Abstract
Aberrant glycosylation has been proven to correlate with various diseases including cancer. An important alteration in cancer progression is an increased level of sialylation, making sialic acid one of the key constituents in tumor-specific glycans and an interesting biomarker for a diversity of cancer types. Developing molecularly imprinted polymers (MIPs) with high affinity toward sialic acids is an important task that can help in early cancer diagnosis. In this work, the glycospecific MIPs are produced using cooperative covalent/noncovalent imprinting. We report here on the fundamental investigation of this termolecular imprinting approach. This comprises studies of the relative contribution of orthogonally interacting functional monomers and their synergetic behavior and the choice of different counterions on the molecular recognition properties for the sialylated targets. Combining three functional monomers targeting different functionalities on the template led to enhanced imprinting factors (IFs) and selectivities. This apparent cooperative effect was supported by 1H NMR and fluorescence titrations of monomers with templates or template analogs. Moreover, highlighting the role of the template counterion use of tetrabutylammonium (TBA) salt of sialic acid resulted in better imprinting than that of sodium salts supported by both in solution interaction studies and in MIP rebinding experiments. The glycospecific MIPs display high affinity for sialylated targets, with an overall low binding of other nontarget saccharides.
Highlights
Sialic acids (SAs) are an important family of 9-carbon monosaccharides that are typically found as terminal moieties of N-glycans, O-glycans, and glycosphingolipids
A cooperative effect of the monomers was supported by the results of the solubility experiments and spectroscopic characterization of the prepolymerization solution. 4-Vinylphenylboronic acid (FM3) targets C7−C8/ C7−C9 diols or the α-hydroxy carboxylate functionality,[26] whereas urea monomer FM1 likely engage in hydrogen bonds with the carboxylate group
A study of the influence of orthogonally interacting functional monomers clearly shows that potent binding sites can be constructed, exploring cooperatively acting monomers. This effect was confirmed by both solution complex formation studies and by preparation and characterization of a small molecularly imprinted polymers (MIPs) combinatorial library
Summary
Sialic acids (SAs) are an important family of 9-carbon monosaccharides that are typically found as terminal moieties of N-glycans, O-glycans, and glycosphingolipids. Various molecular imprinting strategies for carbohydrate recognition have been reported, starting from early monosaccharide covalent boronate imprinting pioneered by Wulff[18] followed by carbohydrate receptors targeting neutral mono/oligosaccharides[19] and charged species such as SAs,[20] hyaluronic acid,[21] and glucuronic acid (GlcA).[21] Impressive glycan recognition has been achieved with molecularly imprinted polymer (MIP) nanoparticles with oriented surface imprinting[22] and tuned microenvironments[23] and by employing reversible boronate interactions or hydrogen-bonded ion pairing to target saccharide diols or acid functionalities Notwithstanding this important advance, applications of this technology to address real-world glycomics problems have not been reported. We have investigated in more detail the relative contribution of these monomers with the aim of developing practical MIP formats compatible with glycomics applications
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