**2.1 Core–shell structure**

Iron oxides with a core/shell structure are widely used as sources of MFMNP platforms. Iron oxides have several crystalline polymorphs, but only γ-Fe2O3 (maghemite) or Fe3O4 (magnetite) can be used for biomedical applications. These particles, which range in diameter from about 5–20 nm, have unique advantages, including (1) superparamagnetic behavior, with no magnetism after removal of the magnetic field; (2) high saturation magnetization values and high magnetic susceptibility, for effective magnetic enrichment; (3) biocompatibility and rapid removal through extravasation and renal clearance; and (4) easily tailored surface chemistry and functionalization.

Iron oxide nanoparticles have a significant tendency to agglomerate as a result of their high surface energy. Massart (1981) first prepared stable aqueous dispersions of Fe3O4 nanoparticles (ferrofluids) that were stabilized by electrical double layers. However, the colloidal electrostatic stabilization arising from surface charge repulsion on the nanoparticles typically is inadequate to prevent aggregation in biological solutions, due to the presence of salts or other electrolytes that can neutralize the charges. Furthermore, the iron oxide surfaces may be subjected to plasma protein adsorption or opsonization, leading to their rapid clearance by the reticuloendothelial system (RES) (Berry & Curtis, 2003).

To solve the above problems, proper surface coatings have been exploited as an integral component of the MFMNP platform for biomedical applications. The iron oxide core can be coated by organic materials [e.g., polymers such as dextrant (Thorek et al., 2006) and polyethylene glycol (PEG) (Gref et al., 1994)], inorganic metallic materials [e.g., gold (Ji et al., 2007)], or oxides [e.g., silica or alumina (Bumb et al., 2008)]. Polymer coatings will be introduced in detail in the next section. Silica shells are attractive as protective coatings on the iron oxide core, due to their stability under aqueous conditions and ease of synthesis. Recently, Ma et al. (2006) described one such core–shell MFMNP, composed of an iron oxide core (approximately 10 nm diameter) surrounded by a SiO2 shell (10–15 nm thick). They doped an organic dye, tris(2,2′-bipyridine) ruthenium, inside a second silica shell to provide luminescence and prevent quenching by interaction with the magnetic core. As a core–shell structure exhibiting superparamagnetic and luminescent properties, this MFMNP platform can be used as a multifunctional imaging agent for biomedical applications.

Gold offers several advantages as a coating material for iron oxide cores, due to its low chemical reactivity and unique ability to form self-assembled monolayers on the core surface using alkanethiols (Prime & Whitesides, 1991). A variety of methods (reversed microemulsion, combined wet chemical, and laser irradiation) can be used to synthesize gold-coated iron oxides (A. H. Lu et al., 2007).

The core/shell structure of MFMNPs offers several advantages, including good dispersibility and high stability against oxidation. In addition, an appreciable amount of therapeutic agent can be loaded on the MFMNP shell. Functionalization chemistries generally are better established when a coating material is used.
