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Cited by 270

The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.

Selective Tumor Cell Targeting Using Low-Affinity, Multivalent Interactions

Carlson, Coby B., Mowery, Patricia, Owen, Robert M., Dykhuizen, Emily C., Kiessling, Laura L.·2007·ACS Chemical Biology
DOI 10.1021/cb6003788
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Abstract

This report highlights the advantages of low-affinity, multivalent interactions to recognize one cell type over another. Our goal was to devise a strategy to mediate selective killing of tumor cells, which are often distinguished from normal cells by their higher levels of particular cell surface receptors. To test whether multivalent interactions could lead to highly specific cell targeting, we used a chemically synthesized small-molecule ligand composed of two distinct motifs: (1) an Arg-Gly-Asp (RGD) peptidomimetic that binds tightly (Kd approximately 10(-9)M) to alphavbeta3 integrins and (2) the galactosyl-alpha(1-3)galactose (alpha-Gal epitope), which is recognized by human anti-alpha-galactosyl antibodies (anti-Gal). Importantly, anti-Gal binding requires a multivalent presentation of carbohydrate residues; anti-Gal antibodies interact weakly with the monovalent oligosaccharide (Kd approximately 10(-5)M) but bind tightly (Kd approximately 10(-11) M) to multivalent displays of alpha-Gal epitopes. Such a display is generated when the bifunctional conjugate decorates a cell possessing a high level of alphavbeta3 integrin; the resulting cell surface, which presents many alpha-Gal epitopes, can recruit anti-Gal, thereby triggering complement-mediated lysis. Only those cells with high levels of the integrin receptor are killed. In contrast, doxorubicin tethered to the RGD-based ligand affords indiscriminate cell death. These results highlight the advantages of exploiting the type of the multivalent recognition processes used by physiological systems to discriminate between cells. The selectivity of this strategy is superior to traditional, abiotic, high-affinity targeting methods. Our results have implications for the treatment of cancer and other diseases characterized by the presence of deleterious cells.

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Metadata

Authors
Carlson, C. B., Mowery, P., Owen, R. M., Dykhuizen, E. C., & Kiessling, L. L.
Venue
ACS Chemical Biology
Publisher
American Chemical Society (ACS)
Published
2007-01-26
Volume
2
Issue
2
Pages
119-127
ISSN
  • 1554-8929 (ISSN-L)
  • 1554-8937
DOI
10.1021/cb6003788
OpenAlex
W1971969520
Cited by
270
References
40
FWCI
11.73
Type
journal article
Language
en
Open access
closed

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