Selective tumor cell targeting using low-affinity, multivalent interactions

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 (K-d approximate to 10(9) M) to alpha(v)beta(3) integrins and (2) the galactosyl-alpha(13)galactose (alpha-Gal epitope), which is recognized by human anti--galactosyl antibodies (anti-Gal). Importantly, anti-Gal binding requires a multivalent presentation of carbohydrate residues; anti-Gal antibodies interact weakly with the monovalent oligosaccharide (K-d approximate to 10(-5) M) but bind tightly (K-d approximate to 10(-11) M) to multivalent displays of -Gal epitopes. Such a display is generated when the bifunctional conjugate decorates a cell possessing a high level of alpha(v)beta(3) integrin; the resulting cell surface, which presents many -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.