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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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Quantum dot 800–prostate-specific membrane antigen antibody J591

QD800-J591
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: May 18, 2011.

Chemical name:Quantum dot 800–prostate-specific membrane antigen antibody J591
Abbreviated name:QD800-J591
Synonym:
Agent category:Antibody
Target:Prostate-specific membrane antigen (PSMA), folate hydrolase
Target category:Antigen
Method of detection:Optical, near-infrared fluorescence (NIR) imaging
Source of signal:Quantum dot (QD)
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about PSMA.

Background

[PubMed]

Optical fluorescence imaging is increasingly used to monitor biological functions of specific targets in small animals (1-3). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light (350–700 nm) are used. Near-infrared (NIR) fluorescence (700–1,000 nm) detection avoids the background fluorescence interference of natural biomolecules, providing a high contrast between target and background tissues. NIR fluorophores have wider dynamic range and minimal background as a result of reduced scattering compared with visible fluorescence detection. They also have high sensitivity, resulting from low infrared background, and high extinction coefficients, which provide high quantum yields. The NIR region is also compatible with solid-state optical components, such as diode lasers and silicon detectors. NIR fluorescence imaging is becoming a noninvasive alternative to radionuclide imaging in small animals (4).

Fluorescent semiconductor quantum dots (QDs) are nanocrystals made of CdSe/CdTe/ZnS with radii of 1–10 nm (5-7). They can be tuned to emit signals in a range of wavelengths by changing their sizes and composition, thus providing broad excitation profiles and high absorption coefficients. They have narrow, symmetric emission spectra with long, excited-state lifetimes (20–50 ns) compared with those of fluorescent dyes (1–10 ns). They process good quantum yields of 40%–90% and possess high extinction coefficients. They are more photo-stable than conventional organic dyes. They can be coated and capped with hydrophilic materials for additional conjugation with biomolecules, such as peptides, antibodies, nucleic acids, and small organic compounds, which have been tested in vitro and in vivo (7-11). Although many cells have been labeled with QDs in vitro with little cytotoxicity, there are limited studies of long-term toxicity of QDs in small animals (12-20); little is known about the toxicity and the mechanisms of clearance and metabolism of QDs in humans.

Prostate-specific membrane antigen (PSMA) is a cell-surface glycoprotein with a molecular weight of ~100 kDa. It is a unique, type II, transmembrane-bound glycoprotein that is overexpressed on prostate tumor cells and in the neovasculature of most solid prostate tumors, but not in the vasculature of normal tissues (21, 22). This unique expression of PSMA makes it an important biomarker as well as a large extracellular target of imaging agents (23, 24). PSMA has also been detected in other tissues such as the kidneys, the proximal small intestine, and the salivary glands (22). PSMA was found to have N-acetyl α-linked acidic dipeptidase (NAALADase) or glutamate carboxypeptidase II activity (25). PSMA may play an important role in the progression of prostate cancer and glutamatergic neurotransmission, as well as in the absorption of folate (26). In the central nervous system, PSMA metabolizes N-acetyl-aspartyl-glutamate, and in the proximal small intestine it removes γ-linked glutamates from poly-γ-glutamate folate and folate hydrolase (22). PSMA can be used as a marker for the detection of metastatic cancers with imaging agents. Although the commercially available monoclonal antibody 111In-labeled Capromomab pendetide (111In-CYT-356) is in clinical use for the detection of prostate cancer, the results obtained with this antibody are not entirely reliable (27). In addition, this antibody has limited access to tumors and may produce low signal/noise ratios because the target is the intracellular domain of PSMA (28, 29). J591, a monoclonal antibody against the extracellular domain of PSMA (30), was conjugated to QD655 (QD655-J591) and was found to accumulate in a human prostate cancer cell line in vitro and in nude mice (15). However, QD655-J591 has suboptimal tissue penetration and autofluorescence from the skin.To improve this approach, Shi et al. (31) used an anti-PSMA antibody J591conjugate with QDs (QD800-J591), which emit light in the NIR 800-nm range.

Synthesis

[PubMed]

Non-cadmium–based QDs (InAs/InP/ZnSe) with polyethylene glycol (PEG) modification were activated using the hetero-bifunctional cross-linker 4-(maleimidomethyl)-1-cyclohexanecarboxylic acid N-hydroxysuccinimide ester (SMCC), yielding a maleimide-nanocrystal surface (31). PSMA monoclonal antibody J591 was reduced with dithiothreitol (DTT) to expose free sulfhydryl functional groups. Excess SMCC and DTT were removed with column chromatography. Activated QD800 PEG conjugates were mixed with the reduced J591 at a ratio of 1:3 and then covalently coupled. The resultant QD800-J591 conjugates were concentrated by ultrafiltration and purified using column chromatography. QD800-J591 emits light at the NIR fluorescence range of 800 nm. The hydrodynamic diameter of QD800-J591 and the number of J591 molecules per DQ were not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

LNCaP human prostate cancer cells were reported to have a Kd of 1.83 nm with 131I-labeled J591 and a Bmax of 600,000–800,000 sites/cell in a saturation binding assay (30). Binding studies of QD800-J591 and QD800-PEG were performed using human prostate cancer cell lines C4-2 (a subclone of LNCaP that is positive for PSMA) and PC-3 (negative for PSMA) (31). QD800-J591 was shown to bind to C4-2 cells, whereas QD800-PEG did not bind to C4-2 cells. No fluorescence was detected on the cell surface of PC-3 cells with QD800-J591. QD800-J591 bound specifically to C4-2 cells, given that PC-3 cells without PSMA showed no binding by QD800-J591. QD800-J591 showed no obvious toxicity to C4-2 cells in culture.

Animal Studies

Rodents

[PubMed]

Tumor-imaging studies of QD800-J591 were performed in nude mice bearing a C4-2 tumor in the mouse tibia (31). Whole-body small animal images were obtained with reflectance planar fluorescence after intravenous injection of QD800-J591 and QD800-PEG. Intense tumor signals were obtained with QD800-J591 (0.1 nmol In) at 30 min after injection (active targeting by specific antibody–antigen recognition). The tumor/background ratio was 2.7. Little tumor fluorescence signals were obtained with QD800-PEG at 30 min after injection (passive targeting by enhanced vascular permeability of tumor). No blocking experiments (with unconjugated J591) were 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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