89Zr-N-Succinyldesferrioxamine-bevacizumab -- Molecular Imaging and Contrast Agent Database -- NCBI Bookshelf

Background

Vascular endothelial growth factor (VEGF) consists of at least six isoforms of various numbers of amino acids (121, 145, 165, 183, 189, and 206 amino acids) produced through alternative splicing (1). VEGF₁₂₁, VEGF₁₆₅, and VEGF₁₈₉ are the forms secreted by most cell types and are active as homodimers linked by disulfide bonds. VEGF₁₂₁ does not bind to heparin like the other VEGF species do (2). VEGF is a potent angiogenic factor that induces proliferation, sprouting, migration, and tube formation of endothelial cells. There are three high-affinity tyrosine kinase VEGF receptors (VEGFR-1, Flt-1; VEGFR-2, KDR/Flt-1; and VEGFR-3, Flt-4) on endothelial cells. Several types of non-endothelial cells such as hematopoietic stem cells, melanoma cells, monocytes, osteoblasts, and pancreatic β cells also express VEGF receptors (1).

VEGF is overexpressed in various tumor cells and tumor-associated endothelial cells (3). Inhibition of VEGF receptor function has been shown to inhibit pathological angiogenesis as well as tumor growth and metastasis (4, 5). Radiolabeled VEGF has been developed as a single-photon emission computed tomography tracer for imaging solid tumors and angiogenesis in humans (6-8). However, several studies have shown that cancer treatments (photodynamic therapy, radiotherapy, and chemotherapy) can lead to increased tumor VEGF expression and subsequently to more aggressive disease (9, 10). Therefore, it is important to measure VEGF levels in the tumors to design better anti-cancer treatment protocols. Bevacizumab is a humanized antibody against VEGF-A. It binds to all VEGF isoforms. Bevacizumab is approved for clinical use in metastatic colon carcinoma and non-small cell lung cancer. Nagengast et al. (11) prepared ⁸⁹Zr-N-succinyldesferrioxamine-bevacizumab (⁸⁹Zr-bevacizumab) for imaging VEGF expression in nude mice bearing SKOV-3 human ovarian tumor xenografts.

Synthesis

[PubMed]

N-Succinyldesferrioxamine (N-sucDf) B-tetrafluorophenol and bevacizumab were incubated in sodium carbonate buffer (pH 9.5) for 30 min at room temperature (11). N-sucDf-Bevacizumab was isolated from the incubation mixture with ultrafiltration. There were 1.5–2.5 chelate groups per antibody. N-sucDf-Bevacizumab was mixed with ⁸⁹Zr-oxalate. The mixture was incubated for 45 min at room temperature. ⁸⁹Zr-Bevacizumab had a radiochemical purity of >99% and a specific activity 8.8 MBq/nmol (0.24 mCi/nmol) with a labeling yield of 98 ± 0.7%. ⁸⁹Zr-Bevacizumab was stable for 7 d at 4°C in ammonium acetate and at 37°C in serum. ⁸⁹Zr-Bevacizumab resulted in 54.0 ± 3.7% binding to VEGF. Bevacizumab (≥500-fold) almost completely blocked ⁸⁹Zr-bevacizumab binding to <5%.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

No publication is currently available.

Animal Studies

Rodents

[PubMed]

Nagengast et al. (11) performed biodistribution studies of 3.5 MBq (0.095 mCi) ⁸⁹Zr-bevacizumab (100 µg, ~0.66 nmol) in nude mice bearing human SKOV-3 ovarian tumor xenografts. Tumor uptake values were 4.85% injected dose (ID)/g at 1 d, 4.36% ID/g at 3 d, and 6.97% ID/g at 7 d. The radioactivity level in the blood was 9.54, 5.60, and 3.75% ID/g at 1, 3, and 7 d, respectively. The organs with the highest uptake were the lung (3.50% ID/g), liver (3.98% ID/g), spleen (3.22% ID/g), and kidneys (2.51% ID/g), with little radioactivity in the muscle (0.60% ID/g) at 3 d after injection. Tumor/muscle ratio was ~10. Tumor uptake determined with positron emission tomography images was 7.38 ± 2.06% ID/g for ⁸⁹Zr-bevacizumab and 3.39 ± 1.16% ID/g for human ⁸⁹Zr-IgG (P = 0.011) at 7 d. 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.

Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004; 25(4): 581–611. [PubMed]

2.

Cohen T., Gitay-Goren H., Sharon R., Shibuya M., Halaban R., Levi B.Z., Neufeld G. VEGF121, a vascular endothelial growth factor (VEGF) isoform lacking heparin binding ability, requires cell-surface heparan sulfates for efficient binding to the VEGF receptors of human melanoma cells. J Biol Chem. 1995; 270(19): 11322–6. [PubMed]

3.

Soria J.C., Fayette J., Armand J.P. Molecular targeting: targeting angiogenesis in solid tumors Ann Oncol 2004. 15:Suppl 4iv223–7. [PubMed].

4.

Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy Oncologist 2004. 9:Suppl 12–10. [PubMed].

5.

Hicklin D.J., Ellis L.M. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005; 23(5): 1011–27. [PubMed]

6.

Li S., Peck-Radosavljevic M., Koller E., Koller F., Kaserer K., Kreil A., Kapiotis S., Hamwi A., Weich H.A., Valent P., Angelberger P., Dudczak R., Virgolini I. Characterization of (123)I-vascular endothelial growth factor-binding sites expressed on human tumour cells: possible implication for tumour scintigraphy. Int J Cancer. 2001; 91(6): 789–96. [PubMed]

7.

Li S., Peck-Radosavljevic M., Kienast O., Preitfellner J., Hamilton G., Kurtaran A., Pirich C., Angelberger P., Dudczak R. Imaging gastrointestinal tumours using vascular endothelial growth factor-165 (VEGF165) receptor scintigraphy. Ann Oncol. 2003; 14(8): 1274–7. [PubMed]

8.

Li S., Peck-Radosavljevic M., Kienast O., Preitfellner J., Havlik E., Schima W., Traub-Weidinger T., Graf S., Beheshti M., Schmid M., Angelberger P., Dudczak R. Iodine-123-vascular endothelial growth factor-165 (123I-VEGF165). Biodistribution, safety and radiation dosimetry in patients with pancreatic carcinoma. Q J Nucl Med Mol Imaging. 2004; 48(3): 198–206. [PubMed]

9.

Gorski D.H., Beckett M.A., Jaskowiak N.T., Calvin D.P., Mauceri H.J., Salloum R.M., Seetharam S., Koons A., Hari D.M., Kufe D.W., Weichselbaum R.R. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res. 1999; 59(14): 3374–8. [PubMed]

10.

Solban N., Selbo P.K., Sinha A.K., Chang S.K., Hasan T. Mechanistic investigation and implications of photodynamic therapy induction of vascular endothelial growth factor in prostate cancer. Cancer Res. 2006; 66(11): 5633–40. [PubMed]

11.

Nagengast W.B., de Vries E.G., Hospers G.A., Mulder N.H., de Jong J.R., Hollema H., Brouwers A.H., van Dongen G.A., Perk L.R., Lub-de Hooge M.N. In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft. J Nucl Med. 2007; 48(8): 1313–9. [PubMed]

Chemical name:	⁸⁹Zr-N-Succinyldesferrioxamine-bevacizumab
Abbreviated name:	⁸⁹Zr-Bevacizumab
Synonym:
Agent category:	Antibody
Target:	Vascular endothelial growth factor (VEGF)
Target category:	Antigen
Method of detection:	PET
Source of signal/contrast:	⁸⁹Zr
Activation:	No
Studies:	Rodents	Click on protein, nucleotide (RefSeq), and gene for more information about VEGF.

89Zr-N-Succinyldesferrioxamine-bevacizumab[89Zr-Bevacizumab]

Background

Synthesis

In Vitro Studies: Testing in Cells and Tissues

Animal Studies

Rodents

Other Non-Primate Mammals

Non-Human Primates

Human Studies

⁸⁹Zr-N-Succinyldesferrioxamine-bevacizumab
[⁸⁹Zr-Bevacizumab]