ABSTRACT

As with many exciting fields of research, nanomedicine has emerged from synergisms between highly divergent scientific disciplines. On the technology side it draws heavily on chemistry, materials science, and engineering while on the biological side molecular biology, pharmacology and pharmaceutics all contribute to nanomedicine’s emphasis on therapeutic applications. In order to attain true mastery of the entire field of nanomedicine a researcher would need a breadth and depth of expertise that encompassed both the quantitative approaches of the physical sciences as well as detailed knowledge of complex biological systems. No doubt a few extraordinarily talented researchers have attained this level of mastery. However, they are clearly exceptions to the more typical situation in which technologists and biological scientists, each with a limited understanding of the other’s field, seek to collaborate in nanomedicine research. There are both opportunities and problems associated with this type of collaborative scenario. Interactions between investigators from different disciplines can be very productive, even synergistic. However, there are also many opportunities for miscommunica-tion; the participants literally do not speak the same language! One type of problem that often arises concerns matching the nan-otechnology appropriately to the biological/medical issue that is being addressed. Misperceptions by both biological and physical scientists can contribute to significant mismatches between means and goals.One aspect of the problem might be termed the “muddled headed biologist” factor. Many biomedical scientists are ill equipped to quantitatively understand the physical and chemical principles that underlie nanotechnology. Thus, they fail to grasp the capabilities or, perhaps more importantly, the limitations of the nanomaterials or nanodevices that they receive from their technologist collaborators. For the most part, biological scientists cannot incisively critique the assertions of their physical science

colleagues. If a nanotechnologist claims that a nanoparticle or nanodevice will have certain properties, the biologist does not have the intellectual tools to meaningfully question or rebut those assertions. Thus, to the biologist, nanotechnology acquires a “magical” aspect and its claims are accepted on faith rather than validated by insightful scientific dialog.Perhaps an even more critical problem is the tendency of physical scientists to try to impose mechanistic simplicity on the inherent complexities and redundancies of biological systems. Most physical scientists lack both the time and the inclination to grapple with the overwhelming amount of detailed information in the biomedical literature. Thus, technologists tend to naively seize upon simplistic half-truths about living systems and then base their nanotechnology approaches on these half-truths. This can result in a great waste of time and energy since the technology employed is then not appropriate to the biomedical problem being addressed.To illustrate this point, I will discuss an important biological finding that has unfortunately become an overused cliché in the nanoparticle drug delivery arena. This concerns a phenomenon termed the enhanced permeability and retention (EPR) effect [6]. Growing tumors develop a blood supply by secreting angiogenic factors that cause existing blood vessels to send new offshoots into the tumor. Indeed anti-angiogenesis has become a major strategy in therapy of certain cancers [7, 8]. The newly developing intra-tumor blood vessels are “leaky” as compared to normal blood vessels; further tumors usually have poorly developed lymphatics and are thus impaired in terms of removal of material from the tumor. These two aspects are the basis of the EPR effect. In theory nanoparticles that are too large to exit the bloodstream in normal tissues will be able to leak into tumors and be retained there, thus providing selective delivery of therapeutic agents to the tumor. A plethora of studies with nanoparticles have been predicated on the universal presence of a strong EPR effect in tumors; indeed this has been termed “a royal gate for targeted anticancer nanomedicines” [9]. In contrast to this simplistic notion, however, the reality is far more complex. Although leaky vessels and strong EPR effects have been observed in rapidly growing xenograft tumors in mice, the situation is quite different in many spontaneous animal tumors and in many slowly growing human tumors. Thus,

tumor blood vessels tend to be very heterogeneous and not all are leaky [10]. There are also multiple factors that work against the facile delivery of therapeutic nanoparticles to tumors. These include increased intra-tumor fluid pressure (due to reduced lymph drainage) that can retard the flow of nanoparticles from the blood into the tumor, as well as extensive extracellular matrix that can hinder the diffusion of the nanoparticles within the tumor [11]. Thus, one would expect a limited and heterogeneous delivery of nanoparticles to typical human tumors rather than the universally effective EPR-mediated delivery projected by some nanotechnologists [12]. The point of this analysis is not to undermine the importance of the discovery of the EPR effect; it clearly is a major aspect of the biology of many tumors. Rather the intent is to illustrate the propensity of some nanotechnologists to over-simplify and over-generalize complex biological realities.A second aspect of the communication issue concerns the relationship between researchers in nanotechnology and the public. The field of nanomedicine represents a premiere example of the emerging coalescence of the physical and biological sciences that will clearly create many new concepts and technologies. Thus, it justly deserves the great interest and excitement it has generated in the scientific community and among the public. However, this enthusiasm should not blind us to the many problems to be overcome before nanotechnology can truly become a valuable part of medical practice. Unfortunately there is a certain amount of hubris among leaders in the nanomedicine field. These individuals should exercise more restraint and not over-promise concerning the impact that nanotechnology will have on healthcare, or the rapidity with which those changes will come to pass. Failure to communicate in a more realistic manner will lead to disappointment of the public and its political representatives and ultimately to loss of support and funding for the field.A substantial portion of federal support for nanomedicine has come through the funding of large research centers of excellence by the National Institutes of Health. These large pools of money have been effective in inducing physical scientists to enter disease-oriented research and to establish collaborations with basic and clinical biomedical investigators. However, it seems fair to say that there has sometimes been considerable inefficiency

in utilizing these large financial resources because of poor conceptualization and communication between technologists and biologists that has led to misguided projects. In these centers of excellence there has been great emphasis on rapid translation of nanotechnologies to the clinic. This is a laudable goal, but it ignores the fact that much basic research is still needed concerning the interactions of nanomaterials with living organisms. The long-running controversy over whether carbon nanotubes are toxic or not [13] is but one of many examples of the dearth of key basic information. Seeking translation to the clinic without fully understanding fundamental interactions of nanomaterials with biological systems is potentially a risky course of action. Much of the work coming out of these large research centers involves the generation of new technologies. While this is certainly important, as discussed above, poor communication between technologists and biomedical scientists sometimes leads to “solutions in search of a problem” rather than technologies that realistically address clinical issues. The nanomedicine literature is replete with publications that describe clever, elegant innovations in nanotechnology accompanied by glowing projections of therapeutic or diagnostic utility. However, when one follows these technologies over time, the observation is that many of them fail to move forward toward practical utilization. In this period of intense competition for research funding it is natural for investigators to cast their work in the best possible terms. However, over the long run this can backfire as promises are not fulfilled.