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QD800-Polyethylene glycol-Cys-ZHER2:342 Affibody.


Leung K1.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2012 Jul 20 [updated 2012 Oct 18].

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National for Biotechnology Information, NLM, NIH, Bethesda, MD


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). Fluorescent semiconductor quantum dots (QDs) are nanocrystals made of CdSe/CdTe-ZnS with radii of 1–10 nm (11-13). They can be tuned to emit in a range of wavelengths by changing their sizes and composition, thus providing broad excitation profiles and high absorption coefficients. They have narrow and symmetric emission spectra with long, excited-state lifetimes (20–50 ns), as compared with that of fluorescent dyes (1–10 ns). They possess good quantum yields of 40%–90% and high extinction coefficients. They are more photostable than conventional organic dyes. They can be coated and capped with hydrophilic materials for additional conjugations with biomolecules, such as peptides, antibodies, nucleic acids, and small organic compounds, which were tested in vitro and in vivo (13-17). Although many cells have been labeled with QDs in vitro with little cytotoxicity, there are only limited studies of long-term toxicity of QDs in small animals (18-26). Furthermore, little is known about the toxicity and the mechanisms of clearance and metabolism of QDs in humans. QDs that do not contain Cd (non-Cd QDs) have been prepared as an alternative to the more toxic Cd-based QDs. These newly developed non-Cd QDs exhibit improved blood half-life and minimal reticuloendothelial system accumulation with rapid renal clearance (27). These QDs easily extravasate leaky tumor blood vessels because of the enhanced permeability and retention effect. Trastuzumab is a humanized IgG1 monoclonal antibody (mAb) against the extracellular domain of recombinant HER2 with an affinity constant (Kd) of 0.1 nM (28). 111In-Trastuzumab, Cy5.5-trastuzumab, and 68Ga-trastuzumab-F(ab')2 have been developed for imaging of human breast cancer (29-33). 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 (34). 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 QD800 coated with polyethylene glycol (PEG) to form QD800-PEG-ZHER2:342 (35). QD800-PEG-ZHER2:342 nanoparticles were evaluated for near-infrared (NIR) fluorescence imaging in nude mice bearing human SKOV3 ovarian carcinoma tumor.

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