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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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Biotinylated bovine serum albumin linked to gadolinium diethylenetriaminepentaacetic acid

Biotin-BSA-GdDTPA
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894, vog.hin.mln.ibcn@dacim

Created: ; Last Update: December 26, 2008.

Chemical name:Biotinylated bovine serum albumin linked to gadolinium diethylenetriamine pentaacetic acid
Abbreviated name:Biotin-BSA-GdDTPA
Synonym:
Agent Category:Protein
Target:Tumor-associated stroma
Target Category:Uptake
Method of detection:Magnetic resonance imaging (MRI)
Source of Signal/Contrast:Gadolinium
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
No structure information is available.

Background

[PubMed]

An interaction between the epithelium and the surrounding stromal tissue that are separated by a basement membrane is responsible for maintenance of the epithelial tissue. Also, the stroma contains fibroblasts, leukocytes, and epithelial cells that are embedded in an extracellular matrix. Development of an epithelial carcinoma caused by a transformation of the epithelium results in stromal changes that involve the fibroblastic stroma and are considered essential for progression of the solid cancerous tumors (1-3). The fibroblasts in the stroma are believed to differentiate into myofibroblasts that have contractile properties and characteristically produce α-smooth muscle actin (α-SMA). The myofibroblasts have been shown to participate in tumor angiogenesis that is considered essential for maintenance and progression of the cancer (1, 4-6). The myofibroblasts in turn differentiate into pericyte-like cells, and there is evidence suggesting that these cells play an important function in angiogenesis (7). Because several cell types are involved in the angiogenic process, the exact interaction between the various cell types, particularly the endothelial cells, the fibroblasts, and the myofibroblasts, is unclear. Granot et al. suggested that in vivo monitoring of the different cell types may reveal the function of each cell type in the tumor angiogenesis process (8).

The technique of magnetic resonance imaging (MRI) with the use of ferromagnetic or fluorinated nanoparticles has been used successfully to investigate cell dynamics in an in vivo setting (9, 10). Granot et al. used a similar approach to study the migration of fibroblasts after labeling them with biotinylated bovine serum albumin linked to gadolinium diethylenetriamine pentaacetate (biotin-BSA-GdDTPA) (8). Biotin-BSA-GdDTPA was also labeled with 5(6)-carboxyfluorescein succinimidyl ester (biotin-BSA-GdDTPA-FAM) to study uptake of the contrast agent (CA) by the myofibroblasts (8). Biotinylated BSA was used to facilitate labeling with avidin-conjugated 5(6)fluorescein isothiocyanate-mixed isomer (FITC) to study the biodistribution of biotin-BSA-GdDTPA in nude mice bearing fibroblast cell xenograft tumors in the hind limbs.

Synthesis

[PubMed]

The synthesis of biotin-BSA-GdDTPA and biotin-BSA-GdDTPA-FAM has been described elsewhere (11, 12). One to two biotin moieties and 27 GdDTPA moieties were reported to be bound to each BSA molecule (8).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

To investigate possible internalization of biotin-BSA-GdDTPA by tumor cells, cells derived from MLS cell (of human ovarian carcinoma origin) xenograft tumors in nude mice and normal human breast fibroblasts which were exposed to biotin-BSA-GdDTPA under ex vivo conditions (8). Confocal fluorescence microscopy of the labeled tumors or fibroblasts showed that the CA was internalized by the cells. Localization of the CA to the myofibroblasts was confirmed with the use of an alkaline phosphate-conjugated anti–α-SMA monoclonal antibody. In addition, MRI of the cells showed an increase in the R1 relaxation rate of the labeled fibroblasts in culture that remained high for at least 2 weeks; this rate also increased on cell proliferation, indicating retention, intracellular processing, and redistribution of the CA in the cells. In another study, exposure of the cells to nystatin (that inhibits caveolae-mediated endocytosis) was shown to significantly (P = 0.006) reduce uptake of biotin-BSA-GdDTPA by the cells, indicating that endocytosis and caveolae have a role in internalization of the CA (8, 13).

Animal Studies

Rodents

[PubMed]

Xenograft tumors were generated in hind limbs of CD-1 nude mice (n = 4 animals) by the co-injection of MLS (a human ovarian carcinoma cell line) and PF42T (human tumor–derived fibroblasts) cells (8). Biotin-BSA-GdDTPA was administered to these animals through the tail vein, and animals were euthanized after 30 min. To investigate CA distribution in the tumor mass, the tumors were retrieved from the animals and tumor histological sections were stained with avidin-FITC. Fluorescence microscopy revealed that the CA was present in a specific pattern associated with stromal cell tracks in the histological sections.

To investigate the in vivo visibility of cells labeled with biotin-BSA-GdDTPA, CD-1 nude mice were co-injected with MLS and cos-7 cells pre-labeled ex vivo with CA (n = 4 animals) or without CA (controls; n = 4 animals) (8). One day after the injection, MRI was performed on the animals, and a significantly higher (P = 0.01) R1 value, compared to the control animal tumors, was obtained from tumors of the CA-treated cells indicating the cells migrated to the stroma and facilitated spread of the cancer.

From these studies the investigators concluded that biotin-BSA-GdDTPA can be used for in vivo tracking of cells using MRI.

Other Non-Primate Mammals

[PubMed]

No references are currently available.

Non-Human Primates

[PubMed]

No references are currently available.

Human Studies

[PubMed]

No references are currently available.

Supplemental Information

[Disclaimers]

NIH Support

Some studies in this chapter were funded by National Institutes of Health grants RO1 CA75334 and RO1 CA90471.

References

1.
De Wever O., Mareel M. Role of tissue stroma in cancer cell invasion. J Pathol. 2003;200(4):429–47. [PubMed: 12845611]
2.
Kunz-Schughart L.A., Knuechel R. Tumor-associated fibroblasts (part II): Functional impact on tumor tissue. Histol Histopathol. 2002;17(2):623–37. [PubMed: 11962762]
3.
Kunz-Schughart L.A., Knuechel R. Tumor-associated fibroblasts (part I): Active stromal participants in tumor development and progression? Histol Histopathol. 2002;17(2):599–621. [PubMed: 11962761]
4.
Elenbaas B., Weinberg R.A. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res. 2001;264(1):169–84. [PubMed: 11237532]
5.
Walter-Yohrling J., Pratt B.M., Ledbetter S., Teicher B.A. Myofibroblasts enable invasion of endothelial cells into three-dimensional tumor cell clusters: a novel in vitro tumor model. Cancer Chemother Pharmacol. 2003;52(4):263–9. [PubMed: 12879277]
6.
Gilead A., Meir G., Neeman M. The role of angiogenesis, vascular maturation, regression and stroma infiltration in dormancy and growth of implanted MLS ovarian carcinoma spheroids. Int J Cancer. 2004;108(4):524–31. [PubMed: 14696116]
7.
Betsholtz C., Lindblom P., Gerhardt H. Role of pericytes in vascular morphogenesis. Exs. 2005;(94):115–25. [PubMed: 15617474]
8.
Granot D., Kunz-Schughart L.A., Neeman M. Labeling fibroblasts with biotin-BSA-GdDTPA-FAM for tracking of tumor-associated stroma by fluorescence and MR imaging. Magn Reson Med. 2005;54(4):789–97. [PMC free article: PMC1382177] [PubMed: 16149062]
9.
Ruiz-Cabello J., Walczak P., Kedziorek D.A., Chacko V.P., Schmieder A.H., Wickline S.A., Lanza G.M., Bulte J.W. In vivo "hot spot" MR imaging of neural stem cells using fluorinated nanoparticles. Magn Reson Med. 2008;60(6):1506–11. [PMC free article: PMC2597664] [PubMed: 19025893]
10.
Focke A., Schwarz S., Foerschler A., Scheibe J., Milosevic J., Zimmer C., Schwarz J. Labeling of human neural precursor cells using ferromagnetic nanoparticles. Magn Reson Med. 2008;60(6):1321–8. [PubMed: 19025881]
11.
Dafni H., Israely T., Bhujwalla Z.M., Benjamin L.E., Neeman M. Overexpression of vascular endothelial growth factor 165 drives peritumor interstitial convection and induces lymphatic drain: magnetic resonance imaging, confocal microscopy, and histological tracking of triple-labeled albumin. Cancer Res. 2002;62(22):6731–9. [PubMed: 12438274]
12.
Dafni H., Landsman L., Schechter B., Kohen F., Neeman M. MRI and fluorescence microscopy of the acute vascular response to VEGF165: vasodilation, hyper-permeability and lymphatic uptake, followed by rapid inactivation of the growth factor. NMR Biomed. 2002;15(2):120–31. [PubMed: 11870908]
13.
Razani B., Woodman S.E., Lisanti M.P. Caveolae: from cell biology to animal physiology. Pharmacol Rev. 2002;54(3):431–67. [PubMed: 12223531]

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