Carbohydrate Dependent Targeting of Cancer Cells by Bleomycin−Microbubble Conjugates

Chapuis, Jean Charles; Schmaltz, Ryan M.; Tsosie, Krystal S.; Bělohlávek, Marek; Hecht, Sidney M.

doi:10.1021/ja8091104

Cited by 44 publications

(61 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5 Microbubbles, used traditionally as contrast agents for ultrasonography, have recently been modified with ligands that bind to specific receptors on cancer (and other) cell surfaces in an effort to probe ligand-cell surface interactions. 6 For this study, the C-terminus of BLM was acylated with biotin and bound to commercially available streptavidin-derivatized microbubbles.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Selective Tumor Cell Targeting by the Disaccharide Moiety of Bleomycin

et al. 2013

Self Cite

View full text Add to dashboard Cite

In a recent study, the well documented tumor targeting properties of the antitumor agent bleomycin (BLM) were studied in cell culture using microbubbles that had been derivatized with multiple copies of BLM. It was shown that BLM selectively targeted MCF-7 human breast carcinoma cells, but not the “normal” breast cell line MCF-10A. Further, the BLM analogue deglycobleomycin, which lacks the disaccharide moiety of BLM, was found not to target either cell line, indicating that the BLM disaccharide moiety is necessary for tumor selectivity. Not resolved in the earlier study was the issue of whether the BLM disaccharide moiety alone is sufficient for tumor cell targeting, as well as the possible cellular uptake of the disaccharide. In the present study, we have conjugated BLM, deglycoBLM and BLM disaccharide to the cyanine dye Cy5**. It was found that the BLM and BLM disaccharide conjugates, but not the deglycoBLM conjugate, bound selectively to MCF-7 cells, and were internalized. The same was also true for the prostate cancer cell line DU-145 (but not for normal PZ-HPV-7 prostate cells) and for the pancreas cancer cell line BxPC-3 (but not for normal SVR A221a pancreas cells). The targeting efficiency of the disaccharide was only slightly less than that of BLM in MCF-7 and DU-145 cells, and comparable to BLM in BxPC-3 cells. These results establish that the BLM disaccharide is both necessary and sufficient for tumor cell targeting, a finding with obvious implications for the design of novel tumor imaging and therapeutic agents.

show abstract

mentioning

confidence: 99%

“…It was shown that BLM-derivatized, but not streptavidin-derivatized microbubbles bound to MCF-7 human breast carcinoma cells but not to the “normal” MCF-10A breast cell line. 5 To define the structural elements in BLM responsible for tumor targeting, the same experiment was performed using deglycoBLM, i.e. lacking the disaccharide moiety.…”

mentioning

confidence: 99%

Selective Tumor Cell Targeting by the Disaccharide Moiety of Bleomycin

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…3 It is employed for the treatment of several types of cancer, notably squamous cell carcinomas and malignant lymphomas. 4 The therapeutically useful effects of bleomycin are believed to be due both to its unique ability to target tumor cells selectively 5,6 and its ability to mediate double-strand cleavage of DNA. 7 …”

mentioning

confidence: 99%

The Carbamoylmannose Moiety of Bleomycin Mediates Selective Tumor Cell Targeting

Bhattacharya

Rishel

et al. 2014

Biochemistry

Self Cite

View full text Add to dashboard Cite

Recently, we reported that both bleomycin (BLM) and its disaccharide, conjugated to the cyanine dye Cy5**, bound selectively to cancer cells. Thus, the disaccharide moiety alone recapitulates the tumor cell targeting properties of BLM. Here, we demonstrate that the conjugate of the BLM carbamoylmannose moiety with Cy5** showed tumor cell selective binding and also enhanced cellular uptake in most cancer cell lines. The carbamoyl functionality was required for tumor cell targeting. A dye conjugate prepared from a trivalent cluster of carbamoylmannose exhibited levels of tumor cell binding and internalization significantly greater than those of the simple carbamoylmannose–dye conjugate, consistent with a possible multivalent receptor.

show abstract

“…15,21,22 The dye Cy5** was chosen as the fluorescent probe to circumvent initially encountered problems of autofluorescence and nonspecific cell surface binding. Cys5** is a cyanine dye exhibiting emission wavelengths in the red or near-infrared region.…”

Section: Discussionmentioning

confidence: 99%

Modified Bleomycin Disaccharides Exhibiting Improved Tumor Cell Targeting

Madathil

Bhattacharya

et al. 2014

Biochemistry

Self Cite

View full text Add to dashboard Cite

The bleomycins (BLMs) are a family of antitumor antibiotics used clinically for anticancer chemotherapy. Their antitumor selectivity derives at least in part from their ability to target tumor cells, a property that resides in the carbohydrate moiety of the antitumor agent. In earlier studies, we have demonstrated that the tumor cell selectivity resides in the mannose carbamoyl moiety of the BLM saccharide and that both the BLM disaccharide and monosaccharide containing the carbamoyl moiety were capable of the delivery/uptake of a conjugated cyanine dye into cultured cancer cell lines. Presently, the nature of the participation of the carbamoyl moiety has been explored further to provide compounds of utility for defining the nature of the mechanism of tumor cell recognition and uptake by BLM saccharides and in the hope that more efficient compounds could be identified. A library of seven disaccharide–Cy5** dye conjugates was prepared that are structural analogues of the BLM disaccharide. These differed from the natural BLM disaccharide in the position, orientation, and substitution of the carbamoyl group. Studies of these compounds in four matched sets of tumor and normal cell lines revealed a few that were both tumor cell selective and internalized 2–4-fold more efficiently than the natural BLM disaccharide.

show abstract

Carbohydrate Dependent Targeting of Cancer Cells by Bleomycin−Microbubble Conjugates

Cited by 44 publications

References 24 publications

Selective Tumor Cell Targeting by the Disaccharide Moiety of Bleomycin

Selective Tumor Cell Targeting by the Disaccharide Moiety of Bleomycin

The Carbamoylmannose Moiety of Bleomycin Mediates Selective Tumor Cell Targeting

Modified Bleomycin Disaccharides Exhibiting Improved Tumor Cell Targeting

Contact Info

Product

Resources

About