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Nanotechnology—The Opportunity For Cancer Treatment
Chemical Heritage Foundation
Joseph Priestly Society Seminar
January 8, 2009
Bob G. Gower
A few years ago, Rick Smalley gave a talk which I think perfectly described the potential for nanotechnology. Rick Smalley had the right background for such a talk since he is credited, along with 2 associates, with the discovery of buckyballs, won the Nobel Prize in Chemistry in 1996 for that discovery, and led most of the breakthrough research on fullerene carbon nanotubes prior to his death 3 years ago. Rick's name is on more than 80 patents in this critical new area.
In that talk, Rick said that, only a few years earlier, many physical scientists at universities, those in chemistry, physics and related fields, had become concerned that most of the great discoveries had already been made. There were still plenty of incremental improvements to be made, but great scientists want to do more than just improve. They want to discover new things. But, as Rick said, there can only be so many Laws of Thermodynamics, Avagadro's number, etc. to discover, and it appeared that most were already known.
So Rick said that a lot of his associates around the world had become a bit discouraged. He used the analogy that it appeared that the physical sciences had finished college, completed graduate school and even completed post-doctoral work. The physical sciences appeared to have become quite mature.
But then, Rick said, the advent of nanotechnology had changed everything. He said that, with nanotechnology, it was now like the physical sciences were just graduating from High School. The best was still to come as a result of nanotechnology.
Nanotechnology is being discussed everywhere today, certainly in scientific journals, but also in newspapers, on the Internet, and on TV. Still, it is not always clear what is meant, what the real benefits are, or how nanotechnology works.
Nanotechnology is a new field only to the extent that it is an extension of physics and chemistry. We already have a great base of laws and knowledge for chemistry and physics, and nanotechnology builds on that base to open new horizons.
Nanotechnology means that what we are working with is very small. It generally means that we are working on the molecular level or, at least, in sizes of a few nanometers. That, of course, is not new but has existed from the beginning of time. Most action within our bodies, within plants is on the molecular basis, or certainly on a nano-size basis.
What is new is that we are now learning some of what has always been practiced in nature. What is new is that we are learning to manipulate nanoparticles and even molecules to achieve great benefit.
Rick Smalley led the research in a major section of nanotechnology, buckyballs and carbon nanotubes. Buckyballs are all-carbon structures which look, on a greatly magnified basis, much like a soccer ball. When the buckyball structure was discovered in 1985, it became the third form of carbon to go along with graphite and diamond. Carbon nanotubes are related to buckyballs. They are also structures of carbon and, on a magnified basis, look like a cylinder of rolled up chicken wire, which is capped on each end with half of a buckyball structure.
The structures are interesting, and the properties are even more interesting. Carbon nanotubes are electrically conductive, comparable to copper and silicon. They have better heat conductivity along the length of the molecule than any other known material. And they have strength on a molecular basis which is 100 times greater than steel. That presents a lot of opportunity. Rick Smalley and I formed a company in 2000 to try to develop this area.
That company, Carbon Nanotechnologies Inc., has now merged with Unidym Corporation, and Unidym is pursuing several markets. They believe they will have a conductive, transparent film available commercially within the next few months. This is the market for touch screens of all types—computers, games, etc. Currently, indium tin oxide is used to get electrical conductivity in this rather large market. Indium tin oxide is effective initially but can become brittle with use or with temperature variation so that the electrical conductivity is degraded. Carbon nanotubes do not have this problem.
Carbon nanotubes are one of the most exciting things underway in nanotechnology. I expect that they will be used eventually in a wide range of applications, including electronics, ballistics, airplane structures, water purification and energy production. The list of applications is almost endless. Unidym is working with customers around the world in probably 50 distinct end use areas.
But the area I am focusing on, myself, is the use of fullerene carbon nanotubes in therapeutics. I formed Ensysce Biosciences early last year for that purpose. We have put together a substantial patent position and are working with some of the best scientists in the field at M. D. Anderson Cancer Center, Stanford and Rice University.
My interest in this area comes for 2 reasons. The first is that carbon nanotubes appear to have ideal structures to solve certain problems which most therapeutics, and especially those for cancer treatment, now have. And second, the current methods for treating many types of cancer could only be described as primitive, and I hope we can improve on this.
When nanotechnology is referred to relative to therapeutics, it generally means that the active agent is targeted to specific locations in the body and that we are working on the molecular basis or with very small particles, such as, for example, gold nanoparticles.
One major problem for current therapeutics is the difficulty of targeting drug delivery to the location where it is desired. The result of non-targeted delivery is that the drug can be active all over the body. That means that large doses, larger than would otherwise be required, must be used, or that we realize a lot of peripheral damage to otherwise healthy parts, killing healthy cells or causing immune reactions.
A second major problem for therapeutics is delivery of the active agent. This issue is related to the targeting problem but is broader than just that. Currently, we design active drugs and expect them to circulate through the body, pass through barriers such as the digestive system, the cell, and the blood-brain barrier, and still to be active as a drug after doing all that. That is a Herculean assignment, and it is not surprising that many drugs can not effectively do this.
The issue is even more critical for cancer treatment where drugs often do great damage at the wrong locations. We are all aware of the major side effect problems with most cancer drugs. This issue will have to be solved by new delivery agents, materials which will do several jobs—that will direct the drug to the desired location, that will help the active agent get through the barriers, that will protect the drug from degradation during delivery, and, finally, that will release the drug once it is inside the cell or in the preferred location.
We have animal data indicating that carbon nanotubes will do all these things. Major work is still required, and everyone knows how difficult it is to move drugs through animal research, into clinical trials and to pass all the requirements to be approved as a new drug. But the following summary is what is known thus far and suggests unusual promise for therapeutics utilizing carbon nanotubes as delivery agents.
  1. Carbon nanotubes can be modified to circulate well within the body. Such modifications can be accomplished with either covalent or non-covalent bonding. And the modifications can be such that they increase or decrease circulation time within the body. Many current drugs, especially for cancer treatment, circulate for only short times before excretion. This can be a significant limitation.
  2. Carbon nanotube drug complexes are readily excreted from the body. Long-term data will be required, but initial studies indicate acceptable excretion.
  3. Carbon nanotubes show no significant toxicity when they have been modified so as to be soluble in aqueous, body-type fluids.
  4. Carbon nanotubes readily enter cells.
  5. A wide range of active agents can be attached to carbon nanotubes and carried into cells along with the nanotubes. It appears that stable structures are formed which protect the active agents during transport. The active agents which can be carried by carbon nanotubes include many cancer drugs and also include short interfering RNA, which may be the hottest current area within therapeutics research.

    These last 5 points are specific for cancer.

  6. Carbon nanotubes can be modified so as to target cancer cells. In general, cancer cells have unique molecular characteristics on the cell surface, and this will attract molecules which have been modified in specific ways.
  7. Cancer cells in tumors are larger than normal cells and also exhibit leakage. This means that there is both leakage out of and leakage into the cells. Large molecules which circulate slowly can leak into and accumulate in the cancer cells. Carbon nanotubes carrying active agents have been demonstrated in animal studies to do this and can be modified to increase circulation time and, therefore, the time for leakage into tumor cells.
  8. For cancer treatment, the active agent can be released once inside the cell, therefore returning that material to its active form. That means that the critical agent would be basically inactive during delivery but then become active inside the cancer cell. Cancer cells generally have a slightly lower pH than healthy cells, and it is the fractionally higher acidity which facilitates the release of the drug inside the cancer cells.
  9. Researchers have also used carbon nanotubes to deliver the precursors of an active drug, which they call a prodrug. The prodrug is then converted to its active form after it is inside the cancer cells. Researchers at MIT and Stanford have demonstrated this with cisplatin, a common cancer drug. Using carbon nanotubes as the delivery agent, the prodrug is delivered with the platinum in its inactive oxidation IV state and then is reduced to the active oxidation II state inside the cancer cell. So, the active agent does not come into contact with other locations. It becomes active only inside the cancer cell.
  10. In one way of treating cancer, carbon nanotubes can even function as the active agent, themselves. They can enter cells and then be treated with external electromagnegic radiation such as radio frequency or near-infrared to heat the carbon nanotubes and kill the cancer cells.
You certainly can see why there is excitement in this area. The potential is substantial. It could be transforming for cancer treatment.
Ensysce Biosciences is focused entirely on the use of carbon nanotubes in therapeutics for cancer treatment. We have put together a strong intellectual property portfolio with a combination of exclusive and non-exclusive licenses for a total license package which includes more than 80 issued patents and numerous additional patent applications. Putting together the patent portfolio, which covers the broad field of therapeutic applications, was a critical step. If therapeutics utilizing carbon nanotubes become important, Ensysce will be a major player.
Ensysce intends to move this research forward rapidly through collaboration with universities and medical centers. There are outstanding scientists at these locations who already have experience both with carbon nanotubes and therapeutics. So, we are funding programs at these institutions and have the right to license technology which is developed. Ensysce will do the development work.
Ensysce is funding research in 3 areas initially.
  1. Delivery of short interfering RNA (siRNA) for cancer treatment. This program is a joint effort with M. D. Anderson Cancer Center and Rice University. It has long been known that siRNA type molecules occur naturally in the body, but it was only recently learned that they can silence gene messages and have substantial control over disease development.

    Short interfering RNA structures can interfere with the delivery of messages and, therefore, prevent the malfunction of genes which leads to diseases. The interest in siRNA research has exploded in the last few years, and major pharmaceutical companies have spent billions of dollars in this area. But there is one issue which has not been resolved, and that is delivery of siRNA to the right place and without degradation. siRNA must be targeted to the desired location, protected in transport by the delivery agent, and then released inside the cell. The research at M. D. Anderson has already shown in animals that carbon nanotubes facilitate the delivery of siRNA into cancer cells and that siRNA suppresses the messages which cause cancer. Those are major steps.
  2. Delivery and improved performance of off-patent cancer drugs. This work is being conducted at Stanford University and their related Medical School and is designed to reduce the side effects of 2 well established cancer drugs, taxol and doxorubicin. The work in animals already shows far more effective delivery, indicating that much lower dose will be possible. If there is continued success here, carbon nanotubes could become the way to deliver a host of existing drugs more effectively and with reduced side effects. For major pharmaceutical companies with drugs going off patent, this may be a way to extend the life of a drug with new patents while, at the same time, developing more effective products.
  3. Use of carbon nanotubes to deliver alpha-emitting radiation. External radiation is, of course, a common treatment for cancer. There also are cases where radiation systems are injected into a tumor and even where they are part of a therapeutic. To my knowledge, in the therapeutic case, this has only been done with beta-emitters. The problem with beta emission is that it extends for relatively long distances and can cause substantial peripheral damage even if the radiation is well directed.

    The preferred case would be to use alpha-emitting radiation and for the radioactive agent to have a short half-life. Researchers at Rice University have learned how to make ultra-short carbon nanotubes which also have holes in the sides of the nanotubes. They can get short half-life alpha-emitting materials to enter the hole of the nanotube and thus be captured. This is an interesting characteristic of carbon nanotubes. They have very strong van der Waals type attraction for many other materials. In this case, the active material enters the hole but can not exit because of these strong forces.

    Two alpha emitters are being worked with, astatine and actinium and meaningful results may be available relatively soon. This is a joint effort of Rice and a major cancer center. The emission from alpha-emitters is only the distance of 2-3 cells, so the potential to kill cancer cells with selectivity is good. The biggest benefit may be that cancer cells will not be able to recognize radiation and adapt to it over time. That would mean that repeated treatments could be done without the cancer being able to make adjustments which allow it to survive.
As we look to the future, we face numerous challenges in our country and in the world—providing sufficient low cost energy, providing adequate water supplies, reducing poverty, producing food, controlling the climate, etc. It is likely that nanotechnology will be critical for all these areas. And I am quite certain of that for medicine. Therapeutics of the future will almost certainly be based on nanotechnology.
I want to close with this quote from Mauro Ferrari. Mauro heads the Alliance for NanoHealth in Houston which includes the University of Texas Health Center and 6 other institutions. He made these comments relative to some therapeutics research very similar to what I have been talking about, "This is next generation nanomedicine. Now, we are engineering sophisticated nanostructures to elude the body's natural defenses, to locate tumors and other diseased cells, and to release a payload of therapeutics, contrasting agents, or both over a controlled period. It's the difference between riding a bicycle and a motorcycle."
I agree with that description, and it speaks well for the future of therapeutics.
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