NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

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

Cover of Molecular Imaging and Contrast Agent Database (MICAD)

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

Show details

ZHER2:342 Affibody-polyethylene glycol-superparamagnetic iron oxide nanoparticles

IO-PEG-ZHER2:342
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: October 18, 2012.

Chemical name:ZHER2:342 Affibody-polyethylene glycol-superparamagnetic iron oxide nanoparticles
Abbreviated name:IO-PEG-ZHER2:342
Synonym:
Agent category:Antibody
Target:Epidermal growth factor receptor (HER2)
Target category:Receptor
Method of detection:Magnetic resonance imaging (MRI)
Source of signal: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 53-amino-acid growth factor (6.2 kDa) secreted by ectodermic cells, monocytes, kidneys, and duodenal glands (1). EGF stimulates growth of epidermal and epithelial cells. EGF, with 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, including 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 patient prognosis because high levels are related to increased proliferation (7-10).

Trastuzumab is a humanized IgG1 monoclonal antibody (mAb) against the extracellular domain of recombinant HER2 with an affinity constant (Kd) of 0.1 nM (11). 111In-Trastuzumab, Cy5.5-trastuzumab, and 68Ga-trastuzumab-F(ab')2 have been developed for imaging of human breast cancer (12-16). However, the pharmacokinetics of intact radiolabeled mAb, with high liver uptake and slow blood elimination, are generally not ideal for imaging. Smaller antibody fragments, such as Fab or F(ab')2, have better imaging pharmacokinetics because they are rapidly excreted by the kidneys. A novel class of recombinant affinity ligands (Affibody molecules) for HER2 was constructed based on a 58-amino-acid Z-domain residues from one of the IgG-binding domains of staphylococcal protein A (17). These Affibody molecules exhibit high binding affinity to HER2, with Kd values of <50 pM. Various radiolabeled HER2 Affibody molecules have been studied in terms of their ability to image HER2 in tumors [PubMed]. The synthetic Affibody molecule Cys-ZHER2:342 Affibody was targeted to HER2 and conjugated to superparamagnetic iron oxide coated with polyethylene glycol (IO-PEG) to form IO-PEG-ZHER2:342 nanoparticles (18). IO-PEG-ZHER2:342 nanoparticles were evaluated for magnetic resonance imaging (MRI) in nude mice bearing human SKOV3 ovarian carcinoma tumor.

Synthesis

[PubMed]

IO nanoparticles (15 nm in diameter) were coated with PEG phosphatidylethanolamine (DSPE-PEG2000 amine) by hydrophobic-hydrophobic interactions (18). IO nanoparticles (10 nmol) and DSPE-PEG2000 amine (10 µmol) in chloroform (0.2 mL) were mixed, and the solvent was completely evaporated in a fume hood at room temperature. The residue was re-dissolved in water and sonicated. IO-PEG nanoparticles (27 nm in diameter) were purified with ultra-centrifugation. For conjugation with Affibody, IO-PEG (1 nmol) was first activated with the biofunctional linker 4-maleimidobutyric acid N-succinimidyl ester (1 µmol) in borate buffer (pH 8.5) for 2 h at room temperature. After column purification, Cys-ZHER2:342 (100 nmol) was incubated with the activated IO-PEG nanoparticles for 20 min at room temperature with a conjugation efficiency of 40%–50%. IO-PEG-ZHER2:342 nanoparticles were purified with column chromatography. There were ~20 Affibody molecules per nanoparticle, with a hydrodynamic diameter of 28 nm.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Lee et al. (19) performed binding experiments with Cys-ZHER2:342 using a Biacore sensor chip immobilized with extracellular domain of chimeric HER2/Fc fusion protein. The dissociation constants (Kd) of ZHER2:342 were calculated to be 30 pM for chimeric HER2/Fc fusion protein.

Gao et al. (18) determined the relaxivity (r2) values (7 T) of IO-PEG and Feridex (dextran-coated IO) to be 172.34 and 152.86 mM−1s−1, respectively. Cellular accumulation of IO-PEG-ZHER2:342 and IO-PEG nanoparticles (200, 400, and 800 µM) was determined in HER2-expressing SKOV3 cells (1 × 106 cells in 5 mL medium) after 30 min of incubation. There was a dose-dependent increase in the relaxation (R2) with cells incubated with IO-PEG-ZHER2:342 nanoparticles, whereas the R2 values of cells incubated with IO-PEG nanoparticles remained close to those of cells incubated with medium alone. The Fe contents of cells incubated with IO-PEG-ZHER2:342 nanoparticles were 68 ± 22, 130 ± 20, and 270 ± 30 nmol at 200, 400, and 800 µM, respectively. On the other hand, the Fe contents of cells incubated with IO-PEG nanoparticles were 2.6, 3.4, and 9.8 nmol at 200, 400, and 800 µM, respectively.

Animal Studies

Rodents

[PubMed]

Gao et al. (18) performed in vivo T2* MRI (7 T) studies of IO-PEG-ZHER2:342 nanoparticles (8 nmol Fe/kg) in mice (the number of mice was not reported) bearing SKOV3 tumor at 0, 30, 60, and 90 min after intravenous injection. Only a slight decrease of MRI signal in the tumor was observed and may have been caused by an insufficient accumulation of nanoparticles (low sensitivity of MRI) in the targeted tumor. The investigators indicated that further studies are ongoing.

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.

NIH support

R21 CA121842, U54 CA119367

References

1.
Carpenter G., Cohen S. Epidermal growth factor. J Biol Chem. 1990;265(14):7709–12. [PubMed: 2186024]
2.
Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37 Suppl 4:S3–8. [PubMed: 11597398]
3.
Rubin I., Yarden Y. The basic biology of HER2. Ann Oncol. 2001;12 Suppl 1:S3–8. [PubMed: 11521719]
4.
Grunwald V., Hidalgo M. Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst. 2003;95(12):851–67. [PubMed: 12813169]
5.
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]
6.
Yasui W., Sumiyoshi H., Hata J., Kameda T., Ochiai A., Ito H., Tahara E. Expression of epidermal growth factor receptor in human gastric and colonic carcinomas. Cancer Res. 1988;48(1):137–41. [PubMed: 2446740]
7.
Ang K.K., Berkey B.A., Tu X., Zhang H.Z., Katz R., Hammond E.H., Fu K.K., Milas L. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62(24):7350–6. [PubMed: 12499279]
8.
Costa S., Stamm H., Almendral A., Ludwig H., Wyss R., Fabbro D., Ernst A., Takahashi A., Eppenberger U. Predictive value of EGF receptor in breast cancer. Lancet. 1988;2(8622):1258. [PubMed: 2903994]
9.
Ethier S.P. Growth factor synthesis and human breast cancer progression. J Natl Cancer Inst. 1995;87(13):964–73. [PubMed: 7629883]
10.
Yarden Y. Biology of HER2 and its importance in breast cancer. Oncology. 2001;61 Suppl 2:1–13. [PubMed: 11694782]
11.
Carter P., Presta L., Gorman C.M., Ridgway J.B., Henner D., Wong W.L., Rowland A.M., Kotts C., Carver M.E., Shepard H.M. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A. 1992;89(10):4285–9. [PMC free article: PMC49066] [PubMed: 1350088]
12.
Perik P.J., Lub-De Hooge M.N., Gietema J.A., van der Graaf W.T., de Korte M.A., Jonkman S., Kosterink J.G., van Veldhuisen D.J., Sleijfer D.T., Jager P.L., de Vries E.G. Indium-111-labeled trastuzumab scintigraphy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2006;24(15):2276–82. [PubMed: 16710024]
13.
Lub-de Hooge M.N., Kosterink J.G., Perik P.J., Nijnuis H., Tran L., Bart J., Suurmeijer A.J., de Jong S., Jager P.L., de Vries E.G. Preclinical characterisation of 111In-DTPA-trastuzumab. Br J Pharmacol. 2004;143(1):99–106. [PMC free article: PMC1575276] [PubMed: 15289297]
14.
Garmestani K., Milenic D.E., Plascjak P.S., Brechbiel M.W. A new and convenient method for purification of 86Y using a Sr(II) selective resin and comparison of biodistribution of 86Y and 111In labeled Herceptin. Nucl Med Biol. 2002;29(5):599–606. [PubMed: 12088731]
15.
Smith-Jones P.M., Solit D., Afroze F., Rosen N., Larson S.M. Early tumor response to Hsp90 therapy using HER2 PET: comparison with 18F-FDG PET. J Nucl Med. 2006;47(5):793–6. [PMC free article: PMC3193602] [PubMed: 16644749]
16.
Smith-Jones P.M., Solit D.B., Akhurst T., Afroze F., Rosen N., Larson S.M. Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Nat Biotechnol. 2004;22(6):701–6. [PubMed: 15133471]
17.
Wikman M., Steffen A.C., Gunneriusson E., Tolmachev V., Adams G.P., Carlsson J., Stahl S. Selection and characterization of HER2/neu-binding affibody ligands. Protein Eng Des Sel. 2004;17(5):455–62. [PubMed: 15208403]
18.
Gao J., Chen K., Miao Z., Ren G., Chen X., Gambhir S.S., Cheng Z. Affibody-based nanoprobes for HER2-expressing cell and tumor imaging. Biomaterials. 2011;32(8):2141–8. [PMC free article: PMC3032351] [PubMed: 21147502]
19.
Lee S.B., Hassan M., Fisher R., Chertov O., Chernomordik V., Kramer-Marek G., Gandjbakhche A., Capala J. Affibody molecules for in vivo characterization of HER2-positive tumors by near-infrared imaging. Clin Cancer Res. 2008;14(12):3840–9. [PMC free article: PMC3398736] [PubMed: 18559604]

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this page (82K)
  • MICAD Summary (CSV file)

Search MICAD

Limit my Search:


Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...