Nanotechnology and the Quest for the Ultimate Drug-Delivery System

The story is told of a flea and an elephant that crossed a bridge together. After reaching the other side, the flea proudly says to the elephant, "Man! We sure did shake that bridge, didn't we!" It is not often that something small can claim to shake a bridge, but recently things that are very small, nanosized materials and systems for example, have begun to cause quite a stir among pharmaceutical scientists.

Melgardt M. de Villiers, PhD

A review of papers indexed in Chemical Abstract Services that refer to nanoparticles revealed that the first paper to use the term was Kopf et al.'s 1976 "Study on Micelle Polymerization in the Presence of Low-Molecular-Weight Drugs. 1. Production and isolation of nanoparticles, residual monomer determination, physical-chemical data," published in Pharmazeutische Industrie. This was the only reference to nanoparticles that year. The number of references increased to four in 1980, 15 in 1985, 39 in 1990, and 478 in 1995. At that point, industry seemed to move into the age of nanotechnology as it is known today and as demonstrated by the huge increase in references from 3185 in the year 2000, to 17,688 in 2005, and 21,553 in 2007. Although the nanotechnology "flea" took a while to start moving the bridge, it is now quite the bridge-shaker.

Pharmaceutical scientists commonly accept Richard Feynman's 1959 talk at the American Physical Society annual meeting as the birth of nanotechnology. "I would like to describe a field, in which little has been done, but in which an enormous amount can be done in principle," he said. "This field is not quite the same as the others in that it will not tell us much of fundamental physics (in the sense of, "What are the strange particles?") but it is more like solid-state physics in the sense that it might tell us much of great interest about the strange phenomena that occur in complex situations.... What I want to talk about is the problem of manipulating and controlling things on a small scale."

In this seminal talk, Feynman proposed the potential to manipulate matter at the atomic scale. Inspired by this notion, the term nanotechnology was coined by Tokyo Science University Professor Norio Taniguchi in 1974 to describe the precision manufacture of materials with nanometer tolerances and was unknowingly appropriated by Drexler in his 1986 book, Engines of Creation: The Coming Era of Nanotechnology.

In Engines of Creation, Drexler extrapolates a world from the bottom up where we can build atom by atom using a process called molecular nanotechnology. Drexler looked at the proteins and enzymes operating inside humans and saw tiny biological machines that could turn genes on and off, thereby creating just about anything inside the human body—including more of themselves. Drexler's vision was extraordinary. If we can replicate biological machines to produce manmade molecular assemblers, we may be able to cure any disease or disability.

Initially, his vision was well supported, including by President William J. Clinton who proposed a nearly $500 million per year National Nanotechnology Initiative (NNI) to fund nanotech work in 2000. In announcing this initiative, Clinton said that one day such systems could lead to a "100% cure and prevention rate for every kind of cancer."

Feynman and Drexler's vision, however, also brought raised fear of these assemblers, which had the potential to become nanosize robots, or nanobots, that could turn into grey goo. Grey goo is also known as ecophagy, a hypothetical end-of-the-world scenario involving molecular nanotechnology in which out-of-control self-replicating nanobots consume all living matter while building more of themselves.

The popularity of Drexler's ideas should have made the fear of runaway nanobots a public issue more than a scientific problem, but statements by prominent scientists in support of this doomsday vision has all but killed Feynman and Drexler's ideal for molecular nanotechnology and the promises it holds for repairing human cells and extending lifespans. For example, Sun Microsystems Co-founder Bill Joy wrote in a landmark Wired magazine essay in 2000, "Why the Future Doesn't Need Us," that "An immediate consequence of the Faustian bargain in obtaining the great power of nanotechnology is that we run a grave risk—the risk that we might destroy the biosphere on which all life depends."

Another attack came from Richard Smalley, Rice University's 1996 Nobel Laureate in chemistry. At first, he supported the benefits of a world in which "We learn to build things at the ultimate level of control, one atom at a time." In 2001, he changed his mind when he said in a Scientific American article that, "such control wouldn't really be possible because the fingers we'd need to handle such a delicate task are too big."

So where does this leave nanotechnology? Perhaps the most widely accepted definition of nanotechnology to date appears on NASA's website: "The creation of functional materials, devices and systems through control of matter on the nanometer length scale (1–100 nanometers), and exploitation of novel phenomena and properties (physical, chemical, biological) at that length scale." This definition seems to claim that nanotechnology is still an immature technology that for the most part refers to research into systems at the scale of 100 nm or less using known experimental techniques. In other words, although there has been a lot of buzz about advances in nanotechnology, an awful lot of the "breakthroughs" seem to simply be about taking anything "small" that sounds like science fiction and building up some buzz around it.

This is especially true for nanotechnology as it deals with drug delivery where many of the current "nano" drug- delivery systems evolved from known drug-delivery systems that happen to be in the nanometer range such as liposomes, polymeric micelles, nanoparticles, dendrimers, and nanocrystals. In a 2007 editorial in the Journal of Controlled Release, Kinam Park, a Showalter Distinguished Professor of biomedical engineering and professor of pharmaceutics at Purdue University, criticized this approach when he wrote: "In drug delivery, however, describing nanotechnology based on a size limit is pointless because the efficiency and usefulness of drug-delivery systems are not based only on their sizes."

What then are the properties of the ideal drug-delivery system developed by nanotechnology? The answer is the same properties that would make a drug-delivery system developed by any technology ideal. These properties were best described by Joseph R. Robinson, a pioneer in the development of controlled-release drug-delivery systems. In the 1996 edition of Modern Pharmaceutics, he wrote, "If one were to imagine the ideal drug-delivery system, two prerequisites would be required. First, it would be a single dose for the duration of a treatment, whether it be for days or weeks, as with infection, or for the lifetime of the patient, as in hypertension or diabetes. Second, it should deliver the active entity directly to the site of action, thereby minimizing or eliminating side effects." Sadly, such a drug-delivery system still does not exist. The truth is that even after four decades of trying, an effective site-specific drug-delivery system has not yet been developed showing how elusive the ideal drug-delivery system still is.

So what is the future of nanotechnology and especially the future of nanotechnology for drug delivery? In December 2007, NNI released a new strategic plan with four key goals: advance a world-class nanotechnology research and development process; foster the transfer of new technologies into products for commercial and public benefits; develop and sustain educational resources, a skilled workforce, and the supporting infrastructure and tools to advance technology; and support responsible developments of nanotechnology.

In a letter accompanying the strategic plan, White House Science Adviser John H. Marburger III commented, "With the implementation of this plan, the United States will remain at the forefront of nanoscale science and engineering and a leader in achieving the economic benefits offered by the emerging technology."

So quo vadis (where are we going)? Based on where we are and what is being proposed as the future of nanotechnology, I believe we should revisit the initial impetus for the development of nanotechnology. Not the nanotechnology that complains about "thick fingers" but the nanotechnology that sees the extraordinary potential in the "Engines of Creation." We should aim for the nanotechnology that cures disease not by administering small, smart drug-delivery systems but by fixing molecular abnormalities permanently. We should shoot for the nanotechnology that uses "nanobots" in such a way that disease or disability cease to exist. I know this is a lofty goal, but I believe it is one we should pursue because throughout history, all new, radical technologies have brought about initial fear and trepidation, but eventually these fears were overcome.

Just how can we change the mindset of those controlling the direction of nanotechnology? We might take solice in a famous passage by the great physicist Max Planck: "A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die and a new generation grows up that is familiar with it." Perhaps a new generation of scientists who grew up with nanobots, nanoids, and nanites as part of their vocabulary, the books they read, the games they played, and the movies and TV shows they saw will not be afraid to explore the incredible possibility of fixing abnormalities in the molecular machinery of life using functional systems engineered at the molecular scale.

Melgardt M. de Villiers, PhD, is an associate professor at the Univ. of Wisconsin-Madison School of Pharmacy, 777 Highland Avenue, Madison, WI 53705-2222, tel. 608. 890.0732 mmdevilliers@pharmacy.wisc.edu