Page 43 - Nanotechnology an introduction

One of the most important manifestations of the nano/bio interface is the application of nanotechnology to that branch of applied biology known as
medicine. Mention has already been made of Feynman's inclusion of “microscopic surgeons” in his vision of what came to be called
nanotechnology [56]. The dictionary definition of medicine is “the science and art concerned with the cure, alleviation, and prevention of disease,
and with the restoration and preservation of health”. As one of the oldest of human activities accessory to survival, it has of course made enormous
strides during the millennia of human civilization. Formally it was well captured by Hippocrates' dictum, “Primum nil nocere”; during the past few
hundred years, and especially during the past few decades, it has been characterized by an enormous technization, and the concomitant enormous
expansion of its possibilities for curing bodily malfunction. The application of nanotechnology, the latest scientific–technical revolution, is a natural
continuation of this trend; the definition of nanomedicine is the application of nanotechnology to medicine.

4.2.1. A Concept System for Nanomedicine
One might usefully divide the applications of nanotechnology to medicine into “auxiliary” and “direct”. The three main activities encompassed by the
former are: (1) any application of nanotechnology assisting drug discovery; (2) any application of nanotechnology assisting drug manufacture; and
(3) the indirect application of nanotechnology to medical diagnostics. The main part of the third activity is taken up by the enhanced processing
power of nanoscale digital information processors, applied to areas such as pattern recognition and telemedicine, which might be defined as
diagnosis and treatment by a medical doctor located geographically remotely from the patient. The first activity covers a very broad spectrum,
including superior digital data processing capability (which impacts laboratory information management systems (LIMS) and laboratory
automation) as well as nanobiology (see Appendix, p. 247 for the definition). The second is mainly concerned with miniature—albeit micro rather
than nano—chemical mixers and reactors; it is hoped that the microsystems paradigms for chemical synthesis will make it feasible to generate
quasicustomized versions of drugs, if not for individual patients at least for groups of them. It would be appropriate to include under this heading
advanced materials, many of which are nanocomposites with superior barrier properties, used for packaging drugs.

The latter (“direct”) encompasses in vitro and in vivo applications. The most important in vitro applications are: materials (“tissue scaffolds”) for
helping to grow, in culture, tissues destined for implanting in the human body (in so far as this depends on superior understanding of the behavior of
living cells, it can be said to be part of nanobiology); and “labs-on-chips”—miniature mixers, reactors, etc. for carrying out analyses of clinical fluids.
A typical lab-on-a-chip belongs to microsystems rather than nanotechnology, however, and is therefore outside the scope of this book, although
there may be nanotechnology incorporated within the microfluidic channels (e.g., a nanoparticulate catalytic surface lining a tube), in which case
one can speak of micro-enabled nanotechnology. A very interesting area is the development of miniature DNA sequencing devices based on the
physical, rather than the chemical, properties of the nucleotides [175]. It might be recalled that an early hope of that quintessentially “nano”
metrology device, the atomic force microscope (Section 5.1), was to determine the base sequence of DNA by directly imaging the polymer, at
sufficient resolution to be able to distinguish the four different bases by shape. This has turned out to be far more difficult than originally envisaged,
but other methods based on examining a single or double DNA chain are being invented and examined.

In vivo applications encompass nanostructured materials, such as materials for regenerative medicine (which might well be rather similar to the
tissue scaffolds used in vitro) and materials for implantable devices, which might include prostheses for replacing bones and stents for keeping
blood vessels open [145]. Nanotechnology is attractive for implants because, through creating novel combinations of material properties, it should
be possible to achieve performances superior to those available using traditional materials.

The most active current field of nanomedicine is the use of nanoparticles of progressively increasing sophistication. The two main classes of
applications are as contrast agents (mainly for imaging purposes but more generally for diagnostics) and as drug delivery agents. In both cases the
particles are administered systemically. The major challenge is to ensure that they circulate long enough before opsonization to be able to
accumulate sufficiently in the target tissue. If the particles are superparamagnetic (see Section 2.6) they can be steered by external
electromagnetic fields, accelerating their accumulation at the target. Since cancer cells typically have a significantly faster metabolic rate than that
of host tissue, substances will tend to be taken up preferentially by cancer cells, assuming that there is a pathway for uptake. In other cases, and
also to enhance the uptake differential between cancerous and noncancerous tissue, the nanoparticles are “functionalized”; that is, their surface is
specially treated in some way (e.g., by coating the surface with a ligand for a receptor known to exist in the target cells).
The simplest medicinal nanoparticles are those made of a single substance, for example magnetite, which, when taken up by the tissue, can be
subjected to an external electromagnetic field such that they will absorb energy, become hot, and transfer the heat to the cells surrounding them,
thereby killing them (necrosis). The particles can themselves be considered as the drug, which requires the external field for activation. Other
examples of single-substance drug particles are gold and silver ones. Nanoparticulate (potable) gold was already introduced as a therapeutic
agent by Paracelsus about 500 years ago. Nanoparticulate silver is nowadays widely used (e.g., in toothpaste) as a general antibacterial agent.
At the next level of sophistication, the particles constitute a reservoir for a small organic-molecular drug. Prior to use the particles (which may
contain numerous pores of an appropriate nature) are saturated with the drug, which starts to dissociate once the particles are introduced into the
human body. At the current level of the technology, this approach works best if the characteristic dissociation time is long compared with the time
needed to become accumulated at the target. Hemoglobin is the paradigm for this type of particle but is still far from having been successfully
imitated by an artificial device (see Chapter 11).
Slightly more sophisticated are particles in which the reservoir is initially closed, the closure being designed to resist opening under conditions
likely to be encountered before final arrival at the target. An example is a calcium carbonate nanoshell enclosing a stomach drug designed to be
administered orally. The calcium carbonate will dissolve in the acidic conditions of the stomach, thereby releasing the drug. This is an example of a
responsive particle, which might even be called adaptive under a highly restrictive set of conditions. The ideal “smart” adaptive nanoparticle will:
sense its surroundings for the presence of its target; bind to the target when it reaches it; sense its surroundings for the local concentrations of the
therapeutic agent it carries; and release its burden if the surrounding concentration is low. At present, most research in the field is concerned with
devising novel adaptive materials for drug delivery (nanostructure is especially useful here because it allows multiple attributes to be combined in a
single material).
Any system based on a reservoir has a finite capacity and, hence, therapeutic lifetime. For many therapeutic regimens this may not be a
disadvantage, since the drug may only be required for a limited duration. For long-term therapy, the goal is to create nano-objects able to
manufacture the drug from substances they can gather from their immediate environment (i.e., veritable nanofactories).