q 2006 by Taylor & Francis Group, LLC - Developers

Active Targeting Strategies in Cancer with a Focus on Potential Nanotechnology Applications 21
methods for their production. Although nanoparticles can be prepared from a wide variety of
materials (inorganic salts, lipids, synthetic organic polymers, polymeric forms of amino acids,
nucleic acids, etc.), this chapter will primarily focus on those prepared from materials that would
be considered sufficiently safe for repeated systemic administrations and/or would be perceived to
have an acceptable safety profile that would warrant use in man. In general, it is desirable for
nanoparticles to be either readily metabolized or sufficiently broken down to produce only nontoxic
metabolites that can be safely excreted. Indeed, tremendous advances have been made in
controlling the chemical nature, degradable characteristics, and dimensions of nanoparticles.
Many of the initial studies examining nanoparticles as delivery tools used particles prepared
from materials such as polyalkylcyanoacrylates (PAA). 5 The extreme stability of PAA is both a
positive and a negative. PAA nanoparticles will not be degraded prior to reaching a tissue or cell
target site; however, once they reach that site, it is unlikely that they will be efficiently metabolized.
Therefore, PAA nanoparticles have been extremely useful for initial studies of nanomaterials for
cancer targeting, but an inability to clear PAA nanoparticles presents uncertainties as to their
ultimate toxicological fate. Concerns over repeated PAA nanoparticle administrations in man
and the need for more acceptable materials were highlighted early on. 3 One of the biggest concerns
regarding poorly metabolized nanoparticles is that of accumulation and the potential sequelae
associated with such an outcome. In some cases where a limited number of exposures would
occur, one could consider the use of materials that are not readily metabolized by the body. In
the case of certain cancer applications, it might be possible to use materials that otherwise would be
considered to have an unacceptable safety signal following repeat dosing or that have the potential
to accumulate. Therefore, rationales exist for the potential application of nanoparticles prepared
from a wide range of materials, even those that, at first glance, would be considered unacceptable.
Methods of production and composition define nanoparticle characteristics; these characteristics
define potential issues (and opportunities) related to biocompatibility, derivitization, and
detection. Nanoparticles can be prepared from a singular subunit that is chemically coupled and
organized in a defined (e.g., dendrimers) or in a more random (e.g., polylactic acid) manner.
Although these materials would not have a defined core, they can be impregnated with compatible
materials and/or chemically modified at their surface. Materials such as glyconanoparticles would
provide one approach where a distinct core with radiating ligands could be positioned using linkers.
In such a case, the solid core, used to anchor each linker used for the attachment of targeting
ligands, could be used to deliver a therapeutic or diagnostic payload. Liposomes are an example of
nanoshell structures that can be loaded internally as well as impregnated within the shell. Many
types of nanomaterials fall into one of these three general structural architectures (Figure 3.2).
(a) (b) (c)
FIGURE 3.2 General schema for three types of nanoparticle structures. (a) Nanoparticles can be formed from
one type of material that can be impregnated with therapeutic or lipophilic imaging reagents (open diamonds)
and modified with targeting ligands (crescents) positioned by chemical coupling through linker moieties. (b)
Metal (or similar) cores (circles can be modified through a linker-targeting ligand system to generate another
type of nanoparticle structure. In this case, it might be possible to use elaborated linkers as an environment
compatible for incorporation of therapeutic or imaging reagents. (c) Shell-type nanoparticles such as liposomes
where an aqueous compartment is enclosed by a bilayer of phospholipids can also be used for the targeted
delivery of hydrophilic therapeutic or imaging reagents (filled hexagons).
q 2006 by Taylor & Francis Group, LLC