Lanthanide complexes as fluorescent indicators for neutral sugars and cancer biomarkers

Abstract

Simple water-soluble lanthanum and europium complexes are effective at detecting neutral sugars as well as glycolipids and phospholipids. In solutions at physiologically relevant pH the fluorescent lanthanum complex binds neutral sugars with apparent binding constants comparable to those of arylboronic acids. Interference from commonly occurring anions is minimal. The europium complex detects sialic acid-containing gangliosides at pH 7.0 over an asialoganglioside. This selectivity is attributed, in large part, to the cooperative complexation of the oligosaccharide and sialic acid residues to the metal center, based on analogous prior studies. In MeOH, lysophosphatidic acid (LPA), a biomarker for several pathological conditions including ovarian cancer, is selectively detected by the europium complex. LPA is also detected via a fluorescence increase in human plasma samples. The 2-sn-OH moiety of LPA plays a key role in promoting binding to the metal center. Other molecules found in common brain ganglioside and phospholipid extracts do not interfere in the ganglioside or LPA fluorescence assays.gangliosides ͉ lysophosphatidic acid ͉ salophenes ͉ saccharides N ature uses tools such as lectins for the molecular recognition of saccharides. An important mode of lectin binding involves the coordination of a carbohydrate ligand to a metal center. C-type lectins recognize saccharides in a calciumdependent manner (1). The similar properties of lanthanides and calcium render trivalent lanthanide ions useful substitutes for Ca 2ϩ in studying proteins (2). Herein we describe the utility of water-soluble salophene (3)-lanthanide complexes toward addressing three current challenges: (i) the detection of neutral carbohydrates at physiologically relevant pH, (ii) the selective detection of gangliosides, and (iii) the selective detection of lysophosphatidic acid (LPA). Results and DiscussionDetection of Neutral Sugars at Physiological pH. A main problem in the detection of neutral sugars with artificial receptors is competitive binding by bulk water. Elevated solution pH is therefore typically required to attain a useful degree of coordination and signal transduction in the most innovative new metal-based detection methods (4, 5). There is an unmet demand for biomimetic sugar-sensing agents that function in neutral buffer solution (4, 5). Because La 3ϩ and Ca 2ϩ exhibit relatively strong affinity for saccharides as compared with most other metal ions (6, 7), we hypothesize that 1 (Fig. 1) may be useful for detecting sugars in neutral aqueous media. Interestingly, lanthanides can extend their ligand coordination number by the addition of either neutral or charged ligands through ligand-sphere extension, leading to highly coordinated complexes (8).Addition of saccharides (1.1 ϫ 10 Ϫ3 M) to a solution of 1 (5.53 ϫ 10 Ϫ6 M, 0.1 M Hepes buffer, pH 7.0) promotes readily monitored increases in emission (Figs. 1 and 2) (ref. 9 and references therein). Lanthanide coordination to salens whereby the ligand conformation is brought into a mor...

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