Controlled Drug Release Technology
Transcript of Part 2: Drug Delivery Technology: Present and Future
00:00:07.17 My name is Bob Langer 00:00:08.28 and I'd like to now go over the second lecture, 00:00:11.19 which is Drug Delivery Technology: 00:00:13.13 Present and Future, 00:00:15.15 but I should briefly summarize 00:00:17.28 what I went over in my first lecture. 00:00:19.27 And, in that first lecture, 00:00:21.08 I discussed the fact that controlled release systems 00:00:23.02 offer long-term drug release 00:00:25.10 with release rates primarily determined 00:00:27.09 by the system itself, 00:00:28.29 and I went over some different ways that one could achieve that, 00:00:32.04 and I in particular went over 00:00:34.20 how one might design certain polymer systems 00:00:37.10 or pump-based systems to do that. 00:00:40.17 Now what I'd like to do is actually go back in time 00:00:42.17 and tell you how I got involved in this area in the first place, 00:00:46.13 and then talk to you about 00:00:49.07 some of the systems we developed 00:00:50.28 and even some of the ones we're developing for the future. 00:00:54.03 So, when I got done with my doctorate it was 1974 00:01:00.05 and I was in chemical engineering, 00:01:01.26 and most of my friends at the time 00:01:03.28 went into the oil industry, there was a gas shortage then 00:01:06.09 and they had lots of jobs, 00:01:08.12 but I got a lot of job offers from the oil companies 00:01:10.24 but I wasn't very excited about it, 00:01:12.28 and I was looking for a way to try to use my chemically engineering background 00:01:16.01 to either help in education or human health, 00:01:19.17 and I was very fortunate that Judah Folkman, 00:01:21.28 who was a surgeon, 00:01:23.25 offered me a job in his lab 00:01:26.14 on something very, very different, 00:01:28.06 but that I felt was incredibly exciting. 00:01:30.10 And I though I'd start out and just show you a picture, 00:01:34.08 actually from the New York Times, in 1971, 00:01:37.07 of Dr. Folkman's vision of how tumors grow, 00:01:40.29 and what he proposed is that a tumor cell 00:01:45.18 would somehow be created 00:01:47.29 and it would grow to a 3-dimensional mass, 00:01:49.25 and it would never get larger than say about a millimeter cubed, 00:01:53.12 because it ran into a nutrition problem. 00:01:55.17 Cells in the center would die 00:01:57.15 because they couldn't get nutrients or get rid of wastes. 00:02:01.07 Well, what he said is that somehow the tumor 00:02:04.02 is able to solve that problem 00:02:06.12 because the tumor would create a chemical signal 00:02:08.21 which he called TAF, tumor angiogenesis factor, 00:02:12.08 that would diffuse to the surrounding blood vessels 00:02:14.23 which normally didn't do anything, 00:02:16.22 but when the TAF was there 00:02:19.02 it would cause them to multiply and grow, 00:02:21.11 and grow right to the tumor, 00:02:22.29 and that would cause a second phase of growth, 00:02:25.14 which you see here. 00:02:27.05 And, in that second phase of growth, 00:02:29.07 the tumor is vascularized 00:02:31.00 and that solves the nutrition problem for the tumor. 00:02:34.03 It gets bigger and bigger 00:02:36.10 and ultimately can spread through those blood vessels, 00:02:38.03 a process called metastasis, 00:02:39.29 and eventually kill. 00:02:41.24 Dr. Folkman's idea, which is I didn't realize 00:02:44.10 but was very controversial at the time, 00:02:46.08 was that it you could stop the blood vessels from growing, 00:02:48.17 achieve anti-angiogenesis, 00:02:51.04 maybe that would be a whole new way of thinking 00:02:53.05 about stopping cancer. 00:02:55.18 So, when I came to his lab in 1974 00:03:01.02 there was no such thing as an angiogenesis inhibitor, 00:03:03.20 and he asked me to isolate, actually, 00:03:06.03 what would become the first of these. 00:03:09.03 How do you think about a problem like that? 00:03:11.05 Well, we kind of broke it up into two parts. 00:03:13.06 First, where could you find something 00:03:15.13 that might stop blood vessels from growing, 00:03:17.13 and one of the things that we thought about was cartilage, 00:03:19.24 which is in your nose and your knee, 00:03:21.24 and cartilage doesn't have blood vessels. 00:03:24.04 So, I was able to get some cartilage 00:03:28.11 from the little rabbits we had in the lab, 00:03:30.00 but I couldn't get that much. 00:03:31.29 So then, I started thinking, 00:03:34.07 you know, well where can I get more? 00:03:35.27 ...you know, and I found a slaughterhouse 00:03:38.07 that had cows and I got some of their bones, 00:03:41.03 but still I could only get a couple bones. 00:03:43.08 So, I found out, where do all of the cow bones 00:03:47.09 in the Northeast go, 00:03:49.02 and they go it turns out to a slaughterhouse, 00:03:51.01 to some meatpacking places in south Boston. 00:03:53.08 So I made an arrangement with them to get all their bones 00:03:55.10 and I'd bring them back to the lab 00:03:57.20 and I would process them, 00:03:59.15 meaning that I would scrape meat off of the bones, 00:04:03.26 I'll actually just show you one. 00:04:06.07 Here's a bone and if you look at the top of it, 00:04:07.23 that's where the cartilage it. 00:04:09.13 And so I'd scrape the meat off the top, 00:04:11.09 which I did in this case, 00:04:13.00 and then I'd slice off the cartilage, 00:04:15.11 and then I'd put it through various extraction 00:04:17.26 and purification procedures 00:04:19.14 so that at the end of several years 00:04:21.08 I maybe had 50 or 100 different what are called fractions 00:04:24.04 that I wanted to study 00:04:26.01 and test to see if they would stop blood vessels from growing. 00:04:28.11 But, that then brings up the second problem. 00:04:30.12 How do you study something 00:04:32.01 like blood vessel growth? 00:04:33.25 And, if you look back at the history of medicine, 00:04:37.23 one of the biggest challenges 00:04:39.29 whenever somebody comes up with a new factor 00:04:41.24 or substance 00:04:43.20 is often finding a bioassay, a way to study it. 00:04:46.24 And there was no such bioassay, 00:04:48.21 really, for studying angiogenesis, 00:04:50.17 so we had to create one. 00:04:53.05 And, one of the things that we thought about was, 00:04:57.03 as we started to think about creating them, was... 00:05:00.04 one of the big issues was that almost everywhere you go 00:05:02.08 in the body or any organism there are background blood vessels, 00:05:05.07 so we wanted to find a place where there weren't, 00:05:07.05 and so we thought about the eye of a rabbit. 00:05:09.16 And, it turns out that Michael Gimbrone had shown 00:05:12.13 that if you put tumors, certain types of tumors like B2 carcinomas 00:05:16.12 in the eyes of rabbit, 00:05:18.17 they will cause, over about a 2-3 month period, 00:05:21.02 blood vessels to grow from the edge of the cornea, 00:05:23.11 the limbus, to the tumor. 00:05:25.07 So, we thought we could take an ophthalmic microscope 00:05:27.13 and actually measure the length of the longest blood vessel, 00:05:31.10 but the problem was, 00:05:32.18 if we wanted to now find an inhibitor, 00:05:34.16 we had to also put the inhibitor in the eye 00:05:37.04 and the inhibitors would quickly diffuse away. 00:05:39.16 So, we thought a way to solve that 00:05:41.18 is to have what we call a controlled release polymer 00:05:43.27 that could take any of the things we isolated from cartilage, 00:05:46.24 all of which were fairly large molecules, 00:05:49.07 and deliver them to the eye and to the tumor 00:05:53.10 and to the blood vessels over this 2-3 month period. 00:05:57.14 So, one of the big challenges, then, 00:05:59.21 became to try to develop such a polymer... 00:06:02.28 and they didn't exist, 00:06:05.11 and in fact Dr. Folkman, he was on the board of the one company, ALZA, 00:06:08.23 working in this area, 00:06:11.06 and he went out to ask them if they could help us. 00:06:13.01 But they said no, they said 00:06:15.17 that large molecules can't slowly diffuse through solid polymers. 00:06:19.18 It's kind of like saying, could any of us walk through a wall? 00:06:22.25 In fact, the literature said similar things, 00:06:25.23 that the use of polymer matrices 00:06:27.19 has been virtually restricted to small molecules. 00:06:30.11 The only thing I really had going for me is 00:06:32.26 I just didn't know any of that, 00:06:35.06 so I went ahead and tried to do it anyhow. 00:06:37.09 I experimented in the lab and I... 00:06:40.20 kind of almost Edisonian-like... 00:06:42.29 and I actually found over 200 different ways 00:06:45.04 to get this to not work. 00:06:47.18 But eventually, I was able to make little microspheres, 00:06:51.16 those shown here and one shown here 00:06:54.14 and then the other's cut in half, 00:06:57.10 and we were able to show 00:06:59.22 that by making these the right way 00:07:01.19 we could actually get release, 00:07:03.12 this is from a paper in Nature in 1976, 00:07:05.25 for over 100 days, 00:07:08.08 for really any molecule. 00:07:10.15 And that enabled us to start to 00:07:13.20 think about doing these bioassays 00:07:18.01 and to do controlled release as well. 00:07:21.05 Later on, one of the challenges 00:07:23.05 was to get constant release, 00:07:25.04 and we worked out some ways, using some engineering models 00:07:28.06 where we could predict certain shapes or drug distributions, 00:07:30.26 where we could get constant release, 00:07:32.17 and here's an example of that. 00:07:36.04 When I first presented some of this work, 00:07:40.03 people were very, very skeptical about it. 00:07:42.28 I remember giving a talk at a major meeting in 1976, 00:07:48.24 and I practiced this talk for many weeks before 00:07:53.12 because I was a very young guy, 00:07:55.01 I was a postdoc and there were all these very famous 00:07:58.00 polymer chemists and engineering in it, 00:08:00.05 and when I got done with the talk 00:08:02.06 I actually felt I did alright, 00:08:04.03 but what happened was all these older scientists, 00:08:06.01 when I got done, 00:08:07.16 they came up to me and they said, 00:08:08.27 "We don't believe anything you said." 00:08:10.22 They were just very skeptical 00:08:12.09 that you could release these large molecules. 00:08:14.23 But what happens, of course, in science 00:08:16.26 is the key is whether people reproduce what you do, 00:08:19.05 and it turned out that over the next couple of years 00:08:21.00 a number of groups did, 00:08:22.23 and the question shifted to how could this happen. 00:08:24.23 So, to understand the way this happened, 00:08:27.25 I had a graduate student, Rajan Bawa, 00:08:30.01 when I was at MIT, 00:08:31.12 and we cut thin sections through the polymer with a cryomicrotome. 00:08:34.29 Here, for example, is one of those thin sections. 00:08:37.12 It's a 5 micron thin section of a polymer we used 00:08:40.11 called ethylene-vinyl acetate copolymer. 00:08:43.07 And, if you had a molecule that was 00:08:46.04 300 molecular weight or greater, 00:08:48.02 it would not be able to diffuse from one side of this to the other. 00:08:51.00 So, how could the molecules get through? 00:08:53.18 Well, now we cut a second section. 00:08:55.23 This section has a red drug in it, 00:08:58.03 actually a red protein, myoglobin, 00:09:00.14 and this is cut before any release has taken place. 00:09:04.01 And we see what we call, in this case, 00:09:05.27 a phase separation. 00:09:07.19 You see the red myoglobin chunks here, 00:09:10.23 and then you see the white polymer here, 00:09:14.04 and you see that throughout. 00:09:16.14 So, this is what happened before any release. 00:09:18.27 Now, let's say you released it for a year 00:09:21.03 and then you cut a thin section. 00:09:22.28 What you'd see is left behind... 00:09:25.16 where the drug was, 00:09:27.19 are these pores, 00:09:29.29 and these pores are large enough so that molecules even millions of 00:09:32.12 molecular weight can get through, 00:09:34.05 but what happens is... 00:09:35.21 we did a lot of serial sectioning 00:09:37.13 and also scanning electron microscopy... 00:09:39.12 and what happens is it turns out that these pores 00:09:41.21 are interconnected, they have tight constrictions between them, 00:09:45.01 and they're incredibly winding and tortuous, 00:09:47.21 so it takes a really long time 00:09:49.20 for the molecules to get through them. 00:09:51.20 One way, when I try to explain this to people 00:09:53.27 when I give lectures around the world, 00:09:55.17 is I sometimes say it's kind of like driving a car through Boston. 00:09:59.04 Boston has, 00:10:01.18 what we call in chemical engineering terms, 00:10:03.20 which I'm a chemical engineer, 00:10:05.11 is Boston and these structures 00:10:07.07 have what we call a very high tortuosity. 00:10:09.19 And, if you have a high tortuosity, 00:10:11.23 that you can use to slow release down, 00:10:13.26 and over the years our graduate students and postdocs 00:10:16.19 have worked out ways 00:10:18.27 to create all kinds of these porous tortuous structures 00:10:21.20 and to even develop mathematical models 00:10:23.27 to predict how to make these, 00:10:25.23 and so you can make these last anywhere 00:10:27.20 from days to years, or any time in between. 00:10:33.11 So now, we were able to go back 00:10:35.22 and try to address the problem, 00:10:37.16 the angiogenesis problem, 00:10:40.04 because now we have these polymers that could deliver 00:10:42.06 molecules of any size 00:10:44.03 and we also were able to make these polymers in a way 00:10:46.18 that would not cause irritation to the eye, 00:10:48.11 which was also a big challenge. 00:10:50.15 So this was the assay I mentioned we wanted to create. 00:10:53.08 The tumor is there 00:10:55.25 and the polymer, 00:10:58.03 and what we did is we put different fractions, 00:11:00.16 we probably did close to 2000 eyes, 00:11:03.02 and when we did... 00:11:06.15 most of them didn't work. 00:11:08.05 There were all different fractions that we isolated 00:11:09.22 and most of them didn't work. 00:11:11.15 I should also almost all but one didn't work. 00:11:14.05 And I'll just show you some pictures 00:11:15.22 of what they look like. 00:11:17.13 So, this is from a paper we wrote in Science in 1976 00:11:21.11 with this what's called rabbit corneal pocket assay. 00:11:23.23 If you didn't have the cartilage-derived inhibitor, 00:11:26.00 that's what I call CDI, 00:11:27.28 if you didn't have it... 00:11:30.28 over, this is about 9 weeks after the start of the experiment, 00:11:34.01 you get a sheet of blood vessels 00:11:36.03 growing from the bottom of the eye 00:11:38.24 over the polymer to the tumor. 00:11:40.19 You can actually see the tumor... 00:11:42.19 where the tumor is it's a little bit cloudy. 00:11:44.26 And, if you looked at this eye, 00:11:46.26 or any eye like it 2-3 weeks after this, 00:11:49.15 what would happen is it would be... 00:11:53.01 the tumor would be 3-dimensional. 00:11:54.16 It would be out of the orbit of the eye... 00:11:56.14 we sacrificed the animals before that, 00:11:58.13 but nonetheless you see the rapid blood vessel growth. 00:12:01.07 In contrast, if you look at the next panel 00:12:04.24 where we put the CDI in the polymer, 00:12:06.19 the cartilage-derived inhibitor, 00:12:08.06 notice how the blood vessels are lower: 00:12:10.10 they avoid the polymer, 00:12:12.12 they don't grow into the tumor. 00:12:14.09 This is at exactly the same time, 00:12:16.04 and it turns out that about 40-50% of the time, 00:12:19.00 the tumors on the right will never grow, 00:12:21.03 whereas 100% of the time the tumors grew on the left, 00:12:24.09 and like I say, we did hundreds, thousands of eyes 00:12:27.26 over the years to look at this. 00:12:31.07 So, that actually enabled us 00:12:33.13 to isolate the first angiogenesis inhibitor. 00:12:35.16 It did a couple of important things, 00:12:37.09 I like to think. 00:12:39.00 One, is that we did develop an assay 00:12:42.09 that people could use in the future 00:12:44.25 for all future angiogenesis inhibitors. 00:12:46.23 Secondly, I like to think that this 00:12:48.22 really established there were angiogenesis inhibitors 00:12:51.05 that were chemical, and they did exist. 00:12:53.22 And then we had this first one. 00:12:56.09 Now, what happened is of course it took... 00:12:59.12 this was just the start. 00:13:01.04 It took the work of many companies, 00:13:03.16 particularly Genentech and others, 00:13:06.04 to really move this field forward, 00:13:09.17 so it's wasn't... 00:13:11.24 you know, many years later. 00:13:13.09 So, it wasn't until 2004 00:13:15.21 when the first angiogenesis inhibitor got approved, 00:13:19.07 and this is just a list of angiogenesis... 00:13:22.18 and it's not even a complete list, 00:13:24.12 that have gotten approved since 2004. 00:13:28.15 Avastin, which is a Genentech drug, 00:13:30.09 is one of the biggest, most widely-used 00:13:33.19 biotech drugs in history, 00:13:35.07 but there are many others as well 00:13:37.08 and they've been, as we can see in this slide, 00:13:39.00 been used for all kinds of cancers. 00:13:41.08 And, not just cancer, 00:13:43.01 but many people have different... 00:13:44.27 of what's called... 00:13:46.13 an eye disease called macular degeneration, 00:13:48.09 where you get blood vessels 00:13:50.02 growing into the back of the eye 00:13:51.21 causing hemorrhage. 00:13:53.11 And, before this, the only way to treat them 00:13:55.01 was to use lasers to do what's called photocoagulation. 00:13:58.15 Now, you can use these inhibitors 00:14:02.01 like Eylea or Lucentis or Macugen 00:14:04.25 to actually stop the blood vessels from growing 00:14:07.16 and even reverse macular degeneration. 00:14:10.01 What's happened is angiogenesis, 00:14:14.01 this whole area 00:14:15.25 has become a quite large area. 00:14:17.19 Now, about 20 million patients 00:14:19.05 have been treated with angiogenesis inhibitors 00:14:21.07 and the FDA has said that there are four kinds of ways of treating cancer: 00:14:25.23 angiogenesis treatment, 00:14:27.02 chemotherapy, 00:14:28.18 surgery, 00:14:29.22 and radiation, 00:14:31.05 and sometimes these are used together. 00:14:33.04 But it also seemed to me that not only might this be useful... 00:14:36.06 the controlled release systems for angiogenesis, 00:14:38.06 but they might be useful... 00:14:40.08 studies... 00:14:42.17 but they might be also useful in their own right, 00:14:44.25 for delivering all kinds of drugs. 00:14:48.18 And, as a proof of principle, Larry Brown, 00:14:50.20 one of my graduate students, 00:14:52.12 just took a molecule, insulin, 00:14:54.06 and again I'm simplifying this, 00:14:56.12 it was actually his whole doctoral thesis, 00:14:58.24 but he put insulin in these pellets, 00:15:00.17 designed a certain way, 00:15:02.28 and was able to get three months release 00:15:06.06 of a fairly large molecule. 00:15:08.07 So, we thought, both Dr. Folkman and I, 00:15:10.16 that this might be, you know... 00:15:12.22 really open up the door 00:15:17.18 to all kinds of new delivery systems. 00:15:19.20 So, I was working at Children's Hospital 00:15:21.04 when I started this work 00:15:23.06 and Dr. Folkman said to me one day, 00:15:24.25 he said, "Bob, we should file for a patent on this." 00:15:27.06 And, it's interesting, 00:15:29.08 I'd never had a patent before at the time, 00:15:31.14 and Dr. Folkman actually said 00:15:33.13 the entire Children's Hospital never had a patent at the time. 00:15:36.02 So, we worked with a lawyer and filed the patent, 00:15:39.09 and five years in a row 00:15:41.00 the patent examiner turned it down 00:15:43.03 and, you know, we felt he didn't understand it, 00:15:44.23 but it really didn't matter. 00:15:46.02 The patent examiner was the one calling the shots. 00:15:48.08 So, the lawyer said to me around 1982, 00:15:51.17 we started this process in 1976, 00:15:54.10 the lawyer said to me, he said, 00:15:55.21 "Bob, you know, you're wasting a lot of money for the hospital, 00:15:57.22 you should just give up." 00:15:59.14 But, I don't like to give up, 00:16:01.07 so I was thinking, 00:16:02.25 how could we convince the examiner, 00:16:04.29 you know legally of course, 00:16:07.05 that the patent... you know that this was novel. 00:16:10.08 And I thought, you know, when I first started talking about this work 00:16:13.27 everybody told me it was impossible, it couldn't work. 00:16:16.10 I remember getting my first nine grants turned down. 00:16:19.29 There was just this enormous skepticism 00:16:22.03 about whether it could work, 00:16:23.18 and I wondered whether anybody ever wrote anything down. 00:16:26.06 So, I actually did what's called the science citation search, 00:16:29.12 meaning that I could go back to our original paper, 00:16:31.08 which we wrote in Nature in 1976, 00:16:33.27 and see who wrote stuff about it 00:16:35.13 and what they said, 00:16:37.05 and it was actually fascinating. 00:16:38.29 I found a number of quotes, 00:16:40.25 but this one in particular was very useful, 00:16:42.25 and I'll just read this. 00:16:44.25 It was by five of the leading polymer scientists in the world, 00:16:48.10 and what they said, 00:16:50.15 and they were describing this field is, 00:16:52.04 "Generally the agent to be released 00:16:53.23 is a relatively small molecule 00:16:55.13 with a molecular weight no larger than a few hundred. 00:16:58.16 One would not expect that macromolecules, 00:17:01.02 e.g. proteins, 00:17:02.29 could be released by such a technique 00:17:05.01 because of their extremely small permeation rates 00:17:07.14 through polymers. 00:17:09.01 However, Folkman and Langer 00:17:10.28 have reported some surprising" 00:17:12.14 ... that surprising word is a very good word for a patent examiner... 00:17:16.14 "have reported some surprising results 00:17:18.09 that clearly demonstrate the opposite." 00:17:20.20 So, I showed this to our lawyer 00:17:22.13 and he was very excited. 00:17:23.22 He said, "I'm gonna fly down to Washington 00:17:25.05 and show it to the examiner." 00:17:26.24 And he did, and the examiner said, 00:17:28.24 he said, "I had no idea". 00:17:30.08 He said, "I'll tell you what, 00:17:31.25 I will allow this patent if Dr. Langer 00:17:33.22 can get written affidavits from these five authors 00:17:35.27 that they really wrote that quote." 00:17:38.07 So, I did that. 00:17:39.15 I wrote each of them, and they were all kind enough to write me back 00:17:41.05 that they really did write that, 00:17:43.04 and then we got this very broad patent issued, 00:17:46.01 and that was the first one in the history of Children's Hospital 00:17:49.00 and then the hospital would license that out 00:17:51.22 to other people 00:17:53.18 and, today, many companies have developed all kinds of products 00:17:55.28 based on either the patent or these ideas, 00:17:59.10 and these are just a few of them shown here. 00:18:01.25 For example, if somebody has certain peptides 00:18:07.00 that you might want to take, l 00:18:10.00 ike leuprolide acetate... 00:18:12.00 people have not figured out ways to give it orally 00:18:14.01 or by skin patches because the molecule is just so big. 00:18:18.01 If it's injected it's destroyed right away. 00:18:20.15 So now, what happens is 00:18:23.14 it's put in little microspheres, just like I showed you, 00:18:25.22 that are injected under the skin 00:18:27.16 and actually deliver the drug for four months. 00:18:29.25 And there are many other too. 00:18:31.24 This is just pictures of different ones. 00:18:33.27 There's systems that can deliver 00:18:37.07 anti-schizophrenic drugs for several weeks. 00:18:40.00 There's systems that can deliver drugs 00:18:41.22 to treat alcoholism for a month, 00:18:43.16 to treat narcotic addiction for a month, 00:18:45.21 so you give the injections once a month, 00:18:47.23 to treat type 2 diabetes, 00:18:50.18 for where you give an injection once a week, 00:18:52.23 and this is really just the start of this. 00:18:54.17 There are many, many others 00:18:56.12 that end up affecting the lives of tens of millions 00:18:58.23 of patients around the world. 00:19:01.03 So, so far what I've done is I've gone over, now, 00:19:04.20 how you can take systems like this, 00:19:07.21 deliver them at steady rates 00:19:09.21 or maybe slightly decreasing rates 00:19:12.09 over long periods of time. 00:19:14.01 And so, what these systems allow you to do 00:19:16.14 is it allows you to control the level of the drug 00:19:18.24 and the duration of the drug, 00:19:20.24 and generally these are given intramuscularly or subcutaneously. 00:19:25.04 But we want to even go further, 00:19:26.16 and now I'd like to sort of turn to nanotechnology 00:19:29.10 and even some of the systems for the future, 00:19:31.15 or at least that I hope will be the future. 00:19:34.07 So, could you actually make these... 00:19:36.21 use a lot of the same principles... 00:19:38.14 but make these even smaller, 00:19:40.29 so that you could put them in the bloodstream 00:19:42.22 so they'll be able to go around the bloodstream 00:19:44.11 and find their way to particular cells 00:19:46.09 that you want them to go to. 00:19:48.24 How could you do this? 00:19:51.04 So, what we published, 00:19:53.23 this was about 20 years ago, 00:19:55.29 it was one of the earliest papers on medical nanotechnology, 00:19:59.07 is that the challenge is 00:20:01.10 if you make a particle 00:20:03.05 that you want to put drugs in, 00:20:04.20 and you inject it into the bloodstream, 00:20:06.20 almost always what will happen quite quickly 00:20:08.29 is macrophages, cells in the body, 00:20:11.01 will eat those particles. 00:20:13.04 So, what we had to do 00:20:14.20 was figure out a disguise for those particles, the nanoparticles, 00:20:17.26 so that that wouldn't happen, 00:20:19.11 and of course you need to get past the macrophages. 00:20:21.09 In a way, you can think of the macrophages 00:20:23.06 as kind of like the guardian. 00:20:24.23 If you could get past the macrophages 00:20:26.20 then maybe you can get to the cells you want, 00:20:28.11 if you can figure out the right other things 00:20:30.14 to add to the nanoparticle. 00:20:33.04 So, what we did is we made this disguise. 00:20:35.06 We picked a substance called polyethylene glycol 00:20:38.28 that we could add to the outside of the nanoparticles, 00:20:42.21 and our thinking was 00:20:44.19 is that takes up a lot of water, 00:20:46.23 and if the cell sees water, well, 00:20:48.22 it's used to seeing water 00:20:50.22 and it doesn't eat water up. 00:20:52.13 So, that was our hope, 00:20:54.01 that we could disguise these particles, 00:20:56.08 you know, to do that. 00:20:58.07 And then what we did 00:21:00.06 is Omid Farokhzadb, who was a postdoctoral fellow in our lab, 00:21:03.10 actually now is a clinician 00:21:06.07 and associate professor at Harvard Med. School, 00:21:08.24 took it even one step further. 00:21:11.00 We not only put the PEG on the nanoparticles, 00:21:13.08 but he put targeting molecules on 00:21:16.12 that might go to a tumor, for example. 00:21:18.07 Examples could be antibodies or aptamers 00:21:21.08 or things that could target things. 00:21:23.15 I realize sometimes 00:21:25.08 I don't always explain this perfectly, 00:21:27.13 but I was fortunate that 00:21:29.25 about a year or two ago Nova, the TV show, 00:21:31.21 they came to our lab and they filmed some of what we did, 00:21:34.03 and they made this video 00:21:36.02 that explains it much, much better than I do, 00:21:37.12 so I thought I'd... 00:21:39.02 I've gotten their permission to use that video, 00:21:40.16 so I thought I'd use it and show it to you 00:21:42.23 because I think it explains pretty well 00:21:44.22 how this kind of technology works. 00:21:46.24 So, let me just go to that video. 00:21:48.27 "He starts with a nanoparticle of anti-cancer drugs. 00:21:53.15 That gets incased in a plastic 00:21:55.14 that releases the drug over time. 00:21:57.28 That, in turn, gets a special wrapping 00:22:00.04 that disguises the package as a water molecule, 00:22:03.08 to fool the body's immune system. 00:22:05.22 And, last but not least, 00:22:07.26 the address where it should be delivered, 00:22:10.09 a key that will only fit the lock of cancer cells." 00:22:20.10 I should say that a lot of the clinicians 00:22:22.03 I work with tell me 00:22:24.01 it doesn't blow the cell up quite that way, 00:22:26.05 but I think it gives you an idea of what's happening. 00:22:28.19 And, then, what we did... 00:22:33.14 we actually, Omid and I got involved in even helping set up a company 00:22:37.17 that created a whole manufacturing plant to make nanoparticles, 00:22:40.13 which was a huge challenge, 00:22:43.02 and this is just a picture of that plant, 00:22:45.22 and then moved it from test tubes 00:22:48.21 to small animals 00:22:50.01 to large animals 00:22:51.16 to humans, where it is now. 00:22:53.24 And, it's been interesting and exciting, the compound... 00:22:58.10 one of the first compounds is one called BIND-014, 00:23:00.19 which is basically putting Docetaxel, 00:23:03.20 a common anti-cancer drug with some side effects, normally, 00:23:08.20 in the nanoparticles. 00:23:10.28 And what happens is, 00:23:12.15 this is a semi-log plot, 00:23:14.22 but if you look at the red dots and the red curve, 00:23:17.16 if you put the drug in by itself, 00:23:22.07 it goes to zero very, very quickly. 00:23:24.22 But, if you put just the same amount of drug 00:23:26.24 in the nanoparticle 00:23:28.20 it lasts for days, so it keeps pounding the tumor. 00:23:32.06 The consequence of that maybe 00:23:33.21 can be seen even better by looking at human pharmacokinetic data, 00:23:37.22 and in particular the thing to focus on might be, 00:23:41.19 let's look at the dose just to make these absolutely equivalent, 00:23:45.08 of BIND-014 at 30 mg 00:23:49.07 and Taxotere, the same drug, also at 30 mg. 00:23:52.17 Well, what you see when you look at the third panel, 00:23:55.12 the area under the curve, 00:23:57.13 is you could take the same drug 00:23:59.09 but we've changed it dramatically. 00:24:01.11 When you put it in the long-circulating nanoparticle, 00:24:03.15 the area under the curve is 127,280. 00:24:07.16 When you don't put it in the nanoparticle it's 512. 00:24:10.25 So, you get something that's almost 00:24:13.04 250 times higher 00:24:15.18 when you put it in the nanoparticle, 00:24:17.05 so it's just pounding the tumor, 00:24:19.05 and it's early yet but the consequence of this, 00:24:21.15 this is from some papers 00:24:23.28 we published in Science Translational Medicine, 00:24:26.21 show that there's at least some hints of efficacy. 00:24:31.24 If you look a the top CAT scan, 00:24:34.07 you look at the patient's lung before 00:24:36.17 and then maybe 42 days after. 00:24:38.27 If you look at the bottom, that's another example 00:24:41.14 where you look at the lung before and 42 days after, 00:24:44.18 and notice that the nodules, that are circled in yellow, 00:24:48.22 go away after this treatment. 00:24:51.06 Now, of course, what's happening is hundreds of patients 00:24:53.25 are being done and we'll get a better feel for where this may work, 00:24:57.13 where it may not work, 00:24:59.10 but I think it's the dawn of a whole new era 00:25:00.27 of using nanotechnology to deliver drugs. 00:25:04.09 This is a small molecule drug. W 00:25:06.08 e're also using nanotechnology 00:25:08.01 in this form and in the form of different lipid systems, 00:25:11.00 to deliver DNA, 00:25:13.05 to deliver siRNA, 00:25:15.18 to deliver mRNA, 00:25:16.29 and all these things I think are 00:25:18.21 a very, very exciting opportunity for the future 00:25:21.12 and, again, I think the problems are still unsolved, 00:25:23.22 but I hope that this is the start 00:25:26.07 of solving some of them 00:25:29.12 and bringing them into patients. 00:25:31.14 I want to mention one other idea 00:25:33.11 that also might be somewhat futuristic, 00:25:35.24 but I think also will be a part 00:25:38.08 of how drug delivery can change 00:25:40.05 how people do things. 00:25:42.16 I was watching this television show 00:25:44.17 a number of years ago 00:25:46.11 about how they made microchips in the computer industry, 00:25:49.03 and I thought when I watched it, 00:25:50.23 you know, that would be a great way 00:25:52.01 to make a drug delivery system. 00:25:53.12 Now, of course, I've spent 34 years of my life 00:25:55.25 working on drug delivery systems, 00:25:57.10 so somebody might think, you know, 00:25:59.00 any TV show I say I might think that, 00:26:00.19 and they may be right. 00:26:03.09 But, I just want to show the idea I had. 00:26:07.27 The idea I had when I watched the show 00:26:10.01 was that maybe what you could do 00:26:13.02 is make a chip, 00:26:15.06 but rather than put electrical things in it, 00:26:17.05 you could also put chemical things in it, 00:26:19.05 and what we see in this chip, 00:26:21.02 this is just a schematic 00:26:24.23 and it's a cut-away where we're just looking at... 00:26:27.05 the chip itself is fully whole 00:26:29.07 and I'll show you some in a minute... 00:26:31.12 but, when you look at it, 00:26:33.03 we have these wells 00:26:34.18 where you could put active substances in. 00:26:36.22 So, you could put different doses of the same substance in, 00:26:39.15 or your could literally, theoretically, 00:26:41.12 have what we call a pharmacy on a chip. 00:26:42.24 You could put multiple drugs in 00:26:44.21 and have them come out whenever you want, 00:26:46.24 and they're really stored in these chips indefinitely. 00:26:49.12 But, notice that the chips 00:26:51.03 have a cover which looks like a gold cover here, 00:26:53.09 it could be gold or it could be a platinum alloy, 00:26:57.16 and they are hermetically sealed 00:27:00.03 and the drugs are underneath them 00:27:02.09 but, as I'll show you, when we apply, 00:27:04.11 by remote control... 00:27:06.25 we can actually take those covers off 00:27:09.29 and the drug could come out 00:27:12.01 whenever we want to make it do so. 00:27:13.24 Let me just show you some of the work that was done. 00:27:16.17 I did this work with my collaborator 00:27:18.09 Michael Cima at MIT, 00:27:19.25 and we had a very good graduate student 00:27:21.14 John Santini, 00:27:23.23 and we made these chips using techniques 00:27:25.22 that were never used in the pharmaceutical industry, 00:27:27.26 but using techniques 00:27:29.19 that we adapted from microelectronics. 00:27:32.02 And here you see in the top two pictures, 00:27:36.26 which is both a top view and a bottom view 00:27:38.28 of one of these chips, 00:27:40.25 and it's got something like 34 wells in it, 00:27:43.09 and these are tiny little wells, 00:27:46.04 but they don't have to be. 00:27:47.20 They can be bigger or smaller, 00:27:49.08 and they don't have to be short, flat chips. 00:27:51.03 We've actually made sort of cylindrical chips 00:27:52.23 that could be injected into the body and so forth, 00:27:55.08 but just to give you a size idea, 00:27:57.27 here's a United States dime. 00:27:59.20 Let me just show you how they work. 00:28:02.00 So, here's a well, it's covered with the metal 00:28:04.11 and you can see this, 00:28:06.02 this is a scanning electron micrograph of it, 00:28:07.19 it would actually stay in the body like this for years, 00:28:09.21 but if you come along 00:28:11.22 and just give one volt by remote control, 00:28:15.21 in nanoseconds the cover comes off 00:28:18.07 and you see that happening here. 00:28:20.27 And when the cover comes off the drug comes out. 00:28:24.01 So, this is from another paper 00:28:25.28 we wrote in Nature, 00:28:27.26 where we put different amounts of drug 00:28:29.15 in different wells 00:28:31.09 and the drug comes out at different times. 00:28:32.18 This is in test tubes, in vitro. 00:28:35.00 Along the lines of the pharmacy on a chip idea, 00:28:38.19 we put multiple model drugs in 00:28:41.26 and triggered release at different times 00:28:43.21 and that's shown here. 00:28:45.23 But over time, 00:28:47.15 what John and Mike 00:28:49.21 and a little company, Microchips, that we were involved with did, 00:28:52.27 is take this all the way from test tubes, 00:28:54.22 to small animals, 00:28:56.06 to large animals, 00:28:57.17 to humans. 00:28:59.03 And what I'm going to mention now 00:29:00.22 might almost sound like space-age medicine, 00:29:02.06 but we actually did it. 00:29:03.24 What was done is you put the chips in the human body 00:29:05.11 and you can communicate with them 00:29:07.02 over a special radiofrequency 00:29:08.24 called the Medical Implant Communications Service Band. 00:29:11.22 It's been approved by both the FCC and the FDA, 00:29:15.24 and sometimes people think about tampering, 00:29:17.16 I mean... I doubt that that's going to be a problem, 00:29:21.05 and that should be the biggest problem we'd face, 00:29:22.25 but to that extent 00:29:24.26 we even can have a special computer code 00:29:27.23 that we built in 00:29:29.16 that only the patient or doctor could know, 00:29:31.07 if they want to change or administer the dose. 00:29:33.11 Also, what we have, 00:29:35.14 what we built in is in a bidirectional communications link 00:29:40.04 between the chip itself and the receiver. 00:29:42.09 The receiver, by the way, could be a cell phone, 00:29:45.06 it could be something like this, 00:29:46.25 and it can give you all kinds of information like, did you take the drug? 00:29:49.07 I have to admit, as I've gotten older, 00:29:50.25 that's something I sometimes forget about, 00:29:52.27 so, did you take the drug, the battery life, and so forth. 00:29:56.25 Okay, let me tell you about the clinical trial that we did. 00:29:59.01 We did 8 patients, 00:30:01.10 this was done in Denmark, 00:30:03.23 and thinking about what kind of trial we wanted to do, 00:30:06.20 one of the things that happened as we'd send our grants in 00:30:09.07 is people would keep telling us 00:30:11.09 why our approach wouldn't work, 00:30:12.26 and the biggest reason they told us it wouldn't work 00:30:14.16 is you'd get what's called fibrous encapsulation 00:30:16.24 around the chip and that would mean that molecules 00:30:18.29 couldn't diffuse through that fibrous capsule 00:30:22.00 and wouldn't get into the bloodstream. 00:30:23.23 So we felt, let's give ourselves a hard test 00:30:26.02 to really see if they're right. 00:30:27.24 Let's give us... 00:30:30.00 let's pick a large molecule, 00:30:31.23 and if that got through certainly 00:30:33.10 we'd expect smaller molecules to get through. 00:30:35.04 So, what we chose was parathyroid hormone, 00:30:37.06 which is a large peptide, 00:30:39.18 and it's used in osteoporosis, 00:30:42.17 and we also chose it because we felt 00:30:45.07 this is a place where someday, maybe, 00:30:47.04 we could even make an impact. 00:30:49.09 In the case of osteoporosis, 00:30:51.04 women are supposed to take parathyroid hormone 00:30:53.16 by injections once a day, 00:30:55.16 but one of the additional problems with this 00:30:58.04 is that the women don't do it. 00:31:01.14 There's actually a 77% dropout rate 00:31:05.10 of the women who have to take these shots. 00:31:07.16 And you can't take it continuously, either, 00:31:09.11 with the little microspheres. 00:31:11.04 Continuous is bad 00:31:13.02 because that'll actually cause bone resorption. 00:31:14.29 So, you really have to give an injection once a day apparently, 00:31:18.10 and that just has been fraught with problems. 00:31:21.22 So, what was done is the trial is a small office procedure 00:31:25.01 in the doctor's office to do the implant, 00:31:27.05 and the results were very positive. 00:31:28.28 The women preferred this to some of the other methods. 00:31:32.03 You got the same pharmacokinetics, 00:31:33.20 I'll go over what I mean by that 00:31:35.19 in a second and show you some of the data, 00:31:38.01 with less variability, 00:31:39.23 which may not be important in this case 00:31:41.17 but could be important in others, 00:31:43.10 and the three major measures 00:31:45.13 of whether you're treating this disease 00:31:49.01 are Ca, PINP, and CTX, 00:31:51.23 and they were the same as daily injections. 00:31:54.05 Just to show you the data, on the next to final slide, 00:31:58.20 the top curve is human data 00:32:02.04 where what you see is data 00:32:05.01 for the woman at day 60, 68, 76, and 84. 00:32:09.17 Notice how the points really are pretty much 00:32:11.26 superimposed on top of each other. 00:32:13.26 It's very reproducible. 00:32:15.06 On the bottom right, 00:32:17.06 what you see are pictures of the chip itself. 00:32:19.17 In this case what we did is we made these little chips 00:32:23.04 and in them we also put electrical components, 00:32:26.25 a battery, a power source, 00:32:31.26 and even a computer program. 00:32:33.18 What you can't see on these chips 00:32:35.12 is on the back end of it 00:32:38.10 we actually built in an antenna, 00:32:41.06 we imprinted an antenna right into the back end of the chip, 00:32:44.01 and that's how you can communicate with it. 00:32:45.27 You can communicate with it by, depending on your device, 00:32:48.20 it could be a cell phone, 00:32:50.11 it could be something like this, and so forth. 00:32:54.15 As you can also see from these pictures, 00:32:56.17 the amount of fibrous encapsulation... 00:32:58.15 it's not zero, we definitely get some, 00:33:00.10 but it's very small 00:33:02.17 and obviously it's small enough 00:33:05.13 so that it has no effect on the release rate of this large molecule 00:33:08.11 and it's also, I'd say maybe 1/20th of what a pacemaker gets. 00:33:12.06 We also did histology, 00:33:14.02 that's actually taking sections of the tissue 00:33:16.10 and seeing whether you got inflammatory cells. 00:33:20.02 And, in the panels on [the left] 00:33:22.02 we see that there are no inflammatory cells 00:33:24.07 over the implant. 00:33:27.02 So, it ended up being very safe, 00:33:30.00 and effective, 00:33:31.25 and now we're moving this project in at least three directions. 00:33:34.19 One is we're making a two-year device. 00:33:38.02 Two, we've been working with the Gates Foundation, 00:33:41.15 where they've been interested in a... 00:33:44.01 for family planning in the third world, 00:33:46.13 that you could have a contraceptive device 00:33:48.14 that you could turn on and off whenever... 00:33:50.07 a woman could turn on and off whenever she wanted. 00:33:51.27 That can't be done with conventional technology, 00:33:54.09 but with this you can, 00:33:56.07 so we're actually designing a 16-year device 00:33:58.20 that could be turned on and off 00:34:00.28 whenever the woman wanted it to. 00:34:03.05 And finally, what we're doing... 00:34:05.02 one of my colleagues, Michael Cima, 00:34:06.23 he's been putting little sensors in these chips, 00:34:08.21 and someday our hope is we'll be able 00:34:10.21 to sense signals in the human body 00:34:12.20 and then tell the chip how much to deliver 00:34:14.17 in response to those signals. 00:34:16.21 So, that's what I wanted to largely go over in this lecture. 00:34:19.24 Just to summarize where we are, 00:34:22.01 in the first lecture I've gone over 00:34:24.25 advances in controlled release technology 00:34:26.18 and gave an overview. 00:34:28.13 Here I've given some examples of both current and possibly future technology. 00:34:32.23 And, in my third lecture, 00:34:34.11 I'll go over biomaterials and biotechnology 00:34:36.20 and talk about how one might use... 00:34:38.22 create new biomaterials for drug delivery, 00:34:40.17 and also how one might use biomaterials 00:34:42.17 to help lay the foundation for tissue engineering. 00:34:45.16 Thank you.