ABSTRACT
Medicine: Does Size Matter?One of the major problems that regulators, policy-makers, re-searchers, and lawyers continue to face regarding nanotechnology is the confusion about its definition [2a, 2b, 3]. Although this “generic” term is widely used, there is no internationally accepted definition or nomenclature for it. In fact, nanotechnology is a misnomer, since it is not one technology but encompasses many technical and scientific fields like medicine, materials science, chemistry, physics,
engineering, and biology. One can view nanotechnology as an umbrella term used to define products, processes, and properties at the nano/microscale. Clearly, the need for an internationally agreed definition for key terms like nanotechnology, nanoscience, nanomedicine, nanobiotechnology, nanodrug, nanotherapeutic, nanopharmaceutical and nanomaterial, has gained urgency. In this chapter, conforming to convention, the applications and products of nanotechnology as they relate to medicine or pharma will be referred to as nanomedicines. Alternate analogous terminology used in the scientific literature or in patents includes nano-biotechnology and medical nanotechnology. Nanomedicines include drugs, therapeutics, vaccines and biologicals that are intended to remedy a medical condition or disease.Due to the confusion over nano-nomenclature, numerous size-based or dimension-based definitions of nanotechnology have sprung up over the years. One often cited, yet clearly incorrect, definition is that proposed in the 1990s by the US National Nanotechnology Initiative (NNI), a federal R&D program established by the US government to coordinate the efforts of government agencies involved in nanotechnology. The NNI defines nanotechnology as “the understanding and control of matter at the nanoscale, at dimensions between approximately 1 and 100 nanometers, where unique phenomena enable novel applications…” [4]. Various regulatory agencies and entities such as the FDA, the European Medicines Agency (EMA), Environmental Protection Agency (EPA), Centers for Disease Control and Prevention (CDC), National Institute for Occupational Safety and Health (NIOSH), the US Patent and Trademark Office (PTO), International Organization for Standardization (ISO), ASTM International and the Organization for Economic Cooperation and Development (OECD) continue to use this definition based on a sub-100 nm size. This overly rigid NNI definition presents numerous difficulties. For example, although the sub-100 nm size range may be important for a nanoelectronics or nanophotonics company where quantum effects are critical, this size limitation is meaningless to a drug company from a formulation, delivery, or efficacy perspective because the desired or novel physiochemical properties (e.g., improved bioavailability, reduced toxicities, lower dose, or enhanced solubility) may be achieved in a size range greater
than the arbitrary size limit of 100 nm. For example, the surface plasmon-resonance (SPR) in gold or silver nanoshells or nanoprisms that imparts their unique property as anticancer thermal drug delivery agents is often because of their size being greater than 100 nm. Similarly, at the tissue level, the enhanced permeability and retention (EPR) effect that makes nanoparticle drug delivery an attractive option operates in a wide range, with nanoparticles of 100-1000 nm diffusing selectively (extravasation and accumulation) into the tumor. At the cellular level, size range for optimal nanoparticle uptake and processing depends on many factors but is often beyond 100 nm. Liposomes in a size range (diameter) of about 150-200 nm have been shown to have a greater blood residence time than those with a size below 70 nm. Furthermore, there are numerous FDA-approved and marketed nanopharmaceuticals where the particle size does not fit the sub-100 nanometer profile (Table 17.1): Abraxane (~130 nm), Myocet (~190 nm), DepoCyt (10-20 micometer), Amphotec (~130 nm), Epaxal (~150 nm), Inflexal (~150 nm), Lipodox (180 nm), Oncaspar (50-200 nm), etc. Moreover, the NNI definition excludes numerous devices and materials of micro-meter dimensions (and also of dimensions less than 1 nm), a scale that is included within the definition of nanotechnology by many nanoscientists.Compounding this confusion is the fact that nanotechnology is nothing new and has been around for hundreds, possibly thousands, of years. For example, Damascus sword blades, encountered by Crusaders in the 5th century, have now been shown to sometimes contain nanowires and carbon nanotubes. Another early example of nanomaterials in products dates back to the 4th century in stained glass where gold nanoparticles were incorporated therein to exhibit a range of colors. The most prominent examples of this is the Lycurgus Cup on display at the British Museum. One of the earliest known use of nanoparticles is in the 9th century when Arab potters used nanoparticles in their glazes so that objects would change color depending on the viewing angle (the so-called “polychrome lustre”). Nanoscale carbon black particles (“high-tech soot nanoparticles”) have been in use as reinforcing additives in tires for over a century. The accidental discovery of precipitation hardening in 1906 by Wilm in Duralumin alloys is considered a landmark development for metallurgists; this is now attributed
to nanometer-sized precipitates. Modern nanotechnology may be considered to start in the 1930s when chemists generated silver coatings for photographic film. In 1947, Bell labs discovered that the semiconductor transistor had components that operated on the nanoscale. A large number of nanomaterials and nanoparticles have been synthesized over the last two decades, yet the Environmental Protection Agency (EPA) and the Food and Drug Agency (FDA) are uncertain as to how to regulate most of them. Obviously, consumers should be cautious about potential exposure but workers should be more concerned. Technically speaking, biologists have been studying nanoscale biomolecules (antibodies, viruses, etc.) long before the term “nanotechnology” was coined or became fashionable.
