Boronic Acid as Glucose-Sensitive Agent Regulates Drug Delivery for Diabetes Treatment

Abstract

In recent years, glucose-sensitive drug delivery systems have attracted considerable attention in the treatment of diabetes. These systems can regulate payload release by the changes of blood glucose levels continuously and automatically with potential application in self-regulated drug delivery. Boronic acid (BA), especially phenylboronic acid (PBA), as glucose-sensitive agent has been the focus of research in the design of glucose-sensitive platforms. This article reviews the previous attempts at the developments of PBA-based glucose-sensitive drug delivery systems regarding the PBA-functionalized materials and glucose-triggered drug delivery. The obstacles and potential developments of glucose-sensitive drug delivery systems based on PBA for diabetes treatment in the future are also described. The PBA-functionalized platforms that regulate drug delivery induced by glucose are expected to contribute significantly to the design and development of advanced intelligent self-regulated drug delivery systems for treatment of diabetes.

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

Figure 1

Illustrational scheme of reversible binding of glucose to PBA.

Figure 2

(a) R_h values of P(NIPAM−PBA) microgel (10.0 mol % PBA) as a function of glucose concentration, measured in 0.005 M PBs of different pH values at T = 25 °C; (b) time-dependent D_h of 6/4 complex polymer micelle under various glucose concentrations; (c) reversible glucose-sensitivity of P(AAPBA4-b-GAMA1) nanoparticle; (d) the stability of blank p(AAPBA-b-GAMA) NP in pH 7.4 PBS. (Reprinted from Refs. 71, 65, and 8.)

Figure 3

(a) In vitro cumulative release of insulin in pH 7.4 PBS from p(AAPBA4-b-GAMA1) nanoparticle at various glucose concentrations (0, 1.0, and 3.0 mg·mL⁻¹), and medium only for the first 12 h and then 3.0 mg·mL⁻¹; (b) glucose-sensitive insulin release from micelle in PBS with alternating glucose concentrations (0 or 3.0 mg·mL⁻¹ marking as 0 glu and 3 glu, respectively, while the marker of 0–3 glu represented the cumulative insulin release in PB with alternant 0 or 3.0 mg·mL⁻¹ glucose) in PBS at pH 7.4, 37 °C; (c) glucose-sensitive ARS release from polypeptide nanogel in PBS with alternating glucose concentrations (0 or 2.0 mg·mL⁻¹) at 37 °C; (d) glucose-triggered on–off release of insulin from polymer vesicles. (Reprinted from Refs. 8, 63, 82, and 66.)

Figure 4

(a) Normalized blood glucose levels in mice by retro-orbital administration of blank GC/SA-PGGA nanogel, free insulin (0.5 IU·kg⁻¹), insulin-loaded GC/SA (0.5 IU·kg⁻¹), and insulin-loaded GC/SA-PGGA nanogel (0.5 IU·kg⁻¹); (b) normalized blood glucose levels in mice by administration of free insulin twice (0.25 IU·kg⁻¹), free insulin (0.5 and 0.25 IU·kg⁻¹), and insulin-loaded GC/SA-PGGA nanogel (0.5 IU·kg⁻¹); (c) in vitro release of insulin from P(NIPAM-Dex-PBA) nanogel in 0.1 M PBS at pH 7.4 with various glucose concentrations (medium only, 2.0 mg·mL⁻¹, and medium only for the first 4 h and then 2.0 mg·mL⁻¹); (d) profiles of glycemia after a subcutaneous administration of free insulin (2.0 IU·kg⁻¹), insulin-loaded nanogel (4 IU·kg⁻¹) and blank nanogel in fed diabetic rats. (Reprinted from Refs. 68 and 83.)