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Trastuzumab-manganese–doped iron oxide nanoparticles.


Leung K.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2007 Apr 19 [updated 2007 May 21].


Epidermal growth factor (EGF) is a cytokine (6.2 kDa) composed of 53 amino acids that is secreted by ectodermic cells, monocytes, kidneys, and duodenal glands (1). EGF stimulates growth of epidermal and epithelial cells. EGF and at least seven other growth factors and their transmembrane receptor kinases play important roles in cell proliferation, survival, adhesion, migration, and differentiation. The EGF receptor (EGFR) family consists of four transmembrane receptors: EGFR (HER1/erbB-1), HER2 (erbB-2/neu), HER3 (erbB-3), and HER4 (erbB-4) (2). HER1, HER3, and HER4 comprise three major functional domains: an extracellular ligand-binding domain, a hydrophobic transmembrane domain, and a cytoplasmic tyrosine kinase domain. No ligand has been clearly identified for HER2. However, HER2 can be activated as a result of ligand binding to other HER receptors with the formation of receptor homodimers and/or heterodimers (3). HER1 as well as HER2 are overexpressed on many solid tumor cells such as breast, non–small cell lung, head and neck, and colon cancers (4-6). The high levels of HER1 and HER2 expression on cancer cells are associated with a poor prognosis (7-10). Superparamagnetic iron oxide (SPIO) structure is composed of ferric iron (Fe3+) and ferrous iron (Fe2+). The iron oxide particles are coated with a protective layer of dextran or other polysaccharide. These particles have large combined magnetic moments or spins that are randomly rotated in the absence of an applied magnetic field. SPIO is used mainly as a T2 contrast agent in magnetic resonance (MR) imaging, though it can shorten both T1 and T2/T2* relaxation processes. SPIO particle uptake into the reticuloendothelial system (RES) is by endocytosis or phagocytosis. SPIO particles are taken up by phagocytic cells such as monocytes, macrophages, and oligodendroglial cells (11). SPIO agents are classified by their sizes with coating material (~20 nm to 3,500 nm in diameters) as large SPIO (LSPIO) nanoparticles, standard SPIO (SSPIO) nanoparticles, ultrasmall SPIO (USPIO) nanoparticles, and cross-linked iron oxide nanoparticles (CLIO). A new class of iron oxide nanoparticles has been created with high and tunable nanomagnetism: magnetism-engineered iron oxide (MEIO) nanoparticles (12). These MEIO nanoparticles were doped with manganese (MnMEIO) to provide further MR signal enhancement. Trastuzumab is a humanized IgG1 monoclonal antibody (mAb) against the extracellular domain of recombinant HER2 with an affinity constant (Kd) of 0.1 nM (13). Cardiotoxicity is the most serious complication of trastuzumab use in humans with breast cancer (14). One potential application of a radiolabeled anti-HER2 mAb is pretreatment imaging of breast cancer patients to predict the therapeutic efficacy of trastuzumab. 111In-Trastuzumab, Cy5.5-trastuzumab, and 68Ga-trastuzumab-F(ab')2 have been developed for imaging of human breast cancer (15-19). Trastuzumab has also been successfully coupled with MnMEIO nanoparticles to study MR imaging of HER2 in tumors in mice (12).

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