Towards the development of imprinted nanoparticles for glycan detection

Brooks, Laura Marie (2024). Towards the development of imprinted nanoparticles for glycan detection. University of Birmingham. Ph.D.

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Abstract

Recent advancements in glycomic profiling have led to the discovery of an extensive library of biomarkers which could be used in future diagnostic tools. The current significant barrier to producing new diagnostic technologies is the ability to engineer highly selective and sensitive synthetic systems for complex biomolecules. Some advances have been made via molecular imprinting (MI) in the field, but the systems are not easily translatable to clinical environments.

Molecular imprinting (MI) entails the formation of complementary spatial pockets using monomers that may bind to the target biomolecule covalently or non-covalently. For example, boronic acid derivatives are commonly used monomers for glycan recognition—often termed “synthetic lectins.” These functional monomers covalently bind to cisdiols to form pH-sensitive reversible esters with glycans. Thus, when boronic acids are used in MI, common issues such as template entrapment are overcome via pH modulation of the system to release the target.

MI systems have previously been reported for drug delivery, chromatography and biosensing systems. Many designed systems have shown excellent binding affinities for biosensing applications to their target glycans. However, few can bind to larger glycan structures and discriminate against specific glycosidic linkages (i.e., α-2,3 vs. α-2,6 glycosidic bonds).

In this thesis, we propose a method for glycan recognition through imprinted nanoparticles entailing boronic acids as the glycan binding monomer. The application of this study could improve future diagnostic assays for glycan detection. The proposed method has not been conducted on nanoparticles before and could result in highly selective and sensitive molecularly imprinted nanoparticles (MINPs). This strategy entails self-assembling glycan boronate esters under anhydrous aprotic solvent conditions. The boronate ester template is imprinted onto nanoparticles by forming a polymeric matrix around the template. The resulting cavities on the nanoparticle's surface should possess multiple boronic acid receptors capable of forming covalent bonds with the target glycan. These functional monomers are spatially locked on the particle surface for a multivalent binding event. Fixing boronic acids in a specific spatial orientation should afford selective cavities to distinguish different glycosidic linkages and glycan motifs with different 3D shapes. The results of this research provide a starting point for the development of MINPs for selective glycan detection.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):