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18F-Labeled N-succinimidyl-4-fluorobenzoate–conjugated rat anti-mouse vascular endothelial growth factor receptor 2 monoclonal antibody linked to microbubbles

[18F]-4SFB-Avas12a1 MB
, PhD
National Center for Biotechnology Information, NLM, Bethesda, MD 20894

Created: ; Last Update: March 15, 2012.

Chemical name:18F-Labeled N-succinimidyl-4-fluorobenzoate–conjugated rat anti-mouse vascular endothelial growth factor receptor 2 monoclonal antibody linked to microbubbles
Abbreviated name:[18F]-4SFB-Avas12a1 MB
Synonym:
Agent Category:Antibody
Target:Vascular endothelial growth factor receptor 2
Target Category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal / contrast:18F
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Structure not available in PubChem.

Background

[PubMed]

Microbubbles (MBs) are spherical shells that are made of various types of biocompatible materials, such as albumin, carbohydrates, lipids or polymers, and are filled with heavy gases (nitrogen, perfluorocarbon, or sulfur hexafluoride) in the core. In the clinic, MBs are commonly used for the noninvasive real-time imaging of inflammation, thrombus formation, and angiogenesis with ultrasonography (1, 2). The features and utility of MBs have been discussed recently by Postema and Gilja (3). Targeted MBs can be generated by coating the MB shells with small molecules, peptides, proteins, or antibodies (Abs) that have a high binding affinity for disease-specific molecular markers, such as αVβ3 integrins, endoglin, and the vascular endothelial growth factor receptor 2 (VEGFR2), which are expressed on the surface of endothelial cells (2). Because MBs are inexpensive, widely available, and easy to use, there is much interest in the preclinical development and evaluation of targeted MBs for the imaging of diseases related to the circulatory system (4). Investigators are particularly interested in targeting the VEGFR2 with MBs because, once activated, this receptor initiates several signal transduction pathways that influence the differentiation, mitogenic potential, and migration of the endothelial cells, and VEGFR2 is overexpressed in cancerous tumors to promote angiogenesis in the lesions. In addition, VEGFR2 is the target of several antiangiogenic drugs that have been approved by the United States Food and Drug Administration for the treatment of various cancers (e.g., bevacizumab, an anti-VEGFR2 Ab). It was shown in a preclinical study that MBs coated with a rat anti-mouse VEGFR2 Ab (Avas12a1 MBs) can be used with ultrasonography imaging to visualize tumor angiogenesis in mice, but the biodistribution of the targeted MBs was not investigated (5). However, it is important to study the biodistribution of a therapeutic drug or an imaging agent because such investigations are essential to determine the pharmacokinetics, nonspecific targets, and side effects of a drug or imaging agent. Therefore, in continuation of the earlier study (5), the biodistribution of 18F-labeled Avas12a1 MBs was investigated with dynamic micro-positron emission tomography (micro-PET) in mice bearing mouse angiosarcoma SVR cell tumors (2).

Synthesis

[PubMed]

The MBs (lipid shells containing perfluorocarbon) and the rat anti-mouse VEGFR2 Ab used in the different studies were obtained from commercial sources (2). Initially 18F-labeled N-succinimidyl 4-fluorobenzoate ([18F]-4SFB; specific activity 200–250 GBq/μmol (5.4–6.75 Ci/μmol)) was conjugated to Avas12a1, and the radiolabeled Ab was then used to coat the MBs for the generation of [18F]-4SFB-Avas12a1 MBs as described by Willmann et al. (2). The radiochemical yield, radiochemical purity, the SFB/Avas12a1 ratio per MB and specific activity of the final labeled product were not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

No publication is currently available.

Animal Studies

Rodents

[PubMed]

The biodistribution of [18F]-4SFB-Avas12a1 MBs was studied in mice bearing SVR cell tumors as detailed by Willmann et al. (2). The animals (n = 4 mice; under anesthesia) were injected with 2.1 MBq (~57 μCi) of the radiolabeled MBs through the tail vein, and dynamic micro-PET imaging of the animals was initiated immediately before injection and continued for up to 60 min postinjection (p.i.) (2). The imaging data was analyzed with suitable nonproprietary software, and the amount of label accumulated in the various tissues was calculated from the images as a percentage of injected dose per gram tissue (% ID/g). The liver and spleen showed accumulation values of 34.4 ± 7.3% ID/g and 11.4 ± 10.1% ID/g, respectively, at 4 min p.i. The amount of label in the liver remained relatively constant (33.4 ± 13.7% ID/g) up to 60 min p.i., but the spleen showed a decrease in accumulated radioactivity (9.3 ± 6.5% ID/g) over this period. The peak amount of tracer in the blood was 24.5 ± 1.1% ID/g at 30 sec p.i., which decreased to 8.8 ± 0.4% ID/g at 4 min p.i. and to 0.5 ± 0.3% ID/g at 60 min p.i. The time taken to clear 50% of radioactivity from the blood was reported to be ~3.5 min. All other organs showed uptake values of <1.0% ID/g up to 60 min p.i. The tumors showed a significantly higher (P < 0.0001) accumulation of radioactivity (1.14 ± 0.41% ID/g at 4 min p.i. and 1.35 ± 0.16% ID/g at 60 min p.i.) compared to the surrounding skeletal muscles (0.84 ± 0.53% ID/g at 4 min p.i. and 0.84 ± 0.58% ID/g at 60 min p.i.). No blocking studies were reported.

To determine the in vivo stability of [18F]-4SFB and [18F]-4SFB-Avas12a1, the biodistribution of these tracers was investigated with dynamic micro-PET imaging in normal mice (n = 3 animals/radiolabeled compound) as described above (2). With the labeled Abs, a high uptake of radioactivity was observed in the liver (29.3 ± 1.9% ID/g at 4 min p.i and 30.2 ± 8.4% ID/g at 60 min p.i.) and the blood (28.5 ± 2.7% ID/g at 4 min p.i. and 20.8 ± 1.8% ID/g at 60 min p.i.). This indicated that, compared with the radiolabeled targeted MBs, the labeled Abs cleared slowly from the blood pool and stayed in circulation for at least 60 min p.i. In addition, a high accumulation of radioactivity was also observed in the kidneys (15.1 ± 4.1% ID/g at 4 min p.i. and 25.4 ± 7.7% ID/g at 60 min p.i.). After the administration of [18F]-4SFB the radioactivity was cleared rapidly through the kidneys (47.9 ± 3.7% ID/g at 4 min p.i. and 72.7 ± 26.3% ID/g at 60 min p.i.). The accumulation of radioactivity in the liver from the [18F]-4SFB was low (6.9 ± 5.2% ID/g at 4 min p.i. and 5.2 ± 2.9% ID/g) at 60 min p.i. compared to the accumulation observed with the radiolabeled MBs or [18F]-4SFB-Avas12a1 at the same time point.

Ex vivo biodistribution studies with the labeled MBs in nude mice (n = 3 animals/time point) showed that the trend of radioactivity uptake by the different organs of the animals was similar to that observed during the in vivo dynamic micro-PET imaging study described above (2).

From these studies, the investigators concluded that dynamic micro-PET imaging can be used to study the biodistribution of 18F-labeled targeted MBs in rodents (2).

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.

Supplemental Information

[Disclaimers]

No information is currently available.

NIH Support

These studies were supported by National Heart, Lung and Blood Institute grant 1 R01 HL078632 and National Cancer Institute grant CA114747.

References

1.
Deshpande N., Needles A., Willmann J.K. Molecular ultrasound imaging: current status and future directions. Clin Radiol. 2010;65(7):567–81. [PMC free article: PMC3144865] [PubMed: 20541656]
2.
Willmann J.K., Cheng Z., Davis C., Lutz A.M., Schipper M.L., Nielsen C.H., Gambhir S.S. Targeted microbubbles for imaging tumor angiogenesis: assessment of whole-body biodistribution with dynamic micro-PET in mice. Radiology. 2008;249(1):212–9. [PMC free article: PMC2657857] [PubMed: 18695212]
3.
Postema M., Gilja O.H. Contrast-enhanced and targeted ultrasound. World J Gastroenterol. 2011;17(1):28–41. [PMC free article: PMC3016677] [PubMed: 21218081]
4.
Pysz M.A., Willmann J.K. Targeted contrast-enhanced ultrasound: an emerging technology in abdominal and pelvic imaging. Gastroenterology. 2011;140(3):785–90. [PMC free article: PMC4162392] [PubMed: 21255573]
5.
Willmann J.K., Paulmurugan R., Chen K., Gheysens O., Rodriguez-Porcel M., Lutz A.M., Chen I.Y., Chen X., Gambhir S.S. US imaging of tumor angiogenesis with microbubbles targeted to vascular endothelial growth factor receptor type 2 in mice. Radiology. 2008;246(2):508–18. [PMC free article: PMC4157631] [PubMed: 18180339]
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