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99mTc-Diethylenetriamine pentaacetic acid superparamagnetic iron oxide nanoparticles conjugated with lactobionic acid

, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: May 20, 2010.

Chemical name:99mTc-Diethylenetriamine pentaacetic acid superparamagnetic iron oxide nanoparticles conjugated with lactobionic acid
Abbreviated name:99mTc-DTPA-SPION-LBA
Agent category:Compound
Target:Asialoglycoprotein receptors (ASGP-Rs)
Target category:Receptor
Method of detection:Magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT)
Source of signal:Iron oxide, 99mTc
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about ASGP-R.



Magnetic resonance imaging (MRI) maps information about tissues spatially and functionally. Protons (hydrogen nuclei) are widely used in imaging because of their abundance in water molecules. Water comprises ~80% of most soft tissue. The contrast of proton MRI depends primarily on the density of the nuclear proton spins, the relaxation times of the nuclear magnetization (T1, longitudinal, and T2, transverse), the magnetic environment of the tissues, and the blood flow to the tissues. However, insufficient contrast between normal and diseased tissues requires the development of contrast agents. Most contrast agents affect the T1 and T2 relaxation times of the surrounding nuclei, mainly the protons of water. T2* is the spin–spin relaxation time composed of variations from molecular interactions and intrinsic magnetic heterogeneities of tissues in the magnetic field (1). Cross-linked iron oxide (CLIO) nanoparticles and other iron oxide formulations affect T2 primarily and lead to decreased signals. On the other hand, paramagnetic T1 agents, such as gadolinium (Gd3+) and manganese (Mn2+), accelerate T1 relaxation and lead to brighter contrast images.

The 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, which are randomly rotated in the absence of an applied magnetic field. SPIO is used mainly as a T2 contrast agent in MRI, though it can shorten both T1 and T2/T2* relaxation processes. SPIO particle uptake into the reticuloendothelial system occurs by endocytosis or phagocytosis. SPIO particles are also taken up by phagocytic cells such as monocytes, macrophages, and oligodendroglial cells. A variety of cells can also be labeled with these particles for cell trafficking and tumor-specific imaging studies. SPIO agents are classified by their sizes with coating material (~20–3,500 nm in diameter) as large SPIO (LSPIO) nanoparticles, standard SPIO (SSPIO) nanoparticles, ultrasmall SPIO (USPIO) nanoparticles, and monocrystalline iron oxide nanoparticles (MION) (1).

Asialoglycoprotein (ASGP) is specifically taken into mammalian hepatocytes by binding to ASGP receptors (ASGP-Rs) (2). The galactosyl moiety of ASGP is recognized on the surface of hepatocytes and is bound by ASGP-R. The ASGP–ASGP-R complex on the cell surface is subsequently taken into cytoplasm by endocytosis and transferred to lysosomes. ASGP-R is then dissociated from ASGP and recycled to the cell surface. ASGP is degraded in the lysosomes and excreted into the bile. The number of ASGP-Rs on the hepatocytes of individuals with liver disease decreases and is thus considered a good indicator for the evaluation of liver function. Because ASGP-R recognizes galactose, 99mTc-diethylenetriamine pentaacetic acid-galactosyl-human serum albumin (99mTc-GSA) (3, 4) and 99mTc-galactosyl-neoglycoalbumin (99mTc-NGA) (5) are ASGP-R probes that accumulate specifically in the liver and are used for liver scintigraphy to determine liver mass and function. SPIO nanoparticles (SPION) modified with dopamine were conjugated with lactobionic acid (LBA) and diethylenetriamine pentaacetic acid (DTPA) to form DTPA-SPION-LBA (6). Each LBA contains one galactosyl moiety for binding to ASGP-Rs. DTPA-SPION-LBA were labeled with 99mTc as a multimodality (single-photon emission computed tomography (SPECT) and MR) imaging agent of ASGP-Rs in the liver.



SPION (12 nm) were coated with dopamine using the method of Shultz et al. (7). In brief, SPION (10 mg in 5 ml toluene) were mixed with 50 mg dopamine for 30 min in a sonication bath. A solution of 1-ethyl-3-(3-(dimethylamino)-propyl)carbodiimide and N-hydroxysuccinimide was added to a solution of dopamine-coated SPION and LBA (6). The mixture was incubated for 48 h at room temperature. SPION-LBA were isolated magnetically and centrifuged to remove larger particles. Subsequently, DTPA was conjugated to the free amine group of dopamine on the surface of SPION with 2-(4-isothiocyanatobenzyl)-DTPA. There were ~2 DTPA molecules per SPION. A mixture of DTPA-SPION-LBA (0.5 mg), SbCl2 (0.002 mg), and 99mTc (46.3 MBq (1.25 mCi)) was incubated for 30 min at room temperature. The radiolabeling yield was >95%. The number of LBA molecules per SPION was not reported.

In Vitro Studies: Testing in Cells and Tissues


Lee et al. (6) performed in vitro uptake studies of DTPA-SPION-LBA (100 µg/ml) and SPION (100 µg/ml) in cultured human hepatoblastoma HepG2 cells, which were shown to express ASPG-Rs. A strong uptake of DTPA-SPION-LBA was observed at 2 h after incubation as measured with Prussian blue staining of Fe in the cytoplasm of the cells, whereas there was little accumulation of SPION.

Animal Studies



Lee et al. (6) performed ex vivo biodistribution studies of 99mTc-DTPA-SPION-LBA in normal mice (n = 4) at 1 h after injection. The radioactivity levels in percent injected dose per gram (% ID/g) were 38.43, 18.69, 12.22, 11.48, 4.88, and 1.30 for the liver, spleen, lung, kidney, blood, and intestine, respectively. SPECT/CT imaging showed that the liver, urinary bladder, and lung were clearly visualized at 1 h after injection. The liver/muscle ratio was 24.1. Coinjection of 0.085 and 0.115 mmol galactose with 99mTc-DTPA-SPION-LBA reduced the liver/muscle ratio to 14.9 and 7.2, respectively. MRI of the liver showed a 51% reduction (n = 3) of T2 signal (1.5 T) at 1 h after SPION-LBA injection. Transmission electron microscopy of liver section showed the presence of 30-nm nanoparticles containing ~12-nm, electron-dense particles in the cytoplasm and mitochondrial matrix.

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


No publication is currently available.

Human Studies


No publication is currently available.


Wang Y.X., Hussain S.M., Krestin G.P. Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging. Eur Radiol. 2001;11(11):2319–31. [PubMed: 11702180]
Stockert R.J. The asialoglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev. 1995;75(3):591–609. [PubMed: 7624395]
Kwon A.H., Ha-Kawa S.K., Uetsuji S., Kamiyama Y., Tanaka Y. Use of technetium 99m diethylenetriamine-pentaacetic acid-galactosyl-human serum albumin liver scintigraphy in the evaluation of preoperative and postoperative hepatic functional reserve for hepatectomy. Surgery. 1995;117(4):429–34. [PubMed: 7716725]
Wu J., Ishikawa N., Takeda T., Tanaka Y., Pan X.Q., Sato M., Todoroki T., Hatakeyama R., Itai Y. The functional hepatic volume assessed by 99mTc-GSA hepatic scintigraphy. Ann Nucl Med. 1995;9(4):229–35. [PubMed: 8770291]
Vera D.R., Stadalnik R.C., Krohn K.A. Technetium-99m galactosyl-neoglycoalbumin: preparation and preclinical studies. J Nucl Med. 1985;26(10):1157–67. [PubMed: 4045560]
Lee C.M., Jeong H.J., Kim E.M., Kim D.W., Lim S.T., Kim H.T., Park I.K., Jeong Y.Y., Kim J.W., Sohn M.H. Superparamagnetic iron oxide nanoparticles as a dual imaging probe for targeting hepatocytes in vivo. Magn Reson Med. 2009;62(6):1440–6. [PubMed: 19859969]
Shultz M.D., Reveles J.U., Khanna S.N., Carpenter E.E. Reactive nature of dopamine as a surface functionalization agent in iron oxide nanoparticles. J Am Chem Soc. 2007;129(9):2482–7. [PubMed: 17290990]


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