Recent Advances in Phenylboronic Acid-Based Gels with Potential for Self-Regulated Drug Delivery

Abstract

Glucose-sensitive drug platforms are highly attractive in the field of self-regulated drug delivery. Drug carriers based on boronic acid (BA), especially phenylboronic acid (PBA), have been designed for glucose-sensitive self-regulated insulin delivery. The PBA-functionalized gels have attracted more interest in recent years. The cross-linked three-dimensional (3D) structure endows the glucose-sensitive gels with great physicochemical properties. The PBA-based platforms with cross-linked structures have found promising applications in self-regulated drug delivery systems. This article summarizes some recent attempts at the developments of PBA-mediated glucose-sensitive gels for self-regulated drug delivery. The PBA-based glucose-sensitive gels, including hydrogels, microgels, and nanogels, are expected to significantly promote the development of smart self-regulated drug delivery systems for diabetes therapy.

Keywords: diabetes therapy; drug delivery; gel; glucose sensitivity; phenylboronic acid.

Scheme 1

Complexation equilibrium between phenylboronic acid (PBA) and glucose.

Figure 1

The structure of the gelator used for self-regulated drug delivery. (Reprinted from ref. [38]).

Figure 2

Schematic and the glucose-sensitive mechanism of the hydrogel composed of PEO-b-PVA, α-CD, and double PBA-terminated poly (ethylene oxide) (PEO) cross-linker. (Reprinted from ref. [45].)

Figure 3

The formation of PBA-containing glycopolymer hydrogel before and after. (Reprinted from ref. [46]).

Figure 4

(a) Structure of PBA-containing glycopolymer BG; (b) the soft and injectable hydrogel formed by polymer BG with 50% PBA, and the SEM image of the obtained hydrogel. Scale bar: 1 μm. (Reprinted from ref. [47]).

Figure 5

(a) Schematic representation of the preparation of the hybrid virus–polymer bioconjugate of end-functionalized PBA- and N-isopropylacrylamide (NIPAM)-containing copolymer to the rod-like M13 virus, and the multiresponsiveness of the hybrid virus–polymer bioconjugate; (b) Internal structure of the gel as revealed by AFM; (c) insulin release behavior of the virus based hydrogel in the presence or absence of glucose. Inset in (c) hydrogel forms instantly when the polymer grafted virus in the sol state was injected into the aqueous solution at 37 °C. (Reprinted from ref. [48]).

Figure 6

Schematic representation of microgel swelling upon glucose addition, showing the importance of the initial state. (Reprinted from ref. [61]).

Figure 7

Schematic representation of glucose-induced microgels shrinking with glucose–bis(boronate) complexation (Reprinted from ref. [66]).

Figure 8

Illustration of the synthesis of the proposed pPBA microgels. (Reprinted from ref. [68]).

Figure 9

(a) Schematic illustration of smart multifunctional microgels with pH-, temperature-, and glucose sensitivity at physiological conditions and gradual degradation; (b) Release profiles of microgels in the presence of glucose in PBS of 7.4 at 37 °C. (Reprinted from ref. [69]).

Figure 10

Schematic illustration of the structure of PNIPAM (core)/P(NIPAM-AAPBA) (shell) microgel particles, where the PNIPAM core can be further divided as highly cross-linked “core” with BIS-rich and lightly cross-linked “shell” that is BIS-poor. (Reprinted from ref. [70]).

Figure 11

Structure of the nanogel and glucose-sensitive behavior of ARS-loaded nanogel in PBS at pH 7.4. (Reprinted from ref. [79]).

Figure 12

(a) Schematic illustration of glucose-triggered insulin release from PBA-functionalized polypeptide nanogel; (b) Cumulative insulin release from the insulin-loaded nanogel in PBS with various glucose concentrations at pH 7.4, 37 °C. (Reprinted from ref. [81]).

Figure 13

(a) Schematic illustration of glucose-sensitive GC/SA-PGGA double-layered nanogel controlled insulin release by complexation between PBA derivatives and glucose; (b) Normalized blood glucose levels in mice by retro-orbital administration of blank GC/SA-PGGA nanogels, free insulin (0.5 IU kg⁻¹), insulin-loaded GC/SA (0.5 IU kg⁻¹), and insulin-loaded GC/SA-PGGA nanogels (0.5 IU kg⁻¹). (Reprinted from ref. [82]).

Figure 14

Profiles of glycemia after a subcutaneous administration of free insulin (2.0 IU kg^–1), insulin-loaded nanogels (4 IU kg^–1), and blank nanogels in fed diabetic rats. Before the injections, glycemia was 426 ± 13 mg mL^–1. Results are expressed as mean ± SD (n = 8). (Reprinted from ref. [83]).

Figure 15

(a) The profiles of rats’ blood glucose concentrations after injection with different samples; (b) Effect of the different nanogels on the aggregation and morphology of red blood cells. (Reprinted from ref. [84]).