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GEN Protocols Expert Exchanges: Nanoparticles in Precision Medicine Diagnostics and Delivery
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GEN Protocols Expert Exchanges: Nanoparticles in Precision Medicine Diagnostics and Delivery
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ANJALI SARKAR: Hello, fellow scientists and science lovers. This is Anajli Sarkar, Senior Science Editor at GEN Protocols, welcoming you to this GEN Protocols Expert Exchange. GEN Protocols is a premier resource for emerging and veteran scientists and industry leaders who want to know more about advances in biotechnology from a trusted source. Researchers from academia and industry share and showcase their technical expertise, nurture collaborations, and discuss technical challenges and solutions on GEN Protocols.
ANJALI SARKAR: You can share your protocols applications and technical insights on GEN Protocols year-round. So together with a rich resource of up-to-date methods, GEN Protocols also brings you expert exchanges, where experts in key areas of biosciences and biotechnology talk about technical developments, challenges, solutions, and visions. In today's expert exchange, I will be talking to Megan Muroski, Senior Product Manager at MilliporeSigma, the US and Canada Life Science business of Merck KGaA, Darmstadt, Germany, on the application of nanomaterials as diagnostic tools and delivery vehicles in precision medicine and the use of graphene nanoribbons in treating spinal cord injury.
ANJALI SARKAR: Megan is a biochemist with over a decades experience in academic, preclinical, translational, and government laboratories at Florida State University, Northwestern, and at the US Naval Research Lab DARPA, the Defense Advanced Research Projects Agency. She has a multidisciplinary background in nanoparticles and their applications in neurosciences, biotechnology, translational studies, drug delivery, sensors and oncology.
ANJALI SARKAR: Welcome to GEN Protocols, Megan.
MEGAN MUROSKI: Thank you for having me.
ANJALI SARKAR: So to start off, could you tell us a bit about your work in nanobiotechnology and how you came to be interested in the field.
MEGAN MUROSKI: Yeah, certainly. Well, I've always been interested in science. In high school and college, I volunteered in biochemistry laboratories. When I eventually got into grad school, I joined an inorganic lab, and the professor was working on molecular rulers using gold nanoparticles. I thought that was just the coolest thing that you could use gold nanoparticles for biological applications.
MEGAN MUROSKI: And from there, I collaborated with professors at the medical school and studied nanoparticles and drug delivery systems in ischemia and traumatic brain injury models before moving to Northwestern as a postdoc, doing work with glioblastoma research and applications of nanoparticles for diagnostics and treatment. And then, from there, I went on to the government lab. So nanoparticles have really always been in my blood.
ANJALI SARKAR: Right. So nanoparticles are increasingly being used as a drug delivery and as well as in a number of diagnostic tools. What are the advantages of using nanoparticles over other conventional traditional approaches for drug delivery and diagnostics?
MEGAN MUROSKI: Well, the great thing about nanoparticles is they really have interesting properties that you don't get at the bulk level. And with nanoparticles, you really have really three different types when you're looking in the diagnostic space. You have your polymer types. You have your inorganic types. And then, you have lipid-based, which everybody knows about now with the COVID-19 vaccine.
MEGAN MUROSKI: But each of these different types of nanomaterial offers really distinct advantages. I work as the product manager for material science at MilliporeSigma. I work on introducing a lot of the inorganic nanomaterials into the portfolio, where we introduce new types of silicon nanoparticles, new types of quantum dots, iron oxide nanoparticles, as well as different golds and different functional innovations.
MEGAN MUROSKI: Now the great thing about inorganic nanoparticles and metal-based nanoparticles is that they really help bridge the gap between physics, and chemistry, and biology. So where you were looking at maybe one die, one drug, and trying to image that into a body, you can now put 10 drugs onto a giant gold nanoparticle and view it that way. You have gold nanoparticles that are often used in lateral flow assays as a colorimetric detection system.
MEGAN MUROSKI: So you really can go through a lot of different areas of expertise in terms of, whether it's going to be bioimaging, whether it's going to be sensing, whether it's going to be for drug delivery. You can use nanomaterials for, really, all of these different applications.
ANJALI SARKAR: Excellent. So these nanoparticles are also being used in drug delivery, as well as diagnostics, but also in the detection of metabolites, proteins, and nucleic acids. Could you talk a bit about the application of these nanoscale structures, particularly gold nanoparticles that you just mentioned in this detection of these biomolecules?
MEGAN MUROSKI: Yeah, certainly. So gold nanoparticles, in particular, have really unique optical and electronic characteristics. So researchers are able to tune the size, shape, and, actually, even the aggregation status of them. So whether they're a single molecule, or a single particle, or grouped together with different properties of each. They are really well known to be biocompatible, so they're stable against oxidation for the most part, and also, they're not really cytotoxic.
MEGAN MUROSKI: And then, as you mentioned, they can be used in the detection with lateral flow assays. But the surface of the gold nanoparticle makes it really amenable to attaching things to the surface. So things like drugs, genes, ligands, even antibodies are able to go onto the surface of the nanoparticle. And with their large surface area, you are able to put a lot of payload onto one nanoparticle, which is advantageous for a lot of things.
MEGAN MUROSKI: And then, really, I mean, the size and shape and ease of making them has really brought them into popularity. When you-- oh, sorry. When you look at the lateral flow assay and how gold nanoparticles were used for that, there are really just a host of FDA approved devices for this. And so, gold nanoparticles show up as colorimetric, so they're red. And so, that makes them really, really advantageous for lateral flow assays.
MEGAN MUROSKI: And you can put multiple antibodies onto one gold nanoparticle. So you can measure, in theory, lots of different things with just one moiety or one nanoparticle.
ANJALI SARKAR: Are these antibodies that are attached to nanoparticles also means by which nanoparticles or nanostructures are targeted to specific cell types or protein types? How does targeting-- how are these nanomaterials customized for specific targets?
MEGAN MUROSKI: Oh, you can write a whole review on it. And antibodies are really a great way of doing it. There are also things, like cell penetrating peptides that people use, so RGD. There are DNA sequences that you can use as RNA. You could target mRNA that you can all put on the surface. So all of those things can help. Or you could even put them on, like I mentioned.
MEGAN MUROSKI: Because the nanoparticles are large compared to DNA sequences, or genes, or ligands, you can put multiple things on the surface. So say you want to get a drug attached to-- you want to deliver a drug. You could put a drug onto the surface of the gold nanoparticle, and then you can put a targeting antibody and then just bring it there. So there's lots of different ways to do targeting using nanoparticles in general.
ANJALI SARKAR: Excellent. So recent work in the animal models preclinical work from work has shown that animal models can be treated with polyethylene glycol graphene rhythms or PEG GNRs to help treat spinal cord injuries. What are these graphene nanoribbons? And could you tell us a bit about how they are made?
MEGAN MUROSKI: Well, in general, the interface between carbon nanomaterials and neuroscience applications started maybe about two decades ago, looking at things like compatibility drug delivery and different manipulation of the particles in the biological space. These graphene is really just an electric carbon, which makes it convenient to use because our bodies are made up of a lot of carbon.
MEGAN MUROSKI: And there are strengths and weaknesses when you're going to use these, looking in vivo. Graphene nanoribbons are really just at the basis, just carbon nanostructures with a honeycomb lattice. And this organized structure of these materials makes them incredible candidates in building blocks for information processing, for electronic properties. And so there's a couple of ways to make them.
MEGAN MUROSKI: You could either use lithography methods. There are bottom-up where you make them from small molecules. There are methods that you unzip them through chemical processing. And so, there's a bunch of different ways to make them, and there's a lot of different properties, depending on how you make them as well. Using graphene nanoribbons for spinal cord applications, you could see that there's been a handful of publications with graphene and the nervous system literature.
MEGAN MUROSKI: And what you see is the spinal cord, as it's just really like a bunch of nerve fibers and joints, a two-way communication system, what it is. What the graphene nanoribbons allow you to do is really generate an electrical stimulation through these functional stimulations.
ANJALI SARKAR: How scalable is this GNR synthesis for manufacturing purposes to develop a treatment, for example?
MEGAN MUROSKI: Well, I think, in general, now, we offer graphene nanoribbons commercially in our product line. So now, you're able to purchase them, which, before was really just not the case. You had to create them in your own lab, which takes a ton of time. So having these available for commercial purposes really will help transform the space just in general. Because what people are now able to do is they're able to get reliable materials time and time again.
MEGAN MUROSKI: So you order the materials in America. You're going to get the same materials in China as in India. Whereas, if you're collaborating with the different labs or different labs, there are slightly different methods, and you don't have the reproducibility that you would getting them from a commercial source.
ANJALI SARKAR: So as I understand that, GNRs have to be combined or are generally combined with things like PEG, polyethylene glycol, or other molecules to help promote the healing, as in the case of spinal cord injuries? What is the advantage of combining these graphene nanoribbons with PEG or such molecules?
MEGAN MUROSKI: Well, just in general, when you look at nanoparticles, and especially when you're using them for a drug delivery or you're using them for in vivo applications, they tend to be decorated in a host of ways. So if you're using drug delivery, you want to make sure that the materials are biocompatible. If you're using them for scaffolding, you might want to put some matrix metalloproteinase or scaffolding proteins at the surface to make sure that the cells are biocompatible with the surface.
MEGAN MUROSKI: So there's a lot of different things that you can add to the surface to the nanoparticles. In the case of carbon and using PEG, in particular-- PEGs been around since the '70s and is used in a whole host of different nanoparticle applications. And then, you find that, actually, PEG is often used as it keeps the nanoparticles from aggregating in general.
MEGAN MUROSKI: So that's always helpful. It makes the particles a little bit more biocompatible, a little bit more stealthy if you will. And because of that-- and it's been around and studied for a long time. And so because of that, that's why you have researchers often use PEG for studies like this.
ANJALI SARKAR: Excellent. So the chemical and physical properties of GNRs combined with PEG or other molecules, they seem to have unique physical and chemical properties to be able to promote treatment of spinal cord lesions. Could you talk a bit about these physical and chemical properties as well as how do these graphene nanorhythms affect the microenvironment of where they are targeted to aid this recovery?
MEGAN MUROSKI: Well, in general, when you have graphene, it has a high electrical conductivity. It has high thermal conductivity. It has high mechanical strength, and it has good optical properties. I think, really, in the most case, I think, for as far as you're looking at carbon structures, graphene oxide has really been used most extensively because of its high specific surface energy and its mechanical strength properties.
MEGAN MUROSKI: And really, graphene oxide in that space has been used for everything, such as adhesion and proliferation of stem cells, as well as things like optical barriers, and drug carriers, and photodynamic for photo-thermal therapy. So looking at all of these methods, it really depends on the type of method you use to create the nanomaterial and what properties they're going to exhibit.
MEGAN MUROSKI: But really, most of the work in this space has been done on graphene oxide. I mean, graphene nanoribbons are still really in its infancy, trying to come up with really great application spaces. So whether it's drug delivery, gene delivery, tissue engineering, or things like photodetectors, or molecular sensors, I think researchers are really trying to figure out that space in general.
ANJALI SARKAR: So a different formulations are being used for different types of spinal cord injuries. Focusing on the spinal cord injury work first, could you talk a bit about the different kinds of formulations that are being tested in this space?
MEGAN MUROSKI: Well, in general, what you see is, for spinal cord injuries, with graphene nanoribbons, there hasn't really been a lot of work in that space. There's been a couple of articles in general, but most of the work really focuses on the stem cells differentiation into neurons or promoting osteogenic differentiation of stem cells for bone, as well as being able to look at them in general because carbon makes a good biosensors.
MEGAN MUROSKI: And so you can have optical outputs of that as well. So you really have-- graphene nanoribbons, right now, are really primarily used for the ultra small devices, such as molecular sensors and the photo and thermal acoustic detectors. But if you're looking in terms of spinal cord injury, using it as the delivery for genes and drugs, you see that.
MEGAN MUROSKI: I think the bio conjugation studies that have been done on it are things such as cellulose. There's been studies where you attach that strand to it. And so, that's really more of a biosensing. You look at PEG for targeted human therapy or siRNA delivery because that helps keep everything stable on the surface. And so these gold nanoribbons, because of their electrical properties, really have a great application space in the nervous system.
MEGAN MUROSKI: Or that's why they're selected anyways for this type of work.
ANJALI SARKAR: In the nervous system space, in the neurophysiological recovery and treatment space, nanostructures have a particular application in regulating cell membrane potential and in visualizing cell membrane potential. Could you talk a bit about this and how nanostructures are being used in visualizing and detecting regulating cell membrane potential?
MEGAN MUROSKI: Well, see, that's the really great thing about nanomaterials, especially with membrane potential, because we are at a point where we didn't have the sensitivity of current techniques. And now, as we get better and better nanomaterials, we're able to look at things more closely. And when you think about it, nearly all of your cells have an electrical potential across the plasma membrane, but electrically excitable cells.
MEGAN MUROSKI: And so, this is your neurons and your muscle cells are able to use the membrane ion channel pumps to really maintain a control across the membrane. And so, they have bigger electrical potentials. And so the type of nanomaterials that you have that expand and look at the differences in the shuttling of the membrane potential, which could be really useful. And so, like I said, for muscle, for neurons, even cancer cells have shown to have slightly different potentials as well.
MEGAN MUROSKI: You can use things like quantum dots and look at the different action potentials with that, whether they're attached to the outside of the plasma membrane, or whether they're attached to an antibody, or whether they're inserted inside of the cell and functionalized with different dyes that measure action potentials. You can do that as well.
MEGAN MUROSKI: I think there's been some work as well. So outside of the quantum dot space in terms of magnetism and ultrasound, and so using superparamagnetic particles in order to look at the different action potentials and induction in that space as well.
ANJALI SARKAR: You mentioned earlier that the PEG attachment to these graphene nanoribbons prevents their clumping or aggregating. So is this a normal phenomenon for a normal challenge in the application of nanoparticles to find that they aggregate in biological tissues or sera? And in addition to PEG attachment, are there other methods being used to prevent nanoparticles from clumping in the system?
MEGAN MUROSKI: Oh, sure. Well, in some applications, you actually do want nanoparticles to accumulate. So in things, like cancer therapy, where nanoparticles are using for drug delivery, having accumulation in the cancer site is actually preferred. So whether that's like EPR or transcytosis. These mechanisms are important when you're looking at neuroscience. But what you don't want is you don't want to inject the nanoparticles and have them not move anywhere.
MEGAN MUROSKI: The idea is to have them circulate, and that has a lot to do with the charge on the surface. And that's, a lot of times, while PEG is used because it helps mitigate having the particles be so charged that they clump together. But this has been a known problem in the field, and this is something that researchers often look at before pursuing any preclinical testing.
ANJALI SARKAR: You mentioned that nanomaterials are being used in the field of oncology. How are nanomaterials being used to trigger the immune system in immunotherapies, for example? And how is this-- you mentioned that you want some aggregation of these nanoparticles in oncology treatments. How does this aggregation help in this case?
MEGAN MUROSKI: The nanomedicine in terms of immunotherapeutics is still very in its infancy. I mean, really just understanding the immune system and how nanoparticles play a part is something that we're really just starting to address and really deduce the mechanisms after exposure or how to promote accumulation, so how to promote aggregation in the tumors, or how to trigger innate immune compartments after signaling, or looking at a single cell level.
MEGAN MUROSKI: So when you look at that, there are many different avenues that you can do in terms of immunotherapy and using nanoparticles. And so you could use magnetic nanoparticles for clustering cargo onto an immune cell for multiple therapeutics. You can work to de-stabilize the endosomal membrane. You can control the kinetics of drug release. You can use, like I said, the enhanced permeation and retention effect, the EPR effect or transcytosis in order to trigger an immune response within the tumor.
MEGAN MUROSKI: Or sometimes, you don't want to. I think, really, the field is just trying to figure out how to really best utilize these nanomaterials. But that being said, using nanomaterials as a drug delivery agent or as a therapeutic, the reliability to monitor these formulations and these creations in real-time has really helped transform the field.
MEGAN MUROSKI: So as we get better imaging technology, we're going to see a lot more advances in this field.
ANJALI SARKAR: Right. You mentioned the field is in its infancy. Are there any new developments in the area of understanding how these nanomaterials, whether they're just nanoparticles or more complex structures, how are they cleared from a biological system once their task, whether it be in delivering a particular drug or diagnostic tool, whether they're used as a diagnostic tool, once their task is done in vivo, in a biological system, how are they cleared?
ANJALI SARKAR: Or whether they stay in the biological system without having too much of deleterious effect on the system, are there any insights in that area?
MEGAN MUROSKI: Oh, certainly. It really depends on the type of nanoparticle you use. So if you're using things, such as inorganic nanomaterials or metal nanomaterials that don't break down easily, there are size recommendations that have been studied over the years by scientists to help promote clearance. And so in translational laboratories, there's testing that you can do to look at circulation time, to look at clearance time of these metal inorganic nanoparticles.
MEGAN MUROSKI: And that's why the lipid nanoparticles and polymer nanoparticles actually have received a lot of attention because those break down very quickly within the body. And so, having that clearance, they really don't hang around any time because your body knows what to do with lipids. They know how to break down polymers. Whereas, a gold metal nanoparticle's solid, so it tends to hang around longer.
MEGAN MUROSKI: So it really depends on your application, but these are all things that are looked at pre-clinically before they're ever even considered to move on to any backstage.
ANJALI SARKAR: Can normal techniques available for metal detection be used for detecting these metal containing nanoparticles in biosystems or other specialized techniques that are being developed to detect the in-vivo presence of these nanoparticles, particularly the metal containing ones, not the lipid nanoparticles?
MEGAN MUROSKI: Well, you know, as our science continues to grow and the technology continues to grow, I always like to say that we stand on the shoulders of giants. You see that our sensitivity has been increasing, and we're able to detect things at parts per billion where we were never able to do that before. So certainly, as the technology progresses, we're able to measure these gold nanoparticles or these metal nanoparticles just in general to see whether they are cleared or not.
MEGAN MUROSKI: But oftentimes, the methods that we have now are pretty good at detecting, but not to say that they can't improve or be better in the future.
ANJALI SARKAR: So are they basically biochemical assays or are they more sophisticated in, such as X-ray detection. Can those be used? Or are other new technologies, do they need to be developed to detect these nanoparticles? What kind of methods are used in the detection of them in vivo?
MEGAN MUROSKI: You can use MRI for iron oxide, right? So they're magnetic, and so you can detect that. You can use a lot. There's a lot of different photo detections that you could use, so what happens with these nanoparticles is that they have some of their properties. What they have is the ability to refract, signaling, and so you're able to see in, like, PET scanning, whether you have metal nanoparticle accumulation.
MEGAN MUROSKI: I think all the researchers who are listening are like, yeah, I've seen the pictures. So you really have a whole host of ways to detect it, just imaging into the body as well. And then you also have methods where you can detect parts per billion of total bio-accumulation in areas as well.
ANJALI SARKAR: OK. So given that the number of devices that are nanomaterial-based are growing in the diagnostic as well as therapeutic space, how do you think are the standardization methodologies for regulatory protocols to gain approval from regulatory agencies for the fabrication and characterization of these new tools and diagnostics? How are these evolving, do you feel?
MEGAN MUROSKI: Oh, ever evolving, evolving different from yesterday than today, trying to find the standardization. You see things in the EU with the reach protocols getting definitions of nanomaterials. You see the FDA posting information. I think in April just posted new information about nanomaterials in order to come with a consensus. I think that having a global definition is always good because, right now, the regulatory space just varies a lot by country.
MEGAN MUROSKI: And so, everybody just trying to get a handle on it and do the best they can in this new field is what we-- we do the best we can with the resources we have.
ANJALI SARKAR: So as we wrap up, is there anything else you'd like to mention, particularly your thoughts on the future of the application of nanomaterials?
MEGAN MUROSKI: Well, I think it's just really an exciting field in general. I mean, I'm probably biased. I have been in it for years. When I moved to industry as a product manager, I live and breathe nanomaterials now, trying to introduce the latest and greatest. We work with R&D teams in the company, developing and working with collaborators across universities all around the world in order to come up with the best technologies that people can use as a building block to accelerate their next level of science.
MEGAN MUROSKI: And so I think it's really exciting. And I really hope to see-- and we've been seeing it recently more of the bridge between chemistry and biology. Really, people have thought about it as a discipline of being separated, but we really find true innovation in the bridge in this space. And that's what I'm looking forward to the next 10 years.
ANJALI SARKAR: Certainly. Thank you so much, Megan. And that brings us to the end of today's GEN Protocol's Expert Exchange. Thank you for a very illuminating discussion, Megan. And a reminder to all our scientists viewers, GEN Protocols is open for submission of your protocols year-round in any aspect of biotechnology. This is Anjali Sarkar, until next time. Good luck in your research, and goodbye from all of us at GEN Protocols.
ANJALI SARKAR:
Segment:0 .
ANJALI SARKAR: Hello, fellow scientists and science lovers. This is Anajli Sarkar, Senior Science Editor at GEN Protocols, welcoming you to this GEN Protocols Expert Exchange. GEN Protocols is a premier resource for emerging and veteran scientists and industry leaders who want to know more about advances in biotechnology from a trusted source. Researchers from academia and industry share and showcase their technical expertise, nurture collaborations, and discuss technical challenges and solutions on GEN Protocols.
ANJALI SARKAR: You can share your protocols applications and technical insights on GEN Protocols year-round. So together with a rich resource of up-to-date methods, GEN Protocols also brings you expert exchanges, where experts in key areas of biosciences and biotechnology talk about technical developments, challenges, solutions, and visions. In today's expert exchange, I will be talking to Megan Muroski, Senior Product Manager at MilliporeSigma, the US and Canada Life Science business of Merck KGaA, Darmstadt, Germany, on the application of nanomaterials as diagnostic tools and delivery vehicles in precision medicine and the use of graphene nanoribbons in treating spinal cord injury.
ANJALI SARKAR: Megan is a biochemist with over a decades experience in academic, preclinical, translational, and government laboratories at Florida State University, Northwestern, and at the US Naval Research Lab DARPA, the Defense Advanced Research Projects Agency. She has a multidisciplinary background in nanoparticles and their applications in neurosciences, biotechnology, translational studies, drug delivery, sensors and oncology.
ANJALI SARKAR: Welcome to GEN Protocols, Megan.
MEGAN MUROSKI: Thank you for having me.
ANJALI SARKAR: So to start off, could you tell us a bit about your work in nanobiotechnology and how you came to be interested in the field.
MEGAN MUROSKI: Yeah, certainly. Well, I've always been interested in science. In high school and college, I volunteered in biochemistry laboratories. When I eventually got into grad school, I joined an inorganic lab, and the professor was working on molecular rulers using gold nanoparticles. I thought that was just the coolest thing that you could use gold nanoparticles for biological applications.
MEGAN MUROSKI: And from there, I collaborated with professors at the medical school and studied nanoparticles and drug delivery systems in ischemia and traumatic brain injury models before moving to Northwestern as a postdoc, doing work with glioblastoma research and applications of nanoparticles for diagnostics and treatment. And then, from there, I went on to the government lab. So nanoparticles have really always been in my blood.
ANJALI SARKAR: Right. So nanoparticles are increasingly being used as a drug delivery and as well as in a number of diagnostic tools. What are the advantages of using nanoparticles over other conventional traditional approaches for drug delivery and diagnostics?
MEGAN MUROSKI: Well, the great thing about nanoparticles is they really have interesting properties that you don't get at the bulk level. And with nanoparticles, you really have really three different types when you're looking in the diagnostic space. You have your polymer types. You have your inorganic types. And then, you have lipid-based, which everybody knows about now with the COVID-19 vaccine.
MEGAN MUROSKI: But each of these different types of nanomaterial offers really distinct advantages. I work as the product manager for material science at MilliporeSigma. I work on introducing a lot of the inorganic nanomaterials into the portfolio, where we introduce new types of silicon nanoparticles, new types of quantum dots, iron oxide nanoparticles, as well as different golds and different functional innovations.
MEGAN MUROSKI: Now the great thing about inorganic nanoparticles and metal-based nanoparticles is that they really help bridge the gap between physics, and chemistry, and biology. So where you were looking at maybe one die, one drug, and trying to image that into a body, you can now put 10 drugs onto a giant gold nanoparticle and view it that way. You have gold nanoparticles that are often used in lateral flow assays as a colorimetric detection system.
MEGAN MUROSKI: So you really can go through a lot of different areas of expertise in terms of, whether it's going to be bioimaging, whether it's going to be sensing, whether it's going to be for drug delivery. You can use nanomaterials for, really, all of these different applications.
ANJALI SARKAR: Excellent. So these nanoparticles are also being used in drug delivery, as well as diagnostics, but also in the detection of metabolites, proteins, and nucleic acids. Could you talk a bit about the application of these nanoscale structures, particularly gold nanoparticles that you just mentioned in this detection of these biomolecules?
MEGAN MUROSKI: Yeah, certainly. So gold nanoparticles, in particular, have really unique optical and electronic characteristics. So researchers are able to tune the size, shape, and, actually, even the aggregation status of them. So whether they're a single molecule, or a single particle, or grouped together with different properties of each. They are really well known to be biocompatible, so they're stable against oxidation for the most part, and also, they're not really cytotoxic.
MEGAN MUROSKI: And then, as you mentioned, they can be used in the detection with lateral flow assays. But the surface of the gold nanoparticle makes it really amenable to attaching things to the surface. So things like drugs, genes, ligands, even antibodies are able to go onto the surface of the nanoparticle. And with their large surface area, you are able to put a lot of payload onto one nanoparticle, which is advantageous for a lot of things.
MEGAN MUROSKI: And then, really, I mean, the size and shape and ease of making them has really brought them into popularity. When you-- oh, sorry. When you look at the lateral flow assay and how gold nanoparticles were used for that, there are really just a host of FDA approved devices for this. And so, gold nanoparticles show up as colorimetric, so they're red. And so, that makes them really, really advantageous for lateral flow assays.
MEGAN MUROSKI: And you can put multiple antibodies onto one gold nanoparticle. So you can measure, in theory, lots of different things with just one moiety or one nanoparticle.
ANJALI SARKAR: Are these antibodies that are attached to nanoparticles also means by which nanoparticles or nanostructures are targeted to specific cell types or protein types? How does targeting-- how are these nanomaterials customized for specific targets?
MEGAN MUROSKI: Oh, you can write a whole review on it. And antibodies are really a great way of doing it. There are also things, like cell penetrating peptides that people use, so RGD. There are DNA sequences that you can use as RNA. You could target mRNA that you can all put on the surface. So all of those things can help. Or you could even put them on, like I mentioned.
MEGAN MUROSKI: Because the nanoparticles are large compared to DNA sequences, or genes, or ligands, you can put multiple things on the surface. So say you want to get a drug attached to-- you want to deliver a drug. You could put a drug onto the surface of the gold nanoparticle, and then you can put a targeting antibody and then just bring it there. So there's lots of different ways to do targeting using nanoparticles in general.
ANJALI SARKAR: Excellent. So recent work in the animal models preclinical work from work has shown that animal models can be treated with polyethylene glycol graphene rhythms or PEG GNRs to help treat spinal cord injuries. What are these graphene nanoribbons? And could you tell us a bit about how they are made?
MEGAN MUROSKI: Well, in general, the interface between carbon nanomaterials and neuroscience applications started maybe about two decades ago, looking at things like compatibility drug delivery and different manipulation of the particles in the biological space. These graphene is really just an electric carbon, which makes it convenient to use because our bodies are made up of a lot of carbon.
MEGAN MUROSKI: And there are strengths and weaknesses when you're going to use these, looking in vivo. Graphene nanoribbons are really just at the basis, just carbon nanostructures with a honeycomb lattice. And this organized structure of these materials makes them incredible candidates in building blocks for information processing, for electronic properties. And so there's a couple of ways to make them.
MEGAN MUROSKI: You could either use lithography methods. There are bottom-up where you make them from small molecules. There are methods that you unzip them through chemical processing. And so, there's a bunch of different ways to make them, and there's a lot of different properties, depending on how you make them as well. Using graphene nanoribbons for spinal cord applications, you could see that there's been a handful of publications with graphene and the nervous system literature.
MEGAN MUROSKI: And what you see is the spinal cord, as it's just really like a bunch of nerve fibers and joints, a two-way communication system, what it is. What the graphene nanoribbons allow you to do is really generate an electrical stimulation through these functional stimulations.
ANJALI SARKAR: How scalable is this GNR synthesis for manufacturing purposes to develop a treatment, for example?
MEGAN MUROSKI: Well, I think, in general, now, we offer graphene nanoribbons commercially in our product line. So now, you're able to purchase them, which, before was really just not the case. You had to create them in your own lab, which takes a ton of time. So having these available for commercial purposes really will help transform the space just in general. Because what people are now able to do is they're able to get reliable materials time and time again.
MEGAN MUROSKI: So you order the materials in America. You're going to get the same materials in China as in India. Whereas, if you're collaborating with the different labs or different labs, there are slightly different methods, and you don't have the reproducibility that you would getting them from a commercial source.
ANJALI SARKAR: So as I understand that, GNRs have to be combined or are generally combined with things like PEG, polyethylene glycol, or other molecules to help promote the healing, as in the case of spinal cord injuries? What is the advantage of combining these graphene nanoribbons with PEG or such molecules?
MEGAN MUROSKI: Well, just in general, when you look at nanoparticles, and especially when you're using them for a drug delivery or you're using them for in vivo applications, they tend to be decorated in a host of ways. So if you're using drug delivery, you want to make sure that the materials are biocompatible. If you're using them for scaffolding, you might want to put some matrix metalloproteinase or scaffolding proteins at the surface to make sure that the cells are biocompatible with the surface.
MEGAN MUROSKI: So there's a lot of different things that you can add to the surface to the nanoparticles. In the case of carbon and using PEG, in particular-- PEGs been around since the '70s and is used in a whole host of different nanoparticle applications. And then, you find that, actually, PEG is often used as it keeps the nanoparticles from aggregating in general.
MEGAN MUROSKI: So that's always helpful. It makes the particles a little bit more biocompatible, a little bit more stealthy if you will. And because of that-- and it's been around and studied for a long time. And so because of that, that's why you have researchers often use PEG for studies like this.
ANJALI SARKAR: Excellent. So the chemical and physical properties of GNRs combined with PEG or other molecules, they seem to have unique physical and chemical properties to be able to promote treatment of spinal cord lesions. Could you talk a bit about these physical and chemical properties as well as how do these graphene nanorhythms affect the microenvironment of where they are targeted to aid this recovery?
MEGAN MUROSKI: Well, in general, when you have graphene, it has a high electrical conductivity. It has high thermal conductivity. It has high mechanical strength, and it has good optical properties. I think, really, in the most case, I think, for as far as you're looking at carbon structures, graphene oxide has really been used most extensively because of its high specific surface energy and its mechanical strength properties.
MEGAN MUROSKI: And really, graphene oxide in that space has been used for everything, such as adhesion and proliferation of stem cells, as well as things like optical barriers, and drug carriers, and photodynamic for photo-thermal therapy. So looking at all of these methods, it really depends on the type of method you use to create the nanomaterial and what properties they're going to exhibit.
MEGAN MUROSKI: But really, most of the work in this space has been done on graphene oxide. I mean, graphene nanoribbons are still really in its infancy, trying to come up with really great application spaces. So whether it's drug delivery, gene delivery, tissue engineering, or things like photodetectors, or molecular sensors, I think researchers are really trying to figure out that space in general.
ANJALI SARKAR: So a different formulations are being used for different types of spinal cord injuries. Focusing on the spinal cord injury work first, could you talk a bit about the different kinds of formulations that are being tested in this space?
MEGAN MUROSKI: Well, in general, what you see is, for spinal cord injuries, with graphene nanoribbons, there hasn't really been a lot of work in that space. There's been a couple of articles in general, but most of the work really focuses on the stem cells differentiation into neurons or promoting osteogenic differentiation of stem cells for bone, as well as being able to look at them in general because carbon makes a good biosensors.
MEGAN MUROSKI: And so you can have optical outputs of that as well. So you really have-- graphene nanoribbons, right now, are really primarily used for the ultra small devices, such as molecular sensors and the photo and thermal acoustic detectors. But if you're looking in terms of spinal cord injury, using it as the delivery for genes and drugs, you see that.
MEGAN MUROSKI: I think the bio conjugation studies that have been done on it are things such as cellulose. There's been studies where you attach that strand to it. And so, that's really more of a biosensing. You look at PEG for targeted human therapy or siRNA delivery because that helps keep everything stable on the surface. And so these gold nanoribbons, because of their electrical properties, really have a great application space in the nervous system.
MEGAN MUROSKI: Or that's why they're selected anyways for this type of work.
ANJALI SARKAR: In the nervous system space, in the neurophysiological recovery and treatment space, nanostructures have a particular application in regulating cell membrane potential and in visualizing cell membrane potential. Could you talk a bit about this and how nanostructures are being used in visualizing and detecting regulating cell membrane potential?
MEGAN MUROSKI: Well, see, that's the really great thing about nanomaterials, especially with membrane potential, because we are at a point where we didn't have the sensitivity of current techniques. And now, as we get better and better nanomaterials, we're able to look at things more closely. And when you think about it, nearly all of your cells have an electrical potential across the plasma membrane, but electrically excitable cells.
MEGAN MUROSKI: And so, this is your neurons and your muscle cells are able to use the membrane ion channel pumps to really maintain a control across the membrane. And so, they have bigger electrical potentials. And so the type of nanomaterials that you have that expand and look at the differences in the shuttling of the membrane potential, which could be really useful. And so, like I said, for muscle, for neurons, even cancer cells have shown to have slightly different potentials as well.
MEGAN MUROSKI: You can use things like quantum dots and look at the different action potentials with that, whether they're attached to the outside of the plasma membrane, or whether they're attached to an antibody, or whether they're inserted inside of the cell and functionalized with different dyes that measure action potentials. You can do that as well.
MEGAN MUROSKI: I think there's been some work as well. So outside of the quantum dot space in terms of magnetism and ultrasound, and so using superparamagnetic particles in order to look at the different action potentials and induction in that space as well.
ANJALI SARKAR: You mentioned earlier that the PEG attachment to these graphene nanoribbons prevents their clumping or aggregating. So is this a normal phenomenon for a normal challenge in the application of nanoparticles to find that they aggregate in biological tissues or sera? And in addition to PEG attachment, are there other methods being used to prevent nanoparticles from clumping in the system?
MEGAN MUROSKI: Oh, sure. Well, in some applications, you actually do want nanoparticles to accumulate. So in things, like cancer therapy, where nanoparticles are using for drug delivery, having accumulation in the cancer site is actually preferred. So whether that's like EPR or transcytosis. These mechanisms are important when you're looking at neuroscience. But what you don't want is you don't want to inject the nanoparticles and have them not move anywhere.
MEGAN MUROSKI: The idea is to have them circulate, and that has a lot to do with the charge on the surface. And that's, a lot of times, while PEG is used because it helps mitigate having the particles be so charged that they clump together. But this has been a known problem in the field, and this is something that researchers often look at before pursuing any preclinical testing.
ANJALI SARKAR: You mentioned that nanomaterials are being used in the field of oncology. How are nanomaterials being used to trigger the immune system in immunotherapies, for example? And how is this-- you mentioned that you want some aggregation of these nanoparticles in oncology treatments. How does this aggregation help in this case?
MEGAN MUROSKI: The nanomedicine in terms of immunotherapeutics is still very in its infancy. I mean, really just understanding the immune system and how nanoparticles play a part is something that we're really just starting to address and really deduce the mechanisms after exposure or how to promote accumulation, so how to promote aggregation in the tumors, or how to trigger innate immune compartments after signaling, or looking at a single cell level.
MEGAN MUROSKI: So when you look at that, there are many different avenues that you can do in terms of immunotherapy and using nanoparticles. And so you could use magnetic nanoparticles for clustering cargo onto an immune cell for multiple therapeutics. You can work to de-stabilize the endosomal membrane. You can control the kinetics of drug release. You can use, like I said, the enhanced permeation and retention effect, the EPR effect or transcytosis in order to trigger an immune response within the tumor.
MEGAN MUROSKI: Or sometimes, you don't want to. I think, really, the field is just trying to figure out how to really best utilize these nanomaterials. But that being said, using nanomaterials as a drug delivery agent or as a therapeutic, the reliability to monitor these formulations and these creations in real-time has really helped transform the field.
MEGAN MUROSKI: So as we get better imaging technology, we're going to see a lot more advances in this field.
ANJALI SARKAR: Right. You mentioned the field is in its infancy. Are there any new developments in the area of understanding how these nanomaterials, whether they're just nanoparticles or more complex structures, how are they cleared from a biological system once their task, whether it be in delivering a particular drug or diagnostic tool, whether they're used as a diagnostic tool, once their task is done in vivo, in a biological system, how are they cleared?
ANJALI SARKAR: Or whether they stay in the biological system without having too much of deleterious effect on the system, are there any insights in that area?
MEGAN MUROSKI: Oh, certainly. It really depends on the type of nanoparticle you use. So if you're using things, such as inorganic nanomaterials or metal nanomaterials that don't break down easily, there are size recommendations that have been studied over the years by scientists to help promote clearance. And so in translational laboratories, there's testing that you can do to look at circulation time, to look at clearance time of these metal inorganic nanoparticles.
MEGAN MUROSKI: And that's why the lipid nanoparticles and polymer nanoparticles actually have received a lot of attention because those break down very quickly within the body. And so, having that clearance, they really don't hang around any time because your body knows what to do with lipids. They know how to break down polymers. Whereas, a gold metal nanoparticle's solid, so it tends to hang around longer.
MEGAN MUROSKI: So it really depends on your application, but these are all things that are looked at pre-clinically before they're ever even considered to move on to any backstage.
ANJALI SARKAR: Can normal techniques available for metal detection be used for detecting these metal containing nanoparticles in biosystems or other specialized techniques that are being developed to detect the in-vivo presence of these nanoparticles, particularly the metal containing ones, not the lipid nanoparticles?
MEGAN MUROSKI: Well, you know, as our science continues to grow and the technology continues to grow, I always like to say that we stand on the shoulders of giants. You see that our sensitivity has been increasing, and we're able to detect things at parts per billion where we were never able to do that before. So certainly, as the technology progresses, we're able to measure these gold nanoparticles or these metal nanoparticles just in general to see whether they are cleared or not.
MEGAN MUROSKI: But oftentimes, the methods that we have now are pretty good at detecting, but not to say that they can't improve or be better in the future.
ANJALI SARKAR: So are they basically biochemical assays or are they more sophisticated in, such as X-ray detection. Can those be used? Or are other new technologies, do they need to be developed to detect these nanoparticles? What kind of methods are used in the detection of them in vivo?
MEGAN MUROSKI: You can use MRI for iron oxide, right? So they're magnetic, and so you can detect that. You can use a lot. There's a lot of different photo detections that you could use, so what happens with these nanoparticles is that they have some of their properties. What they have is the ability to refract, signaling, and so you're able to see in, like, PET scanning, whether you have metal nanoparticle accumulation.
MEGAN MUROSKI: I think all the researchers who are listening are like, yeah, I've seen the pictures. So you really have a whole host of ways to detect it, just imaging into the body as well. And then you also have methods where you can detect parts per billion of total bio-accumulation in areas as well.
ANJALI SARKAR: OK. So given that the number of devices that are nanomaterial-based are growing in the diagnostic as well as therapeutic space, how do you think are the standardization methodologies for regulatory protocols to gain approval from regulatory agencies for the fabrication and characterization of these new tools and diagnostics? How are these evolving, do you feel?
MEGAN MUROSKI: Oh, ever evolving, evolving different from yesterday than today, trying to find the standardization. You see things in the EU with the reach protocols getting definitions of nanomaterials. You see the FDA posting information. I think in April just posted new information about nanomaterials in order to come with a consensus. I think that having a global definition is always good because, right now, the regulatory space just varies a lot by country.
MEGAN MUROSKI: And so, everybody just trying to get a handle on it and do the best they can in this new field is what we-- we do the best we can with the resources we have.
ANJALI SARKAR: So as we wrap up, is there anything else you'd like to mention, particularly your thoughts on the future of the application of nanomaterials?
MEGAN MUROSKI: Well, I think it's just really an exciting field in general. I mean, I'm probably biased. I have been in it for years. When I moved to industry as a product manager, I live and breathe nanomaterials now, trying to introduce the latest and greatest. We work with R&D teams in the company, developing and working with collaborators across universities all around the world in order to come up with the best technologies that people can use as a building block to accelerate their next level of science.
MEGAN MUROSKI: And so I think it's really exciting. And I really hope to see-- and we've been seeing it recently more of the bridge between chemistry and biology. Really, people have thought about it as a discipline of being separated, but we really find true innovation in the bridge in this space. And that's what I'm looking forward to the next 10 years.
ANJALI SARKAR: Certainly. Thank you so much, Megan. And that brings us to the end of today's GEN Protocol's Expert Exchange. Thank you for a very illuminating discussion, Megan. And a reminder to all our scientists viewers, GEN Protocols is open for submission of your protocols year-round in any aspect of biotechnology. This is Anjali Sarkar, until next time. Good luck in your research, and goodbye from all of us at GEN Protocols.
ANJALI SARKAR:
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