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Moleculary imprinted micro- and nanoparticles for cancer associated glycan motifs
Malmö universitet, Fakulteten för hälsa och samhälle (HS), Institutionen för biomedicinsk vetenskap (BMV). Malmö universitet, Biofilms Research Center for Biointerfaces.
2021 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Sialic acids are an important family of monosaccharides that are typically found as terminal moieties of glycans. Aberrant sialylation has been proven to correlate with various diseases including cancer. Glycosylation analysis is complex due to high diversityof the glycan isomers and their low abundance. Antibodies and lectins are commonly used in glycan purification and enrichment. However, high cost, poor availability, and limitation in storage/testing conditions hinders their application on a broader scale. This thesis is focused on the development of alternative glycan specific receptors with their potential applications in glycomics and cell imaging. The underlying technique for producing the synthetic receptors is molecular imprinting. Highly complementary binding sites are formed by fixing pre-ordered template/functional monomer complexes into a highly crosslinked polymer matrix. Fundamental investigation of this intermolecular imprinting approach in the imprinting of glycosylated targets is reported here. The core of this study focuses on the elucidation of relative contribution of orthogonally interacting functional monomers, their structural tuning and the importance of monomer, solvent and counterion choice on the imprinting. Molecularly imprinted polymers (MIPs) are developed as particles of different sizes for glycan/glycopeptide enrichment applications or combined with fluorescent reportergroups for use as glycan imaging nanolabels. Special attention is given to the improvement of sialic acid MIP selectivities toward particular structures associated with cancer biomarkers. Development of MIPs against such complex targets includes design of linkage selective MIPs with comprehensive studies of the affinities and selectivities of the final glycan specific materials.

Ort, förlag, år, upplaga, sidor
Malmö: Malmö universitet, 2021. , s. 67
Serie
Malmö University Health and Society Dissertations, ISSN 1653-5383 ; 2021:4
Nyckelord [en]
Moleculary imprinted polymer, sialic acid, glycan recognition, synthetic receptor
Nationell ämneskategori
Biomedicinsk laboratorievetenskap/teknologi
Identifikatorer
URN: urn:nbn:se:mau:diva-45682DOI: 10.24834/isbn.9789178772063ISBN: 9789178772056 (tryckt)ISBN: 9789178772063 (digital)OAI: oai:DiVA.org:mau-45682DiVA, id: diva2:1591395
Disputation
2021-09-24, Aulan AS:E002 Hälsa och samhälles byggnad, samt digitalt, Jan Waldenströms gata 25, Malmö, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2021-09-06 Skapad: 2021-09-06 Senast uppdaterad: 2023-08-15Bibliografiskt granskad
Delarbeten
1. Combinatorial Design of a Sialic Acid-Imprinted Binding Site
Öppna denna publikation i ny flik eller fönster >>Combinatorial Design of a Sialic Acid-Imprinted Binding Site
2021 (Engelska)Ingår i: ACS Omega, E-ISSN 2470-1343, Vol. 6, nr 18, s. 12229-12237Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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 H-1 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.

Ort, förlag, år, upplaga, sidor
American Chemical Society (ACS), 2021
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:mau:diva-43974 (URN)10.1021/acsomega.1c01111 (DOI)000651520800045 ()34056377 (PubMedID)2-s2.0-85106406646 (Scopus ID)
Tillgänglig från: 2021-06-22 Skapad: 2021-06-22 Senast uppdaterad: 2024-02-05Bibliografiskt granskad
2. Combinatorial design of a sialic acid imprinted binding site exploring a dual ion receptor approach
Öppna denna publikation i ny flik eller fönster >>Combinatorial design of a sialic acid imprinted binding site exploring a dual ion receptor approach
2021 (Engelska)Ingår i: RSC Advances, E-ISSN 2046-2069, Vol. 11, nr 54, artikel-id 34329Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Aberrant sialic acid expression is one of the key indicators of pathological processes. This acidic saccharide is overexpressed in tumor cells and is a potent biomarker. Development of specific capture tools for various sialylated targets is an important step for early cancer diagnosis. However, sialic acid recognition by synthetic hosts is often complicated due to the competition for the anion binding by their counterions, such as Na+ and K+. Here we report on the design of a sialic acid receptor via simultaneous recognition of both the anion and cation of the target analyte. The polymeric receptor was produced using neutral (thio)urea and crown ether based monomers for simultaneous complexation of sialic acid's carboxylate group and its countercation. Thiourea and urea based functional monomers were tested both in solution by 1H NMR titration and in a polymer matrix system for their ability to complex the sodium salt of sialic acid alone and in the presence of crown ether. Combination of both orthogonally acting monomers resulted in higher affinities for the template in organic solvent media. The imprinted polymers displayed enhanced sialic acid recognition driven to a significant extent by the addition of the macrocyclic cation host. The effect of various counterions and solvent systems on the binding affinities is reported. Binding of K+, Na+ and NH4+ salts of sialic acid exceeded the uptake of bulky lipophilic salts. Polymers imprinted with sialic or glucuronic acids displayed a preference for their corresponding templates and showed a promising enrichment of sialylated peptides from the tryptic digest of glycoprotein bovine fetuin.

Ort, förlag, år, upplaga, sidor
Royal Society of Chemistry, 2021
Nyckelord
carbohydrate receptor, mlocular imprinting, crown ether, ion par recognition
Nationell ämneskategori
Biomedicinsk laboratorievetenskap/teknologi
Identifikatorer
urn:nbn:se:mau:diva-45668 (URN)10.1039/D1RA06962D (DOI)000709877800001 ()35497298 (PubMedID)2-s2.0-85120525004 (Scopus ID)
Tillgänglig från: 2021-09-06 Skapad: 2021-09-06 Senast uppdaterad: 2024-02-05Bibliografiskt granskad
3. Discrimination between sialic acid linkage modes using sialyllactose-imprinted polymers
Öppna denna publikation i ny flik eller fönster >>Discrimination between sialic acid linkage modes using sialyllactose-imprinted polymers
Visa övriga...
2021 (Engelska)Ingår i: RSC Advances, E-ISSN 2046-2069, Vol. 11, nr 36, s. 22409-22418Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Glycosylation plays an important role in various pathological processes such as cancer. One key alteration in the glycosylation pattern correlated with cancer progression is an increased level as well as changes in the type of sialylation. Developing molecularly-imprinted polymers (MIPs) with high affinity for sialic acid able to distinguish different glycoforms such as sialic acid linkages is an important task which can help in early cancer diagnosis. Sialyllactose with alpha 2,6 ' vs. alpha 2,3 ' sialic acid linkage served as a model trisaccharide template. Boronate chemistry was employed in combination with a library of imidazolium-based monomers targeting the carboxylate group of sialic acid. The influence of counterions of the cationic monomers and template on their interactions was investigated by means of H-1 NMR titration studies. The highest affinities were afforded using a combination of Br- and Na+ counterions of the monomers and template, respectively. The boronate ester formation was confirmed by MS and H-1/B-11 NMR, indicating 1 : 2 stoichiometries between sialyllactoses and boronic acid monomer. Polymers were synthesized in the form of microparticles using boronate and imidazolium monomers. This combinatorial approach afforded MIPs selective for the sialic acid linkages and compatible with an aqueous environment. The molecular recognition properties with respect to saccharide templates and glycosylated targets were reported.

Ort, förlag, år, upplaga, sidor
Royal Society of Chemistry, 2021
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:mau:diva-44872 (URN)10.1039/d1ra02274a (DOI)000667711300053 ()35480790 (PubMedID)2-s2.0-85108896879 (Scopus ID)
Tillgänglig från: 2021-08-17 Skapad: 2021-08-17 Senast uppdaterad: 2024-02-05Bibliografiskt granskad
4. Sialic acid specific nanogels produced in solution and via solid phase synthesis
Öppna denna publikation i ny flik eller fönster >>Sialic acid specific nanogels produced in solution and via solid phase synthesis
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nyckelord
Molecular imprinting, glycan recognition, boronic acid, nanogel
Nationell ämneskategori
Biomedicinsk laboratorievetenskap/teknologi
Identifikatorer
urn:nbn:se:mau:diva-45680 (URN)
Tillgänglig från: 2021-09-06 Skapad: 2021-09-06 Senast uppdaterad: 2021-09-09Bibliografiskt granskad

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