Nanoparticles and Skin Tumors

August 09, 2021

Information

August 8, 2021

Yale Cancer Center

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email: canceranswers@yale.edu

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00:00Funding for Yale Cancer Answers is provided
00:04by Smilow Cancer Hospital and AstraZeneca.
00:08Welcome to Yale Cancer Answers with
00:10your host doctor Anees Chagpar.
00:12Yale Cancer Answers features the
00:14latest information on cancer care by
00:17welcoming oncologists and specialists
00:18who are on the forefront of the
00:21battle to fight cancer. This week,
00:23it's a conversation about the use of
00:25nanoparticles to treat skin cancer with
00:27doctors Michael Girardi and W. Mark Salzman.
00:30Doctor Girardi is a professor of
00:32dermatology and Doctor Saltzman is a
00:34professor of biomedical engineering,
00:36Cellular and Molecular Physiology
00:37and of Chemical Engineering at
00:39the Yale School of Medicine,
00:41where Doctor Chagpar is a
00:43professor of surgical oncology.
00:45So maybe we'll start off by having
00:47both of you tell us a little bit about
00:51yourselves and what you do.
00:53Mike, maybe I'll start with you.
00:56Sure, I run a research laboratory
00:58with a big focus on skin cancer
01:00development and strategies to try to
01:02prevent skin cancer formation and to treat it.
01:04And how about you, Mark?
01:07I'm a professor in the
01:09Department of Biomedical Engineering.
01:11My training is in chemical engineering,
01:13but for my research career and my
01:15teaching career I've mainly
01:17focused on how to apply principles
01:19from chemical engineering to
01:21make new products for medicine.
01:23This is such an
01:26unusual marriage and something
01:27that I love about academia is that
01:30we can take disciplines that are
01:32truly disperate on the surface
01:35and make them collide and have
01:37really fascinating things happen.
01:41Mike, tell me a little bit more about
01:44how your research evolved and
01:47how you got to meet Mark?
01:49You know we have a really rich
01:52environment for exchange of ideas and just
01:55a tremendous breadth of faculty that is
01:58very welcoming to folks getting together.
02:00Discussing how different perspectives
02:02and takes on research can be combined.
02:05Mark and I have had a
02:07chance to see each other at various
02:10meetings and conferences here
02:12on campus and to
02:15have discussions time to time
02:17over the years after these meetings
02:20and then we really hit it off on Mark's
02:23technology of using nanoparticles
02:25to deliver anti tumor agents.
02:28And a thought bomb went off in my
02:31head regarding all the potential
02:33applications in the skin which is
02:36so accessible and such a burden on
02:39our society in terms of the
02:42number of skin cancers and the
02:45challenges in controlling these and treating them.
02:49And so I reached out to Mark after one
02:52of his talks and he was very receptive.
02:56We had a wonderful meeting and
02:59brainstorming session and that was
03:01several years ago and we've really
03:03grown with our possibilities and directions
03:06research-wise in putting
03:09our heads together.
03:10Mark tell us a little bit more
03:13about your research and this drug
03:16delivery mechanism that you have and
03:19the talk that spurred everything on?
03:23I'll start back almost 30 years ago when I first
03:29got interested in this field,
03:31we had discovered that
03:33there were some polymers,
03:35some polymer materials,
03:36plastics that one could implant in the
03:39skin or put in contact with human tissues,
03:42and they're very inert.
03:44And the key discovery was that you could
03:47combine these materials with drug molecules.
03:50So that you could make such things
03:53like implants that you could
03:54place in contact with tissues or
03:57implant into tissues and they would
03:59slowly release the drug molecules
04:01that you had embedded into them,
04:03and so that really started me on a
04:05path to thinking about how you could
04:08both expand the range of materials
04:10that you could use in this fashion,
04:13and more importantly,
04:14how you could marry this technology
04:16to treat different diseases.
04:17And we really focused a lot on cancer
04:20because of the potential to create
04:23drug delivery systems that would be
04:26more effective at treating cancer.
04:28But at the same time would be safer
04:31and we could use the materials to sort
04:34of focus the drug action on the tumor
04:38cells rather than on normal tissue.
04:41And I think the possibilities for this
04:44really expanded about 15 years ago,
04:46when we discovered you could
04:48make not only implants,
04:50but you could make tiny tiny
04:52particles of these polymer
04:53materials and anti cancer drugs.
04:56So we call those nanoparticles because
04:58their size is measured in the nanometers.
05:01They're very small,
05:02so the particles that Mike and I have been
05:05using are about the same size as a virus.
05:09So because they're so small you can
05:12administer them easily in a
05:13variety of different settings.
05:15You can inject them easily through a needle,
05:17for example.
05:18Or you could suspend them in a
05:20solution and infuse them or apply
05:22them topically on the skin so that
05:25that gives you a lot of possibilities
05:27and thinking about how you're going
05:29to match this delivery system to the
05:32particular tumor that you're trying
05:33to treat and the other thing about
05:35being tiny tiny particles is that
05:37they're much smaller than tumor cells,
05:39and so they can actually enter into
05:42tumor cells and once
05:44they're in the tumor cell,
05:46they'll start releasing slowly their drug,
05:48and this allows the drug, the
05:50source of the drug, to be released
05:52very near its site of action,
05:55which for anti-cancer drugs is
05:57often in the nucleus of the cell,
05:59and so this gives you another level
06:01of control or design that you can
06:04introduce into the the delivery system
06:07in order to match them most
06:09effectively to treat the particular
06:11tumor that you're interested in.
06:13And so Mike, tell us more about
06:16the thought bomb that you had.
06:18You know, it certainly sounds
06:20like this technology that Mark
06:22has is incredibly innovative,
06:24but has so many possible applications.
06:26So how did you really think about its
06:29utility in terms of skin cancer?
06:32I took a broad approach at first.
06:36As to the potential applications in the
06:39skin topical application, for example,
06:41to improve sunscreen performance.
06:44Injection into tumors to improve delivery
06:46of anti tumor agents to skin cancers,
06:49but also about the potential to stimulate
06:51the immune system against cancer.
06:54How these could facilitate
06:55delivery of those agents.
06:57Mark and I also talked about the various
07:00inflammatory diseases of the skin and
07:02how we might use agents that are anti
07:05inflammatory and better deliver
07:07those agents and increase their performance,
07:10increase their safety so they're
07:12not necessarily impacting the
07:13overall immune system in a negative way.
07:16and throughout the entire body,
07:19so it's about local delivery.
07:21It's about increasing drug
07:23availability in terms of cancer.
07:25We have a huge burden
07:28with basal cell carcinoma.
07:30These are a huge number of cancers
07:32across the the world that outnumber all
07:36cancers combined in their occurrence,
07:38and often are treated by surgery or
07:41multiple surgeries on the same patient.
07:45An individual can develop many
07:46of these over a lifetime if
07:49they are fair skinned and
07:51have a lot of sun exposure.
07:53There is squamous cell carcinoma which
07:55presents another set of problems.
07:57They can be numerous as well,
07:59but they can also have a small chance
08:02of traveling throughout the body.
08:04They tend to be deeper as well.
08:11Melanoma not as common as basal
08:13cell and squamous cell carcinoma.
08:16But a whole other set of problems si that
08:18this is a real killer of young people.
08:22Melanoma is
08:22something that has a very high risk
08:25of metastasis after it obtains
08:27a certain level of depth.
08:29There are clear,
08:30unmet needs in some patients who
08:32have intermediate depth Melanoma
08:34that has already metastasized
08:36to regional lymph nodes.
08:38And there are challenges in treating
08:40these patients without necessarily
08:42giving them something aggressive
08:45and systemically delivered.
08:46Chemotherapy to the entire body.
08:49So all of these potential challenges
08:52in the world of skin cancer
08:55have areas that could be
08:58potentially leveraged with this technology.
09:00Mark and I have
09:02been really trying to look at all
09:05of the possibilities and begin
09:07to develop research programs
09:08and strategies to address them.
09:10Mark, a couple
09:13of things that struck me when
09:16you were talking about this
09:18technology, one is that these
09:21nanoparticles are so small that they can
09:24actually be engulfed by the tumor
09:26cell and have a mechanism of action
09:29at their nucleus, essentially,
09:31really targeted therapy,
09:32delivered to the source of the tumor.
09:35But my question there is,
09:36how targeted can it be?
09:38I mean can you make these
09:41nanoparticles such that the tumor cells
09:43and only the tumor cells engulf them?
09:46How does that work?
09:47That's a great question and I think
09:52there's several different aspects to that.
09:53The one that we've been talking about
09:56so far and a major
09:59one that Mike and I have been
10:01exploring is to
10:03put the particles as close to
10:05the tumor cells as possible.
10:06To physically target them,
10:09inject them into a tumor,
10:10for example.
10:13And that's possible with the skin cancers
10:15that Mike is mentioning,
10:17because they're so accessible,
10:18they're on the surface of the skin,
10:21at least some of them are
10:23exclusively on the surface of the skin,
10:27and dermatologists are very comfortable with
10:29using needles to inject locally
10:31in the skin and they're very
10:33talented as well,
10:35and so that makes a
10:37reasonable form of targeting.
10:38But you could also make it more
10:41targeted and one possible way to
10:43make it more targeted is to take
10:45the nanoparticles and engineer
10:47the surface properties of them.
10:49And one of the aspects of the
10:51technology that we've exploited
10:53in many of the projects that we
10:55worked on is to make the particles
10:58themselves very sticky to proteins.
10:59Or tumor cells that have a lot
11:02of proteins on their surface.
11:04And so when you inject these
11:06sticky particles they will
11:08tend to be taken up by whatever
11:10cells are near the site where
11:13you've placed them and this
11:15allows the vast majority of the
11:17particles to stay in a tumor if you
11:20inject them right into the skin tumor,
11:22for example.
11:23And so that's one one way to
11:25augment the targeting that local
11:28delivery naturally provides you.
11:30A second way would be to not just
11:32use physical properties like
11:33stickiness of particles to make
11:35them attractive to tumor cells,
11:37but to make them specifically
11:39adhesive to tumor cells.
11:41So in that case,
11:42if you knew that there was
11:45a protein on the tumor cell surface
11:47that was expressed very abundantly in
11:50the tumor cells and not in normal cells,
11:53you could put some chemicals
11:54that bind to that protein on the
11:57surface of the nanoparticle.
11:58So this might be an antibody.
12:01Or an antibody fragment that
12:03is specific for that protein that's
12:06highly enriched on the tumor cell.
12:09Then that gives you an additional
12:11level of targeting.
12:13And it's even possible to think about
12:18administering those highly
12:20targeted particles systemically and
12:22and asking them to find the tumor
12:25for you instead of you using the
12:27needle to find the tumor yourself.
12:30And that's been a very active area of
12:33study over the past 10 to 15 years or so,
12:37and it turns out to be
12:41hard to achieve practically for
12:43reasons that we could discuss.
12:44But it's also a method of targeting.
12:47I would like
12:49to get into how exactly we target
12:51things and what are the challenges
12:53that are being faced in this
12:55really exciting area, but first
12:57we need to take a short break
12:59for a medical minute, so please stay
13:02tuned to learn more about nanoparticles
13:04and skin tumors with my guests
13:06Doctor Michael Girardi and
13:08Doctor Mark Saltzman.
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14:00Comprehensive cancer centers,
14:01such as the BATTLE II trial at
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14:15More information is available at
14:18yalecancercenter.org. You're listening
14:19to Connecticut Public Radio.
14:21Welcome back to Yale Cancer Answers.
14:24This is Doctor Anees Chagpar
14:27and I'm joined tonight by my guest doctor
14:29Michael Girardi and Doctor Mark Saltzman.
14:32We're talking about research looking
14:35into using nanoparticles to treat
14:37skin tumors and right before the
14:39break we were talking about how these
14:42nanoparticles are so small and how we
14:45can try to make them really attack
14:47tumor cells rather than normal cells.
14:50So Mike, Mark was
14:53talking about how
14:55we can make nanoparticles sticky.
14:58We can try to get them in an
15:01area where these cancers exist.
15:03What have you explored in terms of
15:07trying to treat these skin cancers?
15:11What are the exciting
15:14developments and where are
15:15we with this research?
15:17So I think there's several features that
15:20we're really leveraging about the sticky
15:23type particles and these will bind to proteins.
15:26Any proteins they come in contact
15:28with but what's really special about the
15:30tumor microenvironment is that it's
15:33very protein rich tumor cells secrete
15:35a lot of proteins.
15:37They create their own matrix.
15:39This is helpful for them.
15:41We think they perceive it as such so they
15:45can grow so they can begin to want to travel
15:49if we personify the tumor cells that way,
15:52and so these particles
15:54will bind to both tumor matrix proteins and
15:58bind to the surface of the tumor cells,
16:01so this really not only gets
16:04the drugs into the tumor cells,
16:07but creates anti-tumor
16:09agents all around the tumor.
16:11We think this is really important for
16:14trying to target and eliminate the tumor.
16:18We also have worked on strategies
16:20and how we deliver these tiny
16:23particles beyond the simple
16:25syringe and needle strategy,
16:27which is actually quite
16:28effective in and of itself.
16:30But for certain tumors,
16:33for example,
16:33ones that are more broad
16:35but thin and shallow,
16:37they can create surgical challenges
16:39to cut out a large piece of skin when
16:43something is really not that deep.
16:45That lets us wonder if there is a
16:48way to deliver these agents,
16:50for example over a larger area,
16:52but not as deep and so Mark and I have
16:56explored strategies using what's called
16:58micro needling or micro needle pads,
17:01and so the particles might
17:02be loaded into these hollow
17:04very tiny needles and in
17:07many cases they can be made to be
17:10painless because they just don't
17:12get to the depth where they're going
17:15to trigger the nerve endings and
17:18these pads could be applied and the
17:20particles can be delivered in that fashion.
17:23We've also looked at strategies where
17:25we've accelerated fluid that contains
17:27the nanoparticles
17:28in a way that can push them with
17:32a high pressure system through the
17:35surface of the skin into a tumor
17:38and the surrounding area.
17:40Kind of like a high pressure micro waterjet,
17:43so we're really looking at ways that
17:46we can empower health care providers
17:49to be able to use this technology
17:52to best serve their patients.
17:55But in a number of different
17:58tumor settings, different tumor types,
18:00different tumor sizes,
18:01and different tumor depths.
18:03That's
18:04really interesting, and I guess the
18:07other way to do this is,
18:10as you both were talking about earlier,
18:13was injecting this systemically.
18:15So I would think intravenously to try and
18:18hone these nanoparticles to their target
18:21whether it's an
18:23antibody or other mechanism to
18:26try to find these cancer cells
18:29and target them that way.
18:31Mark, you know another concept
18:33that you had mentioned,
18:35or I think Mike had mentioned before the
18:38break was using nanoparticles to kind
18:40of prime the immune system.
18:43Often on this show we're talking about
18:46immunotherapy and the fact that these
18:49cancers kind of evade the immune system
18:52whose job it is really to get rid of
18:55things that we don't want in our body,
18:58whether it's infections,
18:59or whether it's tumor cells.
19:02Tell us a little bit more about
19:04how you can engineer nanoparticles
19:06to trigger the immune system,
19:09and how that's working in treating cancer?
19:14I'd be happy
19:16to start addressing that,
19:17but Mike is really the expert on that part,
19:19but so I'll talk about the parts that
19:22I know and maybe he can follow up.
19:26One of the interesting things about some
19:28of the cells of the immune system is
19:31that their naturally bagocytic
19:32and part of their job is to take up
19:38particles from the environment
19:39and to sample them to look for
19:42danger signals,
19:43and so you can
19:45exploit those cells by
19:46creating nanoparticles that look
19:48like the natural kinds of things
19:51that they would take up and ingest.
19:53And you can do that by controlling
19:55the size of the particle and by
19:57controlling its surface to make it
19:59most attractive to those
20:02macrophages or antigen presenting cells.
20:04But in addition,
20:05you could further
20:07augment the activity of those
20:09particles by putting in the kind
20:12of danger signals that they might
20:14find from a microorganism and that
20:17revs up their their immune activity.
20:19And so we've been exploring that
20:22and also exploring the idea
20:24that you could present these
20:27signals to immune cells
20:29in a variety of different ways,
20:32either by slowly releasing them,
20:33the concept we talked about before,
20:36or by presenting them in different
20:38fashions on the surface or the
20:41interior of the particle and looking
20:43to see if by changing the way that
20:46the particle is engineered with these
20:48signals for the immune system,
20:51if that changes
20:52the speed or the aggressiveness
20:54that you can introduce into
20:56the immune response.
20:59So Mike, do you want to
21:01kind of pick up on that?
21:03I mean, oftentimes when we're thinking
21:06about generating an immune response,
21:08we kind of talked about
21:10two kinds of systems.
21:13One that's a more generalized immune response,
21:16and one that's more targeted.
21:18Talk a little bit about how you
21:20envision nanoparticles really
21:21working in terms of the immune
21:24response against cancers.
21:27Yeah, I think it's a critical question.
21:30I think that cancer therapy today is
21:33about targeting the tumor and
21:35it's about manipulating the immune
21:37system to to maximize the effects
21:40of the tumor targeting strategies.
21:42No cancer therapy can ignore today
21:45what's going on with the immune system.
21:48It's too powerful an ally in
21:50the fight against the cancer and
21:53there's obstacles to overcome,
21:55so let me explain.
21:58That first dichotomy is
22:02that we have evolved to recognize
22:05foreign substances,
22:06including antigens on tumor cells
22:09and we can stimulate the heck out
22:12of that process through agents,
22:15as Mark has described, that might
22:18be considered dangerous signals,
22:20molecules that might be for example,
22:23normally found on infectious agents,
22:25molecules that might be produced by
22:28our own cells when they have sensed
22:32that they are infected, for example.
22:34We can begin to try to trick
22:37the immune system
22:38in looking at the cancer cells in
22:40a way that makes them appear as if
22:43they're a foreign infection,
22:46whether that be viral resemblance
22:47or bacterial resemblance or others.
22:49And we can do that in a general way,
22:53and so those are common molecules that
22:55are found on a bunch of microorganisms,
22:58so we can just introduce those types
23:00of compounds into the nanoparticles.
23:02Then we can try to facilitate
23:05how they're seen by the immune
23:07system in a more optimized way.
23:10In a more specific way,
23:12we might try to load what
23:14are called tumor antigens,
23:16so these might be real signatures
23:18on very specific types of cancers,
23:21and they may be even specific
23:23to each patient.
23:24In this way,
23:26we're trying to stimulate a very
23:28directed killer T cell response.
23:30That's akin to a vaccine, for example.
23:33That you know is being discussed
23:36these days for a bunch of other reasons,
23:40and so we can use nanoparticles to
23:43develop anti tumor vaccines that
23:45could more specifically stimulate
23:48the immune system
23:53to attack the cancer.
23:57And on another consideration though,
23:59we have to realize that tumors evolve and
24:02grow to try to suppress the immune system.
24:05And this is a major major
24:08consideration in treating cancer,
24:09immune checkpoint inhibitors or something,
24:11for example, that are delivered
24:13throughout the body to try to alleviate
24:16some of these controls that the
24:19tumor has put on the immune system.
24:21But we can also try to target
24:24that with nanoparticles locally.
24:26So for example, there are immune cells that
24:29try to suppress the antitumor effects,
24:32and these need to be
24:36dealt with in a way,
24:38especially at the tumor site,
24:40so that the tumor can become
24:42what we call hot and not cold.
24:45Hot, meaning it can be recognized by the
24:48antitumor immune system more readily.
24:52And it sounds like
24:54you have so many possibilities
24:56in terms of how you can fashion
24:59these nanoparticles, so you can
25:02target the tumor on one
25:04side and potentially attract the
25:06immune system on the other side
25:09and get these two systems in
25:12close proximity to each other in
25:14addition to delivering drugs.
25:16Now the other thing that you mentioned
25:19before the break was using nanoparticles
25:22relating to skin cancers,
25:25but more on the prevention side.
25:28So Mark talk a little bit about
25:31using nanoparticles to make
25:33sunscreens more effective.
25:36Yeah, I'd be happy to do that and that was one of
25:39the first big projects that Mike and I
25:42worked together on and it was quite successful.
25:45So the idea was that we NOTE Confidence: 0.9900481
25:48knew that we could make these
25:51nanoparticles that would adhere to tissues
25:53and we tested them to see if you just
25:56suspended these particles,
25:58these sticky particles and NOTE Confidence: 0.9900481
26:00you put that water on the skin would
26:04the particles adhere and in fact they did.
26:06And they adhered very strongly to the skin.
26:10You could put some particles on the
26:12skin and then you could wash the
26:14skin extensively and the particles
26:16would just stay there and resist
26:18removal with washing.
26:20And so we knew that there was something
26:23special about that technology,
26:24because if you can apply something
26:26topically to the skin and it
26:28stays there for a long time,
26:30that might have some value.
26:32And so in the second phase we learned that
26:35one could take common sunscreen ingredients
26:38and load them at very high levels
26:40inside these nanoparticles,
26:42so that the nanoparticle itself
26:43was 50 percent, 60%,
26:45sometimes even 70% sunscreen agent.
26:47And then if you apply those to the
26:50surface of the skin, they stuck.
26:52They don't penetrate into the skin.
26:55They don't wash off very easily,
26:57but they're sitting on the skin now in
27:00a position to be between the skin and
27:03any ultraviolet light that falls on the skin,
27:07and so they could be
27:09very effective at screening that
27:11ultraviolet light and and absorbing
27:14it and blocking it without anything
27:17ever entering your body and they
27:19stay on there for a long time.
27:21And so we did a number of studies
27:25trying to understand how this works and
27:28trying to perfect it using combinations
27:31of sunscreens so that we could block
27:34all wavelengths of ultraviolet
27:36light and ultimately did a
27:39small pilot clinical trial
27:41here at Yale showing that
27:44indeed you could put these on the
27:46surface of the skin of volunteers
27:49that they were completely safe and
27:51Mike can talk about the details of
27:54that and that they would perform just
27:57as well as the kinds of sunscreens
28:00that you can buy at the drugstore.
28:02So we're very excited about that
28:06and new ways
28:09to use technology
28:10to prevent skin cancer.
28:17And my grandparents all worked on
28:19farms and so are very familiar with the
28:22devastating effects
28:24of skin cancer.
28:26Doctor W. Mark Saltzman is a professor
28:28of biomedical engineering,
28:30cellular and molecular Physiology
28:31and of chemical engineering
28:33and Doctor Michael Girardi is
28:35a professor of dermatology at
28:37the Yale School of Medicine.
28:39If you have questions the address
28:41is canceranswers@yale.edu.
28:42And past editions of the program
28:44are available in audio and written
28:46form at yalecancercenter.org.
28:47We hope you'll join us next week to
28:49learn more about the fight against
28:52cancer here on Connecticut Public
28:53radio funding for Yale Cancer
28:55Answers is provided by Smilow
28:57Cancer Hospital and AstraZeneca.