnostic imaging techniques
for children with cancer.
Her research focuses ondeveloping innovative,
non-invasive imaging agentsthat improve cancer detection
and reduce the need for radiation,
making cancer diagnosticssafer for young children.
(01:04):
Through her work at Stanford,
she combines her expertise inmolecular imaging, radiology,
and oncology to push the boundaries
of how clinicians diagnose, monitor,
and treat pediatric cancers.
Over the past 10 years,Dr. Daldrup-Link's team
has received 77 honors and awards
for innovative cellular imaging research.
(01:25):
Thank you so much, Dr. Daldrup-Link,
for chatting with me today on the podcast.
- Thank you so much for having me.
- I'm excited to chat withyou about this emerging tech,
nanotechnology, and itsutilization in clinical medicine.
For listeners who are lessfamiliar with what this is,
can you talk about what is nanotechnology
in the context of medical imaging?
(01:47):
And what makes it particularly exciting
for pediatric oncology?
- Nanotechnology in general
describes extremely smallmaterials and devices,
in the order of one to 100 nanometers.
In the context of medical imaging,
we mostly talk about new contrast agents,
(02:07):
which are a little largerthan the usual molecules
that we use as contrastagents in the clinic nowadays.
We can use them for improvingmedical imaging diagnosis
and we can also use themas so-called theranostics,
combined diagnostic and therapeutic drugs.
(02:27):
- That's a new term to me. Theranostics.
When you talk about these nanoparticles,
can you explain how theywork within the body
for imaging purposes?
And how they do differ fromtraditional imaging agents?
- There are differenttypes of nanoparticles.
And our group specifically works
with iron oxide nanoparticles.
(02:48):
These nanoparticles contain iron,
which we can detect with an MRI scanner.
They provide a signal on our images.
When we inject theseiron oxide nanoparticles,
because they are relatively large,
they stay in blood vesselsfor a relatively long time,
(03:08):
and that allows us
to generate very high resolutionvascular imaging studies.
Over time, these nanoparticlesaccumulate in various organs.
We can target them so thatthey find a specific organ
where we want them to accumulate.
For example, in tumors,they slowly accumulate
(03:29):
through a process wherethey penetrate the vessels
and then accumulate in the tumor tissue.
We can better image vessels.
We can target certainorgans within the bodies,
and we can also specifically image tumors.
- This is quite interesting.
If I'm hearing you correctly,
it's the property of these molecules
that make them beneficial in oncology
(03:50):
because they bind to the tumor cells.
What are the thingsthat you can appreciate
because of this binding?
- We have non-targeted nanoparticles,
and these are actually more commonly used.
They just behave differentlyto standard contrast agents
because of their large size.
Initially they stay in the black pool
that allows us to imagevessels with very high detail.
(04:14):
Then they leak across tumormicrovessels, into tumors,
and there they arephagocytosed by immune cells.
That allows us conclusions aboutthe immune cell composition
in the tumor.
Now, we can also decoratethe nanoparticles
with antibodies or any other target
(04:35):
that cancer cells can recognize,
which then specificallyallows the nanoparticles
to accumulate in the tumor tissue.
That applies specificallyto the theranostics.
We have some nanoparticles
that we attach to therapeutic drugs.
We can attach them witha linker that is cleaved
(04:57):
by specific enzymes that are only present
in the tumor tissue and not anywhere else.
That then leads to therapeutic drugs
that have very little or no side effects,
and that are only activatedin the tumor tissue.
When the nanoparticlereaches the tumor tissue,
the cargo is cleaved bythe enzyme that is there.
(05:18):
The therapeutic drug isonly released in the tumor,
and not anywhere else.
- It's a tremendous opportunityfor personalized medicine
in terms of allowing cliniciansto identify the tumors
and treat them in ahighly specific manner,
and ultimately improvingpatient outcomes in such a way
that might not be seen throughconventional treatment.
(05:41):
If we talk specifically about
how are we improving theprecision of cancer imaging,
especially for younger patients,
who may be more vulnerable to radiation
and invasive procedures?
- I think we have to differentiatewhat we have available
in the clinic right now,
and then what is in thepipeline of research.
If we look at what we have right now,
(06:03):
these are the non-targeted nanoparticle.
We specifically use an iron oxide compound
that is FDA approvedas an iron supplement.
We use this iron supplement off-label
as a contrast agent for MRI.
In MRI, you might have heard about
(06:24):
the gadolinium-based contrast agents.
There are some concerns becausegadolinium is a heavy metal
and it can deposit in certainorgans including in the brain.
And so there's some concernabout long-term retention
of gadolinium in certain patients.
Using an iron supplement,from a safety perspective,
(06:46):
the iron is incorporated into the body's
reticuloendothelialsystem, in liver, spleen,
and bone marrow, it is metabolized there,
and completely eliminated over time.
Any agent can have a sideeffect, so these nanoparticles
can sometimes lead to allergic reactions.
I think it's very difficult
to say there's theultimate safe procedure.
(07:10):
Any procedure or anydrug has pros and cons.
With regards to the nanoparticles,
the big pro is that it canbe completely metabolized.
We can use it in patientswith renal insufficiency,
for whom immune contrast agents
or urinated contrast agents are a problem
because the kidneys cannot eliminate them.
But we can make a personalizedplan for the patient
(07:32):
to choose the best optionfor their specific condition.
- I appreciate your comment about safety.
It's this check and balance ofwhat would be slightly safer.
I'm curious about whetheryou have seen this reduction
in side effects, compared toconventional imaging methods.
- I have seen different side effects.
(07:53):
For the current clinical contrastagents that we have there,
iodine-based contrast agents,these are for CT imaging,
which involves radiation exposure.
The urinated contrast agentsare usually given in patients
who have an intactfunction of their kidney,
because these contrast agents
are eliminated through the kidney.
(08:14):
In patients who have a problemwith their kidney function,
nanoparticles will be a great alternative
because they are taken up byliver, spleen and bone marrow
and then metabolized there.
They are not eliminatedthrough the kidneys.
It's similar for thegadolinium-based contrast agents.
For MRI, there's a problem if the patient
(08:35):
has renal insufficiency, because again,
these standard clinical contrast agents
are eliminated through the kidney.
If the kidney doesn't function,
then they are not properly excreted,
and that then can cause problems.
All of these contrast agentscan lead to allergic reactions.
The nanoparticles overall statistically
(08:57):
can have a little higherfrequency of allergic reactions
compared to the gadolinium chelates,
and approximately the same
or similar risk of allergic reactions
to urinated contrast agents.
We specifically check ourpatients for any history
of allergic reactions.
We make a personalized decision
(09:18):
and avoid it if a patient has any history
of severe allergic reactions.
- Can you expound on whatyou typically see there,
when you talk about allergicreactions to the nanoparticles?
- There are a numberof different reactions.
These iron oxide nanoparticles have a
carboxymethyl dextran coatthat is a dextran derivative.
(09:40):
A lot of people haveallergies against dextran.
We look for such history.
If that is present, we knowthat the true allergic reaction
against these nanoparticles
is essentially a dextran allergy.
There are new research efforts ongoing
to develop new nanoparticlesthat have a different coat
(10:00):
to have a much risk of allergic reactions.
In addition to thistrue allergic reaction,
iron supplements can cause something
that we call a pseudoallergy.
It presents with similar symptoms,
but it's not a true allergy,but a complementary action.
And that happens when these nanoparticles
(10:23):
are injected into thebloodstream too fast.
If we deliver the nanoparticlestoo fast to the bloodstream,
then complement factors inthe blood can be activated
and that can lead to anallergy-like reaction.
To minimize that effect,
the FDA actually has issueda strong recommendation
(10:44):
that nanoparticles have to be infused
over at least 20 minutes,
so the body has the advantage
to capture these nanoparticlesand transport them properly.
We also have these protocolsin place in our clinic.
I have not seen any, so far,
any allergy-like reaction in our patients.
(11:06):
We had one patient who had alight form of allergic reaction
and that was properly treated,
and didn't lead to any major short-term,
or long-term problems.
- It's clear that nanotechnology
holds this immense potentialfor advancing patient care,
but adopting it in aresponsible way also means
(11:28):
addressing some of these sideeffects that you've mentioned.
The ongoing researchthat you and your team,
and I think countless others are doing,
are obviously some of those crucial steps
to maximize the benefits of nanotechnology
while really ensuring thatthere is safety around it.
I wanna take a step back
and ask you how you cameto focus on nanotechnology
(11:50):
within pediatric oncology imaging.
- I took quite a journey, asyou might hear from my accent.
I'm originally from Germany, actually,
and I went to medical school in Germany.
While I was there,
the first MRI contrastagents were developed.
Gadolinium-DTPA is thefirst MRI contrast agent,
(12:12):
was patented in 1981,
and then the first human patient received
this gadolinium-based contrastagent in Berlin in 1983.
And shortly after that,
the first human volunteerreceived the drug in Berlin
in 1983 because it was developed there,
(12:32):
and then actually thefirst patient underwent
an gadolinium-enhancedimaging study in 1983
at the Hammersmith Hospital in London.
And from there, actually,
research centers aroundthe world, including UCSF,
were involved in the development
of this gadolinium-based contrast agents,
which ultimately broughtme to San Francisco.
(12:55):
In the process,
since I was involved invery early developments
of MRI contrast agents, I alsogot involved in development
of nanoparticle-based alternatives.
So through my careerI was involved in many
phase one to phase three clinical trials
(13:16):
for MRI contrast agents,
including gadolinium-basedcontrast agents.
I believe I was involvedin clinical trials
for every nanoparticle for MRIs
that was ever used in the clinic.
I got a very good foundationwith two nanoparticle studies.
(13:37):
I'm really thrilled toshare that knowledge now
in institution like Stanford,
which has immense resourcesto advance this field.
- Your journey is incredible.
It's almost like you follow the journey
of imaging from Germany,
and you're continuing to develop it,
and that's just incredible.
(13:57):
As someone who has this deep history
into the evolution of imaging,
I'm curious if you couldshare a recent case or a study
where nanotechnology hasreally played a pivotal role
in the diagnosing ormonitoring of pediatric cancer.
- Currently in the clinic,
we start with the moresimple applications.
(14:19):
Applications range from vascular imaging,
delineating tumors better,
and also imaging specific immunecells in the tumor tissue.
The most common applicationis vascular imaging.
We inject the nanoparticles,
they stay in the blood pool much longer
than the current small molecular probes.
(14:42):
Therefore, we can see thevessels to much greater detail
than with standard contrast agents.
We use this technique on a regular basis
for planning of a liver transplant.
Patients who have liver tumorsthat involve the entire liver
and who need a liver transplant.
In order to plan the surgery,
we need to know wherethe vessels are exactly,
(15:04):
and in young children, thesevessels and their branches
can be really small.
Using the nanoparticlescan help us immensely
to see the anatomy that canhelp with surgery planning
and with an improved andmore efficient process
for a liver transplant.
We can use nanoparticlesto better see tumors
(15:24):
that can help to guide biopsies,
or help us to follow these tumors
before and after treatment.
Get more experiment for whichwe examine very few patients,
imaging immune cells in the tumor tissue.
We have nanoparticles that are taken up
by tumor-associated macrophages,
immune cells in the tumor tissue,
(15:44):
and some immunotherapieswith nanoparticles,
we can see this activation of immune cells
in the tumor tissue, and theseimmune cells essentially,
they fight the cancer cells.
- Your response really highlights
some of these promising developments
in pediatric oncology imaging
when it relates to detectionand treatment planning.
(16:07):
I think one of the thingsthat I heard from you is how,
by the improved imaging ofvascular structures in tumors,
it could play the key role,
especially in the pediatric population
where these networks are so complex
that it really provides this opportunity
to shift towards this less destructive
and more targeted interventions
and really enhancing diagnosis precision,
(16:29):
which is just so exciting.
One of the things that you mentioned
is that you have someapplications in clinic,
but you have these experimental things
that are still being researched.
What does the pathway look like
for integrating these innovations
that are experimentalinto clinical practice?
- The nanoparticles that we currently use,
fortunately are FDA approvedas an iron supplement
(16:52):
for the treatment of anemia.
A lot of safety data already available
for these kind of nanoparticles.
And for my specificexperimental applications,
I applied for an IND with the FDA,
an Investigational New Drug application.
This is from anadministrative point of view,
(17:13):
a little more straightforward if the drug
is already FDA approved, sowe apply for off-label use
of an already FDA-approved agent.
And I have to say currently,
these iron supplementsare approved for adults,
and so the off-label useis number one for imaging,
and number two for applicationsin the pediatric population.
(17:36):
Other nanoparticles that arecurrently in development,
they have to go throughthe entire IND process,
so they start with phase zero,phase one clinical trials,
with dose-escalating studieswhere we check the safety
and toxicity of the agents,starting with very low doses,
and then slowly increasing
(17:58):
until we find the lowest possible dose
that leads to a signal on our MR images,
and then from there, wehave to apply to the FDA
for subsequent studies.
Those clinical trials for new agents
are often driven by companies,
because they are veryadministrative and time
(18:18):
and cost-intensive,
and usually only companieshave the resources to do that.
There is at least one company currently
that is very active in this field
to advance new nanoparticleswith this improved coating
that I mentioned earlier.
They just completed aphase two clinical trial
in adult patients with liver tumors.
(18:39):
This will be an agent that willbe specifically FDA-approved
as a contrast agent.
We wouldn't use it off-label anymore,
but the purpose of this agent would be
that it's a contrast agent,
and so we have high hopes for that agent
because that would makeit much easier to use
than through an off-label use.
(19:00):
- With this technologybeing relatively new,
are there any ethical considerations
around using nanoparticles in children?
And how do you approach these concerns?
- With my experimental studies,
we do that through an IRB protocol,
an ethical committeereviewed what we want to do
and they provided input,
(19:21):
and then ultimately approve the study.
We have a consent form.
We meet with parents and the patient
and try to explain as best as possible
what the advantages and disadvantages are
of a nanoparticle-based study.
Then the patient sign an informed consent.
I do believe that it's very important
(19:41):
to explain in muchdetail the pros and cons
of the potential advantagesand potential risks
of nanoparticle-baseddiagnostics and therapies
so that patients and parentscan make an informed decision.
At Stanford, when we have children
who can understand the procedure,
we do obtain a consent from the parents
(20:05):
because they make the decision,
and we also obtain what iscalled an assent from the child.
The parents decide andthe child also decides,
if say, want to participate or not.
- I think that's incredible
that there's this processof transparent communication
with the patients
and for pediatricpopulation with the parent
(20:26):
and the actual child to make sure
that they're fully informedof the implications
of the interventions thatthey will be going through.
I meant to ask you this earlier.
Are there any negativeimpacts on the clinicians
in any way of adopting nanotechnology
or utilizing nanotechnologyin medical spaces?
(20:46):
- Yeah, of course.
For any new technology, initially,
the whole workflow is much longer
because we have the consent procedure.
On the clinical side,
it's really important todefine which questions
can we answer with the technology at hand
and which questions requirethis new technology.
(21:11):
Oftentimes when you havea new tool at your hand,
you want to use it for everything.
In medicine, it's reallyimportant to think this through
very carefully, and defineareas where this can be helpful,
and areas maybe wherethe standard technology
is good enough.
- Here's spot on about the fact
that there seems to bea specialized nature
of nanotechnology,
(21:33):
and this would require anupskilling for clinicians
to understand when and howto administer therapy safely.
Can you talk a little bit
about the accessibilityissues surrounding this?
- I'm a physician scientist,
so I do not know the actualcosts that come out in the end.
Currently for our clinical trials
(21:55):
that my group is conducting,
those are funded by theNational Cancer Institute,
and so the National CancerInstitute funds the entire study,
so there are no costs to the patient.
Once these technologies getinto the clinic, of course,
then eventually thepatient would be billed.
(22:15):
I do believe there is arisk with new technologies
which can be more expensive,
that has downstreamimplications for the cost,
both for the insurance andperhaps also for the patient.
- I appreciate your perspective,
and fully realize thatthis is a little bit
outside of your wheelhouse,
but I think that perspectiveis important for our listeners
to understand the costof new technologies.
(22:37):
We're fortunate, we said at Stanford,
and some of our patients will have access
to these technologies, but over time,
how will these new technologiesactually be available
in other areas?
- For patients who are interested
to participate in a clinical trial,
any clinical trial fora medical condition,
they can go online on ClinicalTrials.gov,
(23:02):
and that is a website by theNational Institute of Health
that lists all clinical trialseverywhere in the country.
There, patients can find clinical trials,
which most of the time coverall the costs for a treatment
and these clinical trialsare open to everyone.
From there, make an informed decision.
(23:23):
This is a resource thatis open to everyone.
I would highly recommend thatinterested listeners here
might want to check it out,
because I think it's a fantastic resource.
- I think that's an excellent point,
and a good resource to be aware of.
When we talked aboutyour specific research,
which uses an iron supplementthat is already FDA approved,
(23:45):
there's a clearer pathwayin terms of understanding
the long-term health effects.
Can you talk a little bit about others
that don't have that same situation?
Can you foresee any potentiallong-term health effects
of nanoparticles in pediatric patients?
- With current research,
there's a lot of emphasis on generating
(24:07):
a good image contrast with nanoparticles,
focusing on achievingaccumulation of nanoparticles
in certain tumors.
There is often not as much emphasis
on the metabolism of these drugs.
I think this is really crucial,even in an early phase,
because nanoparticle would not be viable
(24:29):
if it wouldn't get metabolizedand eliminated from the body.
We have to make sure thatwithin a certain time period,
these nanoparticles arecompletely metabolized
and eliminated.
Sometimes nanoparticlesor other contrast agents
can accumulate in certain tissues.
(24:50):
If they're not metabolized there,
then they can cause an immune response
or an inflammatory reaction.
That can then lead to tissue problems.
This has been described forthe gadolinium chelates,
for example, in patientswith renal insufficiency.
The gadolinium can bedeposited in the skin,
and then cause a skin sclerosis,
(25:12):
thickening and hardening of the skin,
which certainly we want to avoid.
Some nanoparticles are so small
that they can actually be eliminated.
If that is the case, then theymight appear in wastewater
and could have an environmental impact.
So that is a very important issue as well
(25:34):
that we have to be aware of.
- Nanotechnology does offer this potential
to enhance precision in tumor detection,
and that we can leverageit to visualize vasculature
and help clinicians delivermore personalized care,
but also the realization thatthere's still more research
(25:54):
to be done in terms of themetabolism specifically,
but also the impact environment.
To wrap up our conversation,
to someone who's been partof this imaging journey
for a long time,
what do you hope will bethe biggest breakthroughs
in pediatric oncology imagingin the next five to 10 years?
- One big part,
(26:14):
artificial intelligenceapplications currently,
so that's everywhere.
That's a huge area of development.
We are fortunate to work
with a very talented computerscientist in our team.
And some tiny little aspect
where the nanoparticles can come in here
is that they provide a verysteady contrast enhancement
(26:37):
over time.
We don't have as muchvariation in the images,
compared to a contrast agent
that provides a short peak enhancement
and then decreasing enhancement of tissues
so that every imagelooks a little different.
So that can help withcomputer post-processing also,
application of theranostics.
The underlying idea isthat if I can already see
(27:00):
where a drug is going,
and I see that it accumulatesin the tumor tissue,
why not use it as acarrier or Trojan horse
to shot drug into the tumor tissue?
And that would also allow me to monitor
the efficacy of certain therapies.
I believe that theranosticsis a big new area.
(27:23):
Another big area arecancer immunotherapies.
Here we images are trying to develop more
and more sophisticated approaches
that we can image different populations
of immune cells in the body.
The nanoparticles canalso help us with that,
as can many other imagingtechniques as well.
- Really exciting work thatis happening in this field
(27:45):
and exciting to seethe promise of a future
that leverages this technology.
Thank you so much forchatting with me today.
- Thank you. It was a great pleasure.
- This episode was broughtto you by Stanford CME.
To claim CME forlistening to this episode,
click on the Claim CME Link below,
or visit Medcast.Stanford.edu.
(28:06):
Check back for new episodes by subscribing
to "Stanford Medcast" whereveryou listen to podcasts.
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