Session 8: 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.