Many health conditions require medicines that can be delivered to specific parts of the body. For instance, someone with asthma requires medication that targets the lungs, while someone with a neurodegenerative disease needs therapeutics that can penetrate the blood-brain barrier. But how do scientists create medicines that not only reach their intended targets but also produce the desired pharmacological effect while minimizing side effects and ensuring convenience for the patient? In this episode, co-host Danielle Mandikian chats with Karthik Nagapudi, Executive Director of Pharmaceutics, to explore the pivotal role of drug delivery strategies, highlighting how incorporating drug delivery considerations from the initial stages of drug development is crucial for creating next-generation medications.
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Transcript of Two Scientists Walk Into A Bar: “No Delivery, No Drug” with Karthik Nagapudi
Maria: I’m Maria Wilson.
Danielle: And I’m Danielle Mandikian.
Maria: And we are scientists. We. Love. Science.
Danielle: Yeah, we do. So, when we aren’t doing it, the next best thing is to talk about science! And what’s really awesome is we’re surrounded by some of the most brilliant minds in research!
Maria: We are going to step away from the labs today to talk to other scientists about the cool stuff they are thinking about, working on, and imagining…
Danielle: …as well as how some of these discoveries just might lead to new medicines. So, grab your favorite drink, get ready to unlock your science brain and join us for Two Scientists Walk into a Bar…
Maria: The show for scientists, science geeks and the people who love them!
Danielle: What is drug delivery and how many different types can you name?
Employee responses:
I think it's a vehicle to deliver your payload or a therapeutic/modality to the place of your body that it's needed.
Wait, what do we know about drug delivery? So we know infusions…
Parenteral? Subcutaneous?
LNP is another one.
We got nanoparticles, we got bacteria…
Compounds in general. Then route of administration.
Antibodies.
Danielle: Bonus question. In a utopian future, what do you think the best possible drug delivery option would be?
Employee responses:
Cell specific pharmacology would be the future.
The ideal delivery would be just one time, curative.
Just by, like, holding it in your hand. Right? [Laughs]
Danielle: Hi, everyone! Welcome to the show. Today I get to talk with Karthik Nagapudi about drug delivery, one of my all time favorite topics. Thanks for joining us!
Karthik: I'm always super excited to talk about drug delivery. It's what we do, and so it's a pleasure to talk about that, but thank you all for having me on this podcast.
Danielle: So, what is drug delivery?
Karthik: So, typically, many of us are used to over-the-counter drugs. We take a pill. So what's inside the pill, right? That is the therapeutic drug substance. But we're not just taking the powder and shoveling that inside your mouth. Right?
Danielle: I hope not, yeah. [Laughs]
Karthik: I hope not, right? I'll give you the ideal definition –
Danielle: [Laughs]
Karthik: – and then say where we are. In my opinion, the ideal definition is a formulation or device or combination thereof of a therapeutic drug substance when administered to humans will go to the site of action and nowhere else – specific to where we want to deliver it – and produce the pharmacological effect that we want safely.
Danielle: Fingers crossed!
Karthik: Fingers crossed. So, this is the ideal drug delivery system. Of course, we are far from ideal, right? We try to do the best that we can, but an ideal drug delivery system should do all of that. And what I've not mentioned is in a way that is palatable to humans.
Danielle: What do you mean by that?
Karthik: It means it is convenient. I mean, the typical analogy I give is that, yeah, I mean, if you think about how we drive cars, we've gotten safer and safer and safer, right? But this safety cannot come at the expense of doing some crazy stuff like attaching you to the sides of the car or something.
Danielle: [Laughs]
Karthik: But it's something that human beings actually like to do, right?
Danielle: Yeah, yeah.
Karthik: Where you can drive, but it doesn't impose on you. So similarly, if you give a drug, or whatever, it cannot be that a patient has to take 20 tablets, right? Well yeah, it can produce the pharmacological effect that you want, but quickly. Nobody's going to do it. And you'll be surprised because you think, "Woo! It's curing the disease, why wouldn't they do it?" But as human beings, we have to make it easy for them. So that's a part of the drug delivery system as well. Not only just producing the pharmacological effect that you want, but to administer them in a safe, convenient way so actually people stick to their therapies, right?
Danielle: You know that really resonates a lot with me. A lot of times when we think about diseases, sometimes we fall into this pattern of thinking about just the organ that it affects. So, can you make your drug delivery strategy target a specific organ, and is it truly targeting just that organ or is there other things you have to consider?
Karthik: That's the goal, right? Very difficult, but that's where we are driving towards. When I say difficult, it's simply because the body does whatever it wants to do, right? And you are going to try to target it towards a particular organ. I mean, there have been several strategies. One is a local strategy where we just take an inhaler, go directly to the lung. Or we, you know, have a device go directly to the eye or a device and take it directly to the brain. But sometimes those are not convenient. But if you're wanting to deliver something systemically, either through injection or through orally, and it has to get to where it wants it, that's the challenge, right? You need to make it convenient, but we also want to target that one specific thing that we want to target without it going anywhere else. That's a tall order, right? And so, therefore, there are several strategies. But I think one of the interesting ones is what we call targeting strategies, right? Can we, for example, if we go into a cancer cell, cancer cells may express some receptor there, right? Which, you know, can we hook onto that receptor with something very specific like an antibody, or whatever, and target it into that cell? Yeah, people have tried this, but does it work flawlessly? No, it doesn't, because biology intervenes. How much is the target? How much does the target recycle? Now, what do you want to do, right? So many factors that you don't understand. Yeah, so there are many strategies. And the goal is that, where we want to selectively deliver only that. Only where we want to go.
Danielle: You know what? I think we should –
Karthik: Maybe before I'm six feet under. [Laughs]
Danielle: No! [Laughs] You know, I think we should make like a – this is a great time to make a request to all the scientists out there. If you had some, what do I want to say, distribution to a tissue that you weren't expecting, you should probably still include that in your publication. Because some of the coolest work has come out of, like, molecule A's goal might have failed, but we can leverage that failing for future stuff.
Karthik: Absolutely.
Danielle: So, please publish what you think is crappy, because it's not. [Laughs]
Karthik: Yeah, yeah. You mean, somebody else maybe already leveraged that distribution to modify that disease in that organ, right?
Danielle: Yeah.
Karthik: Absolutely, yeah.
Wellington: Hi, Danielle.
Danielle: Hey, Wellington.
Karen: Hi, everyone.
Wellington: When Karthik brought up a delivery system that people can stick to, why did that resonate with you?
Danielle: Because not all ways to get your medicine is convenient. For example, if you have to do something to take a medicine, and it's deeply unpleasant, that makes it hard. It's hard to actually stick to it.
Karen: Danielle, I was really curious about why it's important from a drug development perspective, to create a medicine that's easy for a patient to take?
Danielle: Because I want it to work, you know? We want patients to get better. That's what all of us show up to work for. And if the patient can't get their medication administered to the right dose so that it actually functions, they'll never get progress. They'll never see any kind of effect from the therapy.
Danielle: Let's take a step back for folks that maybe aren't as familiar with drug delivery. Could you kind of give some examples of buckets or like different kinds of strategies?
Karthik: Sure.
Danielle: You had mentioned, like a port or a pill, but what else is out there?
Karthik: I'm going to give you some historical perspective, right?
Danielle: Let's hear it.
Karthik: It's good to know a little bit of the past. And so, I think there was a nice review article that kind of summarized this really well, so I'm going to pull off from that. So, you know, what those people essentially did is – just to make it an analogy with a cell phone, I'm going to call 1950s to 1980s first-generation drug-delivery systems, okay? And then '80s to about, let's say 2010 or so, is the second generation of drug delivery. And then, now we are trying to jump up to the fifth generation of drug delivery – 5G, if you will, right? [Laughs]
Danielle: [Laughs]
Karthik: So what does it actually mean? So, in the first generation of drug delivery, what did we think about this? I think it's some very common things, right? You go take an aspirin. And you see there are 10 different things, right? Aspirin, once-daily aspirin, you know, it works for 12 hours. This works for eight hours. That was the first generation of delivery. They have a medicine that works, typically an oral pill, but you've got to take three of those a day. And they immediately went back then they realized, "this is bad.” Who's going to remember to take one at 12:00 in the afternoon, one at 8:00 in the night? Nobody. I mean, and I do this all the time, right? So, it's – you know, we are in this, but, you know, even we – it's because life gets in the way, right? So what they did is that they said, "okay, can we prolong the action of the drug?" Basically, the problem was the drug was getting cleared out in the body fast. You take it, it goes for two hours, it's fine. Then it gets chewed up, and it clears from the body, right? So then they said, "can we make it last longer?" Because if you think about what a drug does – right? – so we typically say that there should be, when you take the drug, there should be some minimum amount of the drug present in the body to actually make the disease modification. So, that's what we call a minimum therapeutic concentration. That's all we need really, right? But there was no way to control it, so we just give it, and then we hope that there's a window where there's a maximum concentration where you'll see adverse events and a minimum concentration which will cure the disease, and we are somewhere in between.
Danielle: Trying to find that sweet spot?
Karthik: Sweet spot. Can we make something a little bit easier, right? And which means it's a proven drug, can we just make it less cumbersome for the patient to take it? And all that we did was that we said that we only thought about what I call as the physical chemical properties of the drug. What do I mean by that? Chemically, the drug – so, how do I make it more throughout the day? I make it come out slower from whatever molecule, right? I'm going to make it come out slower and there are several physical processes in which we can do this, but essentially, that's the idea. That's the first generation of drug delivery that we did. And that's where all your pills that come up when you say the box – oh, once daily and stuff, you know, three times a day or, you know, sustained release. It will have you covered for your headaches for the whole day or whatever it is saying. But that's where all these labels come from. And so it's been quite successful. But if you think about it, we never did anything to understand the biology or anything. We just had a drug, it worked, and we said, "I'm just going to play around with it on the outside." Right? That's okay. All the low-hanging fruit. Maybe you can do all of that, right?
Danielle: [Laughs]
Karthik: Then we wanted to do something more interesting, right? Said that, "Oh, we want to deliver things like proteins.” Bigger molecules, not our traditional small molecules. By the way, I mean I hope some people will know it, but traditionally the small molecule drugs are the synthetic drugs that we make. And then the bigger drugs, the protein drugs, are expressed and proteins and sometimes even peptides and so forth. So these drugs, we wanted to say that can we, similarly, can we extend the duration of action? Right? Can we, you know, somehow make a depot of that? It's okay, when you take it orally, I can try to play around with the chemistry. When I take it as injectable, what do I do? Then people came up and said that "maybe we can put an implant in somebody." And many of us know what implants are. They are like some dosage forms in which the therapeutic agent is dispersed in a polymer or something like that, and they are surgically implanted into you. They are a slowly released drug over a period of time. Therefore, you don't need to have regular injections. Okay. Then we started getting into problems because there the biology is very important.
Danielle: What do you mean by that? Is it like your body isn't okay with having the implant in?
Karthik: Yeah, exactly. I mean, there is one is what the body, how it reacts to the drug delivery system is one, right? And secondly, in the body – I mean, how do you test these systems? Let's say I want something to release a drug over two months, right? So, then I must do some experiments in the lab. I have some system and it beautifully releases my drug over two months. Then when you take it inside the body, we don't know what happens. There's a black box, and it says, "Oh, in three days, you are done." After that, there's no action, right?
Danielle: That’s the bane of like, so many people's existence, right?
Karthik: Yeah. So, then we are like, "what's going on here?" Because we had no way to correlate what we see in the lab to what really happens in the real world.
Danielle: But just to be clear for folks listening at home, sometimes that might be due to what models are available in the lab. They just can't really mimic humans perfectly.
Karthik: Yes. Yeah, and because if you think about it, that's why it went from first-generation. We didn't care about these things, right?
Danielle: Mm-hmm.
Karthik: We said, yeah, we can control certain things chemically, and we can do all these modifications, nice ones in the lab. And for an oral drug, or whatever, it tended to work quite well with what it does, and so we were very happy, right? And then when we wanted to do a little bit more complex things we realized that the body does something to these drug delivery systems, which we don't understand. Not only in terms of its reaction to the drug delivery system – maybe there's an immune reaction or one of the other things, that's a dangerous safety thing, right? But in general, it has a variety of components wherever you put it that is going to impact that system. So that's why you'll see in the second generation of drug delivery, which we'll call from 1980 to 2010, there are very few products that we actually made. First generation, widely successful – 30, 40 products that we made. Because then we understood that, oh, we have a big black box where we really don't understand the biology. So, we have to lean on a biologist to educate us, right? And then the drug designers themselves have to learn a little bit of it. And the delivery people should also learn about it, otherwise, you're just not going to have a product that is working.
Danielle: Yeah. You know what this kind of makes me think of? I think sometimes we assume there's so much about basic physiology, maybe we don't have all pathologies sorted out, but like we think basic physiology – we've got a good handle on that. But like not too long ago, there was a great paper that was published where people were showing that what we thought we understood about, for example, just renal filtration – totally wrong. We always thought it was this molecular weight shape, you know, weight that guided whether or not something's going to be cleared renally. And it ended up being, like, degrees of flexibility and overall shape and not the molecular weight at all. And that's just a classic example as we're introducing these novel types of therapeutics, how much we can actually learn about how the body will process it?
Karthik: I think in a way, we are being spoiled a little bit by coming from a physics background and other things where there are a lot of unknowns, of course, but things are rather settled in the way they think about theoretical things, right? Yeah, they're just tinkering around the edges, they don't understand a few things, but the standard model of physics has been around and pretty much predicts most of what they want to do. But in biology, I think every so often we have to just completely change our paradigm because we just didn't understand it at the level that we needed to understand it. And I think the tools are getting much better. But still, it's going to be a huge cross-collaborative effort because no one person – I mean, they don't know about the physio-chemical aspects, and we don't know about the biology.
Danielle: Yeah.
Karthik: There's no one person who's going to be able to do all this, but yeah.
Karen: It's really interesting that Karthik was talking about drug delivery in these different generations. How do you think about that in oncology?
Danielle: I think we all kind of have the same mentality. Anytime we talk about drug delivery, it's getting something to the right place at the right concentration. And each tissue has its own challenge. So like, you know, there's a lot of work that's being done for like devices to kind of hold a local depot. But the fifth generation in my mind are like the most optimal, wouldn't even require that.
Danielle: So, you had mentioned oral pills, you had mentioned these local delivery devices and even generating depots. But there's other stuff that's been coming up on the scene that I kind of feel like – I don't know if I tried to do like a lit search and found the same paper that you were just mentioning. It's like this one that – it was a nice review that talked about from the '50s and onward.
Karthik: Yeah.
Danielle: Yeah. And one of the things as I was going through it, it kind of caught me in the right moment was there's also like different ways to kind of get at delivery that are focused at coming across barriers. So, there's some like physical manipulations, right? Like, you know, shoot, what is it? I think it's an ultrasound is now being re-evaluated for localized ultrasound for opening up kind of physiological barriers for delivery to the brain or even in some cases like solid tumors. So how do you take that into context with your vision of drug delivery and these different kind of generations and seeing these technologies come back onto the field?
Karthik: Yeah, I think, that's why right at the beginning I defined it as not only as a formulation – it's a formulation device, all of the above, right? And that's moving so rapidly. There are so many things that sometimes I just feel depressed after reading –
Danielle: No! No, no, no!
Karthik: – what's going on because I think I'm just getting old, and I can't keep up with this anymore. But, you know, the pace of change is dramatic, right? Third generation, we started realizing what are those biological barriers, right? We, you know, if we're going to deliver some drug to the lung, yeah of course we can do it locally. We can take an inhaler – many of us have used it one way or the other – and give a drug there. But still you've got to carry it around with you. Can I give you a pill and can it go there, right? Or, you know, some once-in-a-six-month injection and that's enough, or whatever it is. But then we have to understand the barriers, because different – locally, of course, I can go and I can be quite intrusive. For example, we can do intrathecal delivery to the brain with a device. Is that a good standard of life for somebody? Maybe not. But maybe the disease is so debilitating that they're willing to put up with it. But our job is to see that's the first generation, good, we're getting some handle on the disease. But can we make this better, right?
Danielle: Yeah.
Karthik: So therefore, there may be devices, there may be formulations, and how do you get the combination of those two? So, the older delivery was always like, we took a pill, and that's been widely accepted as one of the best ones because you can carry it wherever you want. I'm not saying it's the silver bullet or whatever, but it's much better than having an injection, even today –
Danielle: You can ship it. There's a lot – there's a lot of benefit, yeah.
Karthik: You can ship it, you can do a lot of things at room temperature. You know, all those things that make things convenient. But then we started getting into these biotherapeutics, and we said, oh, proteins or antibodies, all these things have to be injected because if we take them orally, they get chewed up. You don't get anything across the GI because our gut is designed evolutionally to prevent these things from getting across for good reason. You don't want some random stuff to get across. But then when you're trying to get things across from a drug standpoint, we run into those barriers – there's a mucus barrier, there's a gut barrier, right? That simply will allow small molecules in, but not the big molecules. How do we overcome this? There are several formulation approaches people have tried, but one of the cool approaches in the last 10 years is take a pill, but the pill will inject the drug across your GI.
Danielle: What? What do you mean? Wait. Tell me more about this. I'm not familiar.
Karthik: [Laughs] So it's kind of a fascinating thing that people are trying. Of course, it's all preclinical, and people are trying to figure out how to take it. But there are different technologies. And I think one company, which is in the Bay Area, developed this technology where you can put your drug in a pill, and the pill will – once it's swallowed and once it reaches the small intestine or where you have – will have little injecting needles that come out of the pill, and it will deliver the drug through your GI, right? GI lumen.
Danielle: Like, are we talking like glass shards coming out of a pill, or like – I'm just trying to imagine this.
Karthik: [Laughs] These are – I mean, I don't want to go into the details fully because –
Danielle: That's okay.
Karthik: – these are confidential things of the company. They don't even publish these too much. But these are, what you call retractable, injectable needles.
Danielle: Interesting.
Karthik: And they come, and they, you know, push the drug out. So now, what it opens up is it opens up an opportunity for you to deliver biologics through the gut. Would I have thought about it 10 years ago? I would have thought it's crazy, right? But people are doing this, right? And because one, our materials have become very good. Our electronics have become very good. And our miniaturization potential has become very good. So now we can think about all this because we have a confluence where our materials, chemistry, everything is much better than, you know, the last 10 years where we really started to explore in these areas, right? So these all would have seemed crazy 10, 15 years ago, but it's possible now to do those things. And this is like a – well, I shouldn't date myself here, I think, but –
Danielle: [Laughs]
Karthik: It's like an old –
Danielle: You know what? In science, it's an advantage. Date yourself all you want.
Karthik: It's like an old, you know, Raquel Welch movie, "The Fantastic Voyage," where you miniaturize people, and they go into . . . you know, okay. I think the kids would be like, "what the hell are you talking about?" Anyway, I think it's, you know, can we put some nanobots or something inside as a futuristic way? But it's kind of, you know, getting towards that part, right? Where you have a robotic pill, you take it, and it injects it. And therefore, now you can expand the space of molecules that you can deliver orally.
Danielle: But you know what? In some ways, it's kind of like an interesting take on old themes, right? Because whether you're talking about like the robotic pill or you're talking about the port device in the eye, you're actually utilizing barriers that would have sucked otherwise to actually keep what you want where you need it to be until you're ready for it.
Karthik: Yes.
Danielle: You know? So, yeah . . .
Karthik: Turning those into things that –
Danielle: Something positive.
Karthik: Something positive. So, this is where what I call almost like, we bypass the fourth generation, gone to the fifth generation drug delivery barrier. Drugs are not possible without the delivery, right? In the other instances, a drug was possible. So that's what we did. But now, we are like coming to a stage where we cannot deliver these things without the proper packaging, without the proper drug delivery systems. So that's where I want all the people who are listening, the postdocs and others when they say, "why drug delivery?" Because, now we're getting to a stage where all these fancy new things that we do –
Danielle: Yeah.
Karthik: – cannot even be delivered without getting into the right packaging.
Danielle: It can't fix it if it doesn't show up to the right room, right? [Laughs]
Karthik: Yeah, exactly. So that's why I say, with all due respect to all our drug developers and, you know, whatever it is, if it ain't going where it is, it's not a drug.
Danielle: Right.
Karthik: Right?
Danielle: Right.
Karthik: So, if you can't – I mean, all the nice promises are not worth it, on – what's on paper if you can't deliver it.
Danielle: Tell me about how the immune system responds to all of this. Like what types of drug delivery is it a challenge? What types of drug delivery are more amicable to getting past people's immune systems?
Karthik: Yeah, I mean, first of course I have to give you the full disclaimer as you have to talk to an immunologist, right? I mean –
Danielle: What? [Laughs]
Karthik: – about that. I mean – [Laughs]
Danielle: No, you're on record now. [Laughs]
Karthik: I'm just like a second-rate, you know, chem engineer trying to understand these things.
Danielle: No, no, no, no, no. [Laughs]
Karthik: But I think broadly what we understand, at least what they have taught us, is that – I mean, you do know that immune response is a problem, right? I mean, when you put foreign bodies in there – especially when you're injecting drugs, right? The body for a very good reason doesn't want these things in there. And so that's when, you know, I used to have this joke with my nanoparticle friends that everybody talks about these great nanoparticles, and I'm like, on one hand, you talked about vaccination, immunization, but you're not worried about the immune response of these fancy nanoparticles that you're putting into the body?
Danielle: [Laughs]
Karthik: Of course, you're going to be worried about them, right? And there are immune reactions. In fact, you know, I think, certain drugs are – I think Alnylam was the first one to come out of the lipid nanoparticles for taking disease indications in the liver, I think.
Danielle: Mm-hmm.
Karthik: And they had to give patients and keep the patients on steroids, right? Because they needed to suppress the immune system because they didn't want them to go haywire. Yeah, so I think that's – and I think that to a large extent, drugs that are administered parenterally, you've got to be careful, right? Because you're directly going into the body. Oral because you have the GI to protect you, you know, and we're trying to get across the GI that way.
Danielle: Yeah.
Karthik: Similarly, when we deliver with these robotic pills directly, we also have to understand the immune reactions there as well. But typically for oral and other molecules, we have not been that concerned, about those – could be, alright, in some cases – but we are not that concerned because you have the GI to protect you and, you know, GI barrier to protect you. But you are going directly IV, into directly, you should be concerned about what the immune system is going to do, right? I think what we tried to do is what we call the immune silent kind of systems, what we want to develop, right? Because they kind of fool the immune system to some extent.
Wellington: Okay Danielle, vocabulary alert! Parent-er-ally?
Karen: Parenterally.
Danielle: Parenteral.
Wellington: What is it?
Danielle: My brain is now, okay, that is basically an administration route. So kind of like, you know, you might take an oral pill – it's oral. That means that you're administering to the gut.
Karen: Danielle, I have a question. What are LNPs – lipid nanoparticles – and how are we using them in drug delivery?
Danielle: Basically, it's a ball of lipids. You can kind of think of it as a carrier style. Like, there's like a whole bunch of stuff where we try to figure out some way to target a type of therapy to some place. We often think about, like, antibody drug conjugates as a way to target. LNPs are a carrier, just like an antibody might be a carrier for, like, some kind of chemo agent. An LNP can be a carrier for nucleic acid-based medicines like RNA or DNA.
Danielle: One of the things I definitely wanted to ask you about in that same vein of thought, right? Now thinking about it in the context that we are constantly having paradigm shifts in what we think we understand about the intersection between biology, chemistry and all of this – how do you see machine learning and AI guiding and supporting these kinds of efforts?
Karthik: So, I think that, you know, we have to be a little careful not to get carried away, right? I think that there's great things that we can do, right? Obviously, now with the computing power and with the power of large data sets that we can generate biologically, modern materials or whatever it is, yes, you know, we can do and mine to get a lot of information. But I think you also have to be careful about that. I do prefer to some extent an old-fashioned, hypothesis-driven science that machine learning and AI can help with, right?
Danielle: Mm-hmm.
Karthik: You know, sometimes, people do the opposite as well where we come from the other end, and there's nothing wrong with that.
Danielle: Yeah.
Karthik: I mean, there are different flavors to how you can do it. But definitely, it is going to change our thinking a lot because biological systems are complex. It's not a simple experiment that you can do and, you know, we can figure out everything. So, therefore, we need to have big data sets. We need to be able to interpolate, possibly extrapolate some around those data sets, and that's where machine learning and AI are going to come in. They're going to be huge tools that are definitely going to affect the way we think, not only about how we design, what kind of targets impact the diseases, how we design molecules for them, or how we design drug delivery systems for these molecules, right? All of them are going to be impacted broadly. So, of course, I don't have a crystal ball to tell you where that's going.
Danielle: [Laughs]
Karthik: But I do see instances where things can be really useful because on a theoretical basis, maybe it's not as good.
Danielle: Yeah.
Karthik: So maybe empirically trying to go out and dig out these connections using machine learning or AI can be useful.
Danielle: You're singing the song of my people, because I feel like I'm very much a strong proponent of like AI and machine learning in this biological context, but I'm also very heavily still pushing very specific types of in vitro and in vivo assays because I think that the second that we think we can fully rely on one without the other, we're going to be in a lot of hot water. And there's still so much – even though, like, just take these kind of preclinical in vitro assays that we might use for anything related to drug delivery, these have been happening for years. But there's still stuff that we're learning about how to redesign them to be much more specific about the readout under, you know, X biology, X system and how you can translate it and not over-interpret, you know? Yeah.
Karthik: Yeah. I think we are well in agreement here. [Laughs]
Danielle: [Laughs]
Karthik: You know, we should – these are tools, like any other tools.
Danielle: Yeah, yeah.
Karthik: And these are tools that are really advanced tools, certainly, in terms of what they bring to the table. But they're tools, right?
Danielle: Right.
Karthik: In the end, that is not going to substitute for what our, you know, aggregated wisdom and what, you know, all that is going to be. It can help us do better, certainly. But that's how we should treat these tools as well. Because sometimes people treat the tool itself as a means to an end, right?
Danielle: Right.
Karthik: This is going to solve all my problems. It's not going to solve all your problems. We still are going to have problems.
Danielle: I get the hope though. I get the hope. [Laughs]
Karthik: Yeah. But I think it can help us do much better. And hopefully help us to get the answers sooner, right?
Danielle: Yeah.
Karthik: That's certainly, you know, worthwhile.
Danielle: Yeah. So a lot of people have been using the buzzword "new modalities" when I don't know if they're technically new, because it's – I feel like these are cyclical trends. But what about drug delivery for nucleic acid-based medicines or, you know, molecules along that ilk?
Karthik: Yeah. I think maybe, I think just to parse a little bit on that new modality kind of thing. Yeah, I mean, these have been around. Some of this – I mean, I think it's just that from a perspective of materials and chemistry, we've gotten very good at biologically expressing them. We've gotten good at it. The constructs and what they understood people to be, these new modalities were around for a while. People did realize that if you could do this with the parts of our DNA or RNA or, you know, oligonucleotides or even mRNA as it stands now –
Danielle: Mm-hmm.
Karthik: – we could convert them to therapeutics. I think that understanding was there in the '80s and '90s as well. It's not new, per se, right? For us, it's new because we can operationalize it.
Danielle: What do you mean?
Karthik: We can actually make it, right?
Danielle: Oh, it's like feasible now. Yeah.
Karthik: Right? I'm saying, we can put it into – if we can put it into action, right, and therefore, we are super excited about it. I mean, obviously, that's, you know, from a theoretical construct. I mean, they could make it in some small amounts in the lab and all this, but now we have methodologies and, you know, synthetic chemistry and biology or even synthetic biology nowadays –
Danielle: Mm-hmm.
Karthik: If you think about, you know, where we can even modify cells and so forth. So, we are having the tools to actually put this into practice, right? So that's why the whole industry is buzzing in the last 10, 15 years with these new modalities, and now we're all modality-agnostic, in a way. We don't care. We're not going to solve every problem with a hammer. Whatever is the best tool to do the job, we'll pick that, right? It's not that we were unaware of the tools, but we couldn't make those tools.
Danielle: Yeah. [Laughs]
Karthik: So now we can make them. Therefore, now you have a screwdriver, and you have other things with you, and therefore, we will use it for that. So, that's where we are now, and it's exciting. I mean, and that’s really exciting because each of these things come with their own set of issues, right? I mean, they are different chemical structures, they have different liabilities. I mean, of course they have advantages, and that's why we like them. And then, you know, some help us to treat disease at a genetic level – that's fantastic –
Danielle: Mm-hmm.
Karthik: – if we can understand those correlations. And you know, all these are very new to us.
Danielle: So, what do you think is the coolest thing on the horizon? And like, you know, sooner horizon rather than later horizons?
Karthik: Yeah. I believe that this is going to be – of course I'm biased, but it's going to be one of the most essential components of designing new drugs, right? We have thought this as an afterthought. We thought, ah, it's something that we need to think about. No, drug delivery should be front and center to what you want to do, especially as you're considering more of these challenging molecules. And I think in that – I mean, that's where the future will yield what you asked about in terms of can we go to specific organs? Yeah. We can, but we have to start with intentionality – not as an afterthought, right? And I think we are getting there now. More and more people are realizing that this is front and center. Just as important to get a therapeutic, it's just as important to get a delivery system to take you, you know, to where you want to go and hone in on where you want to go. So, I think that's where I think the future is exciting, because I hope that we are going to have highly, highly specific drugs without toxicities that we can actually deliver conveniently to the patient. So I think I'm pretty excited. Very excited.
Danielle: [Laughs] You think? Come on.
Karthik: No, I'm not – I'm not too excitable, but anyway –
Danielle: [Laughs]
Karthik: – I think I'm very excited for that future, right? Where we can give a drug, patient takes it, they'll feel better. Nothing else happens to them. No side effects.
Danielle: That's the goal.
Karthik: Nothing else happens. But, yeah, one can dream about that. But that's where drug delivery can take you.
Danielle: We're hoping. There's been a lot of excitement about new possible treatments for diseases like Alzheimer's where we're trying to clear out crappy proteins, right? So, do you foresee drug delivery changing any in the neuro space?
Karthik: I'd say the drug delivery is critical to get into, get across the blood-brain barrier systemically for patient convenience. We can do crazy stuff and get it there right now, not so crazy. We can do clinical stuff and get it there intrusively. But that's not the goal is it? To make somebody's life comfortable, you have to get there with a systemic administration. The probability of success is quite low because blood – still, we do not have good ways of getting there. But absolutely a lot of investment and research is going on there because we are all aging. That's not going to go away and those diseases are there. And we do believe we have good therapeutics. But to get it there I think is the challenge. And it does remain the challenge, I think we’ve made not much headway. But hopefully that's another thing to look forward to.
Danielle: I mean, that area is the poster child for why drug delivery is so important, right?
Karthik: Yeah, absolutely. I mean, if we can get there, it's fantastic.
Danielle: Yeah. Thanks so much for being here! It was a lot of fun to chat with you. Always and forever, I thank you.
Karthik: Thanks again for having me.
Karen: That was a really great episode. What was your favorite part?
Danielle: You know, I just love hearing the back history of how drug delivery for certain types of diseases or certain target tissues changes over time. I find that really entertaining because it's this really nice intersection between kind of just like practicality, basic biology and, yeah, it's an interesting field.
Wellington: It seems like there's some correlation between your goals in oncology and drug delivery goals when I hear him talking.
Danielle: Yeah. I mean, that's a whole thing. I think the other thing that kind of makes it really interesting is that sometimes when, you know, it depends on what school you come from, who's your PI that trains you. But a lot of times when you're thinking about basic biology, what would your target be? How would you try to, you know, cure a disease? You don't often partner that with the practicality of what it takes to actually make that happen. And so that's where I live and breathe for oncology space. And it's such an interesting question that I never really was challenged with in my earlier days in research. And I just really love that space.
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And now for me it's back to stalking cells!
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