Nanoparticle Characteristics

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 non-toxic 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).

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).

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).

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