'Borono-lectin' based engineering as a versatile platform for biomedical applications

Abstract

Boronic acids are well known for their ability to reversibly interact with the diol groups, a common motif of biomolecules including sugars and ribose. Due to their ability to interact with carbohydrates, they can be regarded as synthetic mimics of lectins, termed 'borono-lectins'. The borono-lectins can be tailored to elicit a broad profile of binding strength and specificity. This special property has been translated into many creative biomedical applications in a way interactive with biology. This review provides a brief overview of recent efforts of polymeric materials-based engineering taking advantage of such virtue of 'borono-lectins' chemistry, related to the field of biomaterials and drug delivery applications.

Keywords: 212 Surface and interfaces; 30 Bio-inspired and biomedical materials; Boronic acids; borono-lectins; diabetes; drug delivery systems; insulin; siRNA; sialic acids.

Graphical abstract

Figure 1.

Schematic representation of the phenylboronic acid-based strategy for siRNA delivery; the chemical formula of the polymer, enhanced stability of the micelle, and the mechanism of selective intracellular release are shown. Reprinted from Ref. [47] with permission. © 2012, WILEY-VCH Verlag.

Figure 2.

Potentiometric SA detection at cell membrane using PBA modified electrode. Reprinted from Ref. [60] with permission. © 2009, American Chemical Society.

Figure 3.

Preparation of PBA-installed DACHPt-loaded micelles by self-assembly through polymer–metal complex formation between DACHPt and PBA-poly(ethylene glycol)-b-poly(l-glutamic acid) in distilled water. PBA moieties on the surface of the micelles can bind to SA. Reprinted from Ref. [64] with permission. © 2013, American Chemical Society.

Figure 4.

Binding constants (K, M⁻¹) for SA binding to a variety of boronic acids as a function of pH, as determined by B¹¹NMR analysis; A: 3-pyridylboronic acid, B: 5-pyrimidine boronic acid, C: 5-boronopicolinic acid, D: (6-propylcarbamoyl)pyridine-3-)boronic acid, E: 3-borono-1-(carboxymethyl)pyridine, F: 3-propionamidophenylboronic acid, G: 4-(methylsulfonyl)benzeneboronic acid. Values in B and C represent mean S. D. (n = 3). Reprinted from Ref. [74] with permission. © 2012, Royal Society of Chemistry.

Figure 5.

Diphosphate-specific recognition under weakly acidic pH conditions identified with by some boronates with relatively strong acidity, as determined by ¹¹B and ³¹P NMR studies. Reprinted from Ref. [75] with permission. © 2015, American Chemical Society.

Figure 6.

Schematic illustrating the strategy for insulin modification. (A) Generalized scheme to prepare small molecules used in the preparation of Ins-PBA-F, Ins-PBA-N, and Ins-PBA-A. (B) Final carboxylic acid-containing small molecule is conjugated to the native human insulin protein through the ε-amine of the lysine at the B29 position (yellow). (C) Structures of the four PBA-modified long-acting insulin derivatives along with the positive control, Ins-LA-C14, commercially known as insulin detemir. Reprinted from Ref. [90] with permission. © 2015, PNAS.

Figure 7.

(a) Chemical structure of glucose-responsive gel: monomers and their polymerized (cross-linked) chemical structures shown with their optimized molar fraction (l:m:n = 87.5:7.5:5) to yield the glucose-sensitivity under physiological conditions (pH 7.4 and 37 °C) accompanied by a threshold concentration of glucose at normoglycemic 100 mg/dl (above which the gel delivers insulin). (b) Schematic illustration of ‘pancreas-like’ self-regulated insulin delivery function of the gel. Reprinted from Ref. [102] with permission. © 2017, American Chemical Society.

Figure 8.

Lysine ε-amino group modification based on the formation of stable imines with 2-formylbenzeneboronic acid. Reprinted from Ref. [102] with permission. © 2012, American Chemical Society.

Figure 9.

Iminoboronate-mediated peptide cyclization in which intramolecular iminoboronate formation allows spontaneous cyclization under physiologic conditions to yield monocyclic and bicyclic peptides. Importantly the iminoboronate-based cyclization can be rapidly reversed in response to multiple stimuli, including pH, oxidation, and small molecules. PBS; phosphate buffered saline. Reprinted from Ref. [105] with permission. © 2016, American Chemical Society.

Scheme 1.

Reversible boronate ester formation in aqueous solution.