Selective Binding of Folic Acid and Derivatives by Imprinted Nanoparticle Receptors in Water

Abstract

Folate receptors are overexpressed on cancer cells and frequently used for targeted delivery. Creation of synthetic receptors to bind folic acid and its analogues in water, however, is challenging because of its complex hydrogen-bonding patterns and competition for hydrogen bonds from the solvent. Micellar imprinting within cross-linkable surfactants circumvented these problems because the nonpolar micellar environment strengthened the hydrogen bonds between the amide group in the surfactant and the template molecule. Incorporation of polymerizable thiouronium functional monomers further enhanced the binding through hydrogen-bond-reinforced ion pairs with the glutamate moiety of the template. The resulting imprinted micelles were able to bind folate and their analogues with submicromolar affinity and distinguish small changes in the hydrogen-bonding patterns as well as the number/position of carboxylic acids. The binding constant obtained was 2-3 orders of magnitude higher than those reported for small-molecule synthetic receptors. Our binding study also revealed interesting details in the binding. For example, the relative contributions of different segments of the molecule to the binding followed the order of carboxylates > pyrimidine ring > pyrazine ring.

Tuning surface‐cross‐linking of molecularly imprinted cross‐linked micelles for molecular recognition in water

“…Because the emission of compound 10 and 12 was quite weak in 50 mM Tris buffer (pH 7.3), for the purpose of comparisons, we used ITC binding data exclusively in this study. We have in multiple cases confirmed that binding constants and stoichiometry obtained from these two techniques agree with each other …”

“…The excellent functional‐group compatibility of the click reaction gives us much flexibility in the design of surface cross‐linkers and different ways of surface‐cross‐linking. Diazide 2 is our most commonly used surface‐cross‐linker (Scheme ) . Since flexibility of the surface‐cross‐linker and surface ligand is important to the binding of MINPs, we designed two diazide cross‐linkers 4 and 5 from ketone 6 that was prepared in one step from commercially available 1,3‐dichloroacetone.…”

“…The preparation of MINPs followed Scheme , with detailed procedures for the synthesis and characterization reported previously . Generally, the surface‐ and core‐cross‐linking of the micelles was monitored by 1 H NMR spectroscopy.…”

“…Importantly, either amphiphilic or hydrophilic molecules, sometimes with suitable FMs, can be incorporated into the micelles as templates. The resulting MINPs displayed excellent molecular recognition in water for a wide range of biologically interesting molecules including small‐molecule drugs, carbohydrates, and peptides .…”

A Bait‐and‐Switch Method for the Construction of Artificial Esterases for Substrate‐Selective Hydrolysis

“…First, its thiouronium group can bind the negatively charged phosphonate through a hydrogen bond‐reinforced salt bridge, similar to other cationic groups such as guanidinium and amidinium. We recently found this particular salt bridge had sufficient stability for the micellar imprinting as long as the FM possesses significant hydrophobicity for its inclusion in the micelle . Second, the FM contains a methacrylate group and thus can be co‐polymerized with the methacrylate of 1 and DVB to become part of the core of the MINP.…”