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Cyclo(Arg-Gly-Asp-D-Try-Glu) conjugated to ultrasmall superparamagnetic iron oxide nanoparticles

c(RGDyE)-USPIO
, PhD
National Center for Biotechnology Information, NLM, NIH, vog.hin.mln.ibcn@dacim

Created: ; Last Update: April 30, 2008.

Chemical name:Cyclo(Arg-Gly-Asp-D-Try-Glu) conjugated to ultrasmall superparamagnetic iron oxide nanoparticles
Abbreviated name:RGD-USPIO, c(RGDyE)-USPIO
Synonym:
Agent Category:Peptide
Target:Integrin αvβ3
Target Category:Receptor binding
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 Integrin αv.

Background

[PubMed]

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 mainly on the density of the nucleus (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).

The superparamagnetic iron oxide (SPIO) structure is composed of ferric iron (Fe3+) and ferrous iron (Fe2+). The iron oxide particles are coated with a 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 (RES) is 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).

USPIO nanoparticles are composed of iron nanoparticles ~4–6 nm in diameter and the hydrodynamic diameter with dextran coating is ~20–50 nm. USPIO nanoparticles have a long plasma half-life because of their small size. The blood pool half-life of plasma relaxation times is calculated at ~24 h in humans (2) and 2 h in mice (3). Because of its long blood half-life, USPIO can be used as blood pool agent during the early phase of intravenous administration (4). In the late phase, USPIO is suitable for the evaluation of RES in the body, particularly in lymph nodes (5).

Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (6). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The αvβ3 integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (7-12). Expression of αvβ3 integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. The αvβ3 antagonists are being studied as antitumor and antiangiogenic agents, and the agonists are being studied as angiogenic agents for coronary angiogenesis (11, 13, 14). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including αvβ3. Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (15).

Most of the cyclic RGD peptides comprise five amino acids. Haubner et al. (16) reported that various cyclic RGD peptides exhibit selective inhibition of binding to αvβ3 integrin (inhibition concentration (IC50), 7–40 nM) but not to αvβ5 (IC50, 600–4,000 nM) or αIIbβ3 (IC50, 700–5,000 nM) integrins. Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (17). The cyclo(Arg-Gly-Asp-D-Try-Glu) (c(RGDyE)) peptide was conjugated to USPIO nanoparticles for non-invasive MRI of αvβ3 expression on activated endothelial cells in tumor (18).

Synthesis

[PubMed]

Zhang et al. (18) reported the synthesis of c(RGDyE)-USPIO nanoparticles by conjugation of c(RGDyE) to USPIO nanoparticles coated with 3-aminopropyltrimethoxysilane (APTMS). First, 200 μg of c(RGDyE) were added to a mixture of N-hydrosuccinimide and 1-ethyl-3-(dimethylaminopropyl)carbodimide hydrochloride at room temperature for 15 min. Then APTMS-coated USPIO nanoparticles (20 mg) were mixed into the solution at room temperature for 60 min. The c(RGDyE)-USPIO nanoparticles were separated with a magnet. The c(RGDyE)-USPIO exhibited an r2 value of 134 mM-1 s-1 and had a diameter of 10 ± 3 nm as determined by transmission electron microscopy.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Zhang et al. (18) performed in vitro binding studies of c(RGDyE)-USPIO and USPIO in cultured human umbilical vein endothelial cells (HUVECs) with T2-weighted MRI. Image intensity and T2 relaxation time measurements demonstrated a significantly higher (P<0.01) negative enhancement of c(RGDyE)-USPIO (79.90 ± 8.04 ms) than USPIO (176.20 ± 0.84 ms) on HUVECs after 10 min of incubation. Co-incubation with c(RGDyE) partially reversed the T2 relaxation time to 99.2 ± 10.03 ms. However, the USPIO nanoparticle uptake values were similar for all conditions after 3 h of incubation.

Animal Studies

Rodents

[PubMed]

Zhang et al. (18) used a clinical 1.5-T MRI scanner to perform in vivo MRI in nude mice with human squamous cell carcinoma HaCaT-ras-A-5RT3 (HaCaT; high αvβ3 expression) or A431 (low αvβ3 expression) xenografts. Injection of c(RGDyE)-USPIO (0.9 mmol Fe/kg) nanoparticles provided significantly larger decreases in MRI signal intensity and T2 relaxation time in the mice (n = 8) with a HaCaT tumor than in mice (n = 6) with an A431 tumor at 6 h after injection. Furthermore, T2*-weighted images clearly identified the heterogeneous arrangement of blood vessels with αvβ3 integrins in HaCaT tumors by an irregular decrease in signal intensity. In contrast, in A431 tumors with predominantly small and uniformly distributed blood vessels, the signal intensity decreased more homogeneously. Immunohistochemical measurements of the excised tumors revealed focal vascularized areas with high levels of αvβ3 integrins in HaCaT tumors and more homogeneous vascularization in A431 tumors. The liver exhibited a significant decrease in T2 relaxation time, whereas no significant changes in T2 relaxation times were observed in the kidney or muscle. There were no differences in changes of T2 relaxation time in the tumors or liver between the control USPIO nanoparticles and the c(RGDyE)-USPIO. 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.

References

1.
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]
2.
McLachlan S.J., Morris M.R., Lucas M.A., Fisco R.A., Eakins M.N., Fowler D.R., Scheetz R.B., Olukotun A.Y. Phase I clinical evaluation of a new iron oxide MR contrast agent. J Magn Reson Imaging. 1994;4(3):301–7. [PubMed: 8061425]
3.
Weissleder R., Elizondo G., Wittenberg J., Rabito C.A., Bengele H.H., Josephson L. Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. Radiology. 1990;175(2):489–93. [PubMed: 2326474]
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Stillman A.E., Wilke N., Li D., Haacke M., McLachlan S. Ultrasmall superparamagnetic iron oxide to enhance MRA of the renal and coronary arteries: studies in human patients. J Comput Assist Tomogr. 1996;20(1):51–5. [PubMed: 8576482]
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Anzai Y., Piccoli C.W., Outwater E.K., Stanford W., Bluemke D.A., Nurenberg P., Saini S., Maravilla K.R., Feldman D.E., Schmiedl U.P., Brunberg J.A., Francis I.R., Harms S.E., Som P.M., Tempany C.M. Evaluation of neck and body metastases to nodes with ferumoxtran 10-enhanced MR imaging: phase III safety and efficacy study. Radiology. 2003;228(3):777–88. [PubMed: 12954896]
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Hynes R.O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992;69(1):11–25. [PubMed: 1555235]
7.
Jin H., Varner J. Integrins: roles in cancer development and as treatment targets. Br J Cancer. 2004;90(3):561–5. [PMC free article: PMC2410157] [PubMed: 14760364]
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Varner J.A., Cheresh D.A. Tumor angiogenesis and the role of vascular cell integrin alphavbeta3. Important Adv Oncol. 1996:69–87. [PubMed: 8791129]
9.
Wilder R.L. Integrin alpha V beta 3 as a target for treatment of rheumatoid arthritis and related rheumatic diseases Ann Rheum Dis 2002. 61Suppl 2ii96–9. [PMC free article: PMC1766704] [PubMed: 12379637]
10.
Grzesik W.J. Integrins and bone--cell adhesion and beyond. Arch Immunol Ther Exp (Warsz) 1997;45(4):271–5. [PubMed: 9523000]
11.
Kumar C.C. Integrin alpha v beta 3 as a therapeutic target for blocking tumor-induced angiogenesis. Curr Drug Targets. 2003;4(2):123–31. [PubMed: 12558065]
12.
Ruegg C., Dormond O., Foletti A. Suppression of tumor angiogenesis through the inhibition of integrin function and signaling in endothelial cells: which side to target? Endothelium. 2002;9(3):151–60. [PubMed: 12380640]
13.
Kerr J.S., Mousa S.A., Slee A.M. Alpha(v)beta(3) integrin in angiogenesis and restenosis. Drug News Perspect. 2001;14(3):143–50. [PubMed: 12819820]
14.
Mousa S.A. alphav Vitronectin receptors in vascular-mediated disorders. Med Res Rev. 2003;23(2):190–9. [PubMed: 12500288]
15.
Haubner R., Wester H.J. Radiolabeled tracers for imaging of tumor angiogenesis and evaluation of anti-angiogenic therapies. Curr Pharm Des. 2004;10(13):1439–55. [PubMed: 15134568]
16.
Haubner R., Wester H.J., Burkhart F., Senekowitsch-Schmidtke R., Weber W., Goodman S.L., Kessler H., Schwaiger M. Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics. J Nucl Med. 2001;42(2):326–36. [PubMed: 11216533]
17.
Chen X., Park R., Shahinian A.H., Tohme M., Khankaldyyan V., Bozorgzadeh M.H., Bading J.R., Moats R., Laug W.E., Conti P.S. 18F-labeled RGD peptide: initial evaluation for imaging brain tumor angiogenesis. Nucl Med Biol. 2004;31(2):179–89. [PubMed: 15013483]
18.
Zhang C., Jugold M., Woenne E.C., Lammers T., Morgenstern B., Mueller M.M., Zentgraf H., Bock M., Eisenhut M., Semmler W., Kiessling F. Specific targeting of tumor angiogenesis by RGD-conjugated ultrasmall superparamagnetic iron oxide particles using a clinical 1.5-T magnetic resonance scanner. Cancer Res. 2007;67(4):1555–62. [PubMed: 17308094]
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