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

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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Trastuzumab-manganese–doped iron oxide nanoparticles

Trastuzumab-MnMEIO nanoparticles
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, vog.hin.mln.ibcn@dacim

Created: ; Last Update: May 21, 2007.

Chemical name:Trastuzumab-manganese–doped iron oxide nanoparticles
Abbreviated name:Trast-MnMEIO nanoparticles
Synonym:MnMEIO-Herceptin
Agent Category:Antibody
Target:EGF HER2 receptor
Target Category:Antibody binding to EGF receptor
Method of detection:Magnetic resonance imaging (MRI)
Source of signal/contrast:Iron oxide
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents

Click on protein, nucleotide (RefSeq), and gene for more information about HER2.

Background

[PubMed]

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).

Synthesis

[PubMed]

Lee et al. (12) prepared MnMEIO nanoparticels by means of a high-temperature nonhydrolytic reaction between MnCl2 and iron tris-2,4-pentadionate in the presence of oleic acid and oleylamine as surfactants. MnMEIO nanoparticles were then coated with 2,3-dimercaptosuccinic acid molecules.MnMEIO nanoparticles (~12 nm in diameter) exhibited a high mass magnetization of 110 emu/mass of magnetic atoms with a high magnetic spin of 5 μB and a high R2 relaxivity value (R2 = 1/T2) of 358 liters/mmol/s. Trastuzumab (2 mg) was first activated with the heterobifunctional cross-linker sulfo-succinimidyl-4-(maleimidomethyl)-1-cyclohexanecarboxylate to yield maleimide-activated trastuzumab. MnMEIO nanoparticles (0.2 mg Fe) were mixed with the maleimide-activated trastuzumab for 8 h at 4°C. Trastuzumab-conjugated MnMEIO (trast-MnMEIO) nanoparticles were purified by gel filtration. There were ~6 antibodies/nanoparticle.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Lee et al. (12) performed cell-binding assays with trast-MnMEIO nanoparticles using various cell lines with different levels of HER2/neu overexpression: Bx-PC-3, MDA-MB-231, MCF-7, and NIH3T6.7 (relative HER2/neu expression levels are 1, 3, 28, and 2,300, respectively) with R2 enhancement of 10%, 40%, 70%, and 130%, respectively. Trastuzumab-MEIO conjugates exhibited R2 relaxivity enhancements of 8%, 18%, 29%, and 52% for Bx-PC-3, MDA-MB-231, MCF-7, and NIH3T6.7 cell lines, respectively. On the other hand, binding of trastuzumab-CLIO nanoparticles was negligible in all cell lines with only 10% R2 enhancement in NIH3T6.7 cells. Fluorescence flow cytometry showed that nearly identical numbers of MnMEIO and CLIO nanoparticles were bound to each cell line. The observed high MR enhancement effect of MnMEIO seems to be attributable to the fact that its R2 relaxivity coefficient per nanoparticle is much higher than that of CLIO. No blocking experiment was performed.

Animal Studies

Rodents

[PubMed]

Lee et al. (12) studied the accumulation of trast-MnMEIO nanoparticles in nude mice bearing NIH3T6.7 tumors (n = 8) using a 1.5 T clinical MR imaging system before and after injection of trast-MnMEIO (20 mg/kg). The small tumors (~50 mg) were clearly delineated at 1 h (25% R2 increase) and 2 h (34% R2 increase) after injection. In contrast, trastuzumab-CLIO (20 mg/kg) showed only a <5% R2 increase, and trastuzumab-MEIO (20 mg/kg) showed only a 10% R2 increase. No blocking experiment was performed.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

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Mendelsohn J. Anti-epidermal growth factor receptor monoclonal antibodies as potential anti-cancer agents. J Steroid Biochem Mol Biol. 1990;37(6):889–92. [PubMed: 2285602]
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Ethier S.P. Growth factor synthesis and human breast cancer progression. J Natl Cancer Inst. 1995;87(13):964–73. [PubMed: 7629883]
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Yarden Y. Biology of HER2 and its importance in breast cancer Oncology 2001. 61Suppl 21–13. [PubMed: 11694782]
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