Glucose Oxidase-Based Glucose-Sensitive Drug Delivery for Diabetes Treatment

Abstract

The glucose-sensitive drug delivery systems based on glucose oxidase (GOD), which exhibit highly promising applications in diabetes therapy, have attracted much more interest in recent years. The self-regulated drug delivery systems regulate drug release by glucose concentration automatically and continuously to control the blood glucose level (BGL) in normoglycemic state. This review covers the recent advances at the developments of GOD-based glucose-sensitive drug delivery systems and their in vivo applications for diabetes treatment. The applications of GOD-immobilized platforms, such as self-assembly layer-by-layer (LbL) films and polymer vesicles, cross-linking hydrogels and microgels, hybrid mesoporous silica nanoparticles, and microdevices fabricated with insulin reservoirs have been surveyed. The glucose-sensitive drug delivery systems based on GOD are expected to be a typical candidate for smart platforms for potential applications in diabetes therapy.

Keywords: diabetes therapy; drug delivery; glucose oxidase; glucose sensitivity.

Figure 1

Glucose-sensitive self-regulated drug delivery platforms based on glucose oxidase (GOD).

Figure 2

Glucose-sensitive insulin release mechanism and glycemic control in diabetic rats implanted with LbL films. (A) Schematic presentation of glucose-sensitive insulin release mechanism of LbL films under a coupled reaction of GOD and CAT; (B) BGL of diabetic rats (both nonfasting and fasting models) implanted with LbL films (n = 6); (C) Enlarged figure of (B). The control group is diabetic rats without treatment. The loading amounts of P-SIA in the films were Film-1 < Film-2, while Film-C was fabricated with denatured CAT to be the control sample of Film-2 to explore the role of CAT in this system in further experiments. (Reprinted with permission from [12]).

Figure 3

Injectable nanovesicle formulation made from enzyme-based glucose-responsive nanovesicle-embedded thermo-responsive matrix (A) Schematic of enzyme-based glucose-responsive nanovesicle and chemical structure of pH-sensitive copolymer PEG-poly(Ser-Ketal) (inset); (B) Immediate formation of hydrogel from nanovesicle integrated with thermo-responsive PF127 solution at 37 °C (left) in vitro and 3 min after subcutaneous injection (right). (Reprinted with permission from [44]).

Figure 4

Schematic of chemical structure of mPEG-b-P(Ser-PBE) with H₂O₂-sensitive moieties and its degradation products. (Reprinted with permission from [47]).

Figure 5

Schematic of formation and mechanism of hypoxia and H₂O₂ dual-sensitive polymersome-based vesicle comprised of PEG-poly(Ser-S-NI) for glucose-induced insulin delivery. (Reprinted with permission from [48]).

Figure 6

pH-sensitive self-assembled peptide hydrogels for glycemic control in diabetic mice. (A) Diagram of glucose-sensitive insulin delivery system using pH-sensitive self-assembled peptide hydrogel. The inset indicates the process of hydrogel formation; (B) BGL in the first 12 h and (C) in the long-term after administration of PBS solution (control), G(E+I) (hydrogel with both insulin and enzymes), and G(I) (hydrogel with insulin alone) to STZ-induced diabetic mice. The blank group was healthy mice. (Reprinted with permission from [52]).

Figure 7

Schematic representation of structures of SCS and AHA, and SCS and AHA-based Schiff-base crosslinking hydrogel using for insulin release triggered by glucose. (Reprinted with permission from [54]).

Figure 8

Glucose-sensitive nanocapsule for insulin delivery. (A) Schematic of microgel encapsulating insulin and enzyme nanocapsule and glucose-mediated insulin release; (B) BGL in diabetic mice after subcutaneous injection with PBS, MGs(E+I), MGs(I), and MGs(E) within 24 h, where MGs(E+I), MGs(I), and MGs(E) were microgels encapsulating insulin and enzymes, insulin alone, enzymes alone, respectively. (Reprinted with permission from [57]).

Figure 9

Schematics of alginate particle composition (left panel) and reduction in cross-linking (right panel) in the presence of glucose with FITC-insulin release. FITC labels are denoted by F. (Reprinted with permission from [61]).

Figure 10

Schematic of hemoglobin (Hb, red) and GOD (blue) immobilized MSN nanoparticles with GA as a cross-linker, and reaction scheme of a coupled enzymatic system catalyzing d-glucose. (Reprinted with permission from [70]).

Figure 11

Schematic illustration of glucose-mediated drug release from mesoporous silica nanoparticle capped by β-CD-modified glucose oxidase. (Reprinted with permission from [74]).

Figure 12

Schematic illustration of Janus-based nanodevice as a smart delivery system controlled by integrated enzymes. (Reprinted with permission from [13]).

Figure 13

An insulin delivery prototype device for BGL regulation in STZ-induced diabetic rats. (A) (a) Schematics of an insulin delivery prototype device and its components, (b) photograph of insulin delivery device prototype; (B) Change in blood glucose after intraperitoneal implantation with saline-filled devices (Sham) or insulin-filled devices (Insulin Device); (C) Change in plasma insulin level after intraperitoneal implantation with Sham or Insulin Device. (Reprinted with permission from [75]).

Figure 13

An insulin delivery prototype device for BGL regulation in STZ-induced diabetic rats. (A) (a) Schematics of an insulin delivery prototype device and its components, (b) photograph of insulin delivery device prototype; (B) Change in blood glucose after intraperitoneal implantation with saline-filled devices (Sham) or insulin-filled devices (Insulin Device); (C) Change in plasma insulin level after intraperitoneal implantation with Sham or Insulin Device. (Reprinted with permission from [75]).

Figure 14

PDMS grid-gel microdevice implanted in STZ-induced diabetic rats. (A) (a) Schematic representation of PDMS grid-gel microdevice with integrated bioinorganic membrane (with inset for (c)); (b) Size comparison of the PDMS grid-gel microdevice; (c) Cross-sectional diagram and schematic of glucose-triggered insulin release; (B) Long-term plasma blood glucose regulations and (C) long-term plasma insulin measurements in STZ-induced diabetic rats treated with a microdevice filled with insulin or saline (control) (n = 5). Shaded area indicates normoglycemic range. Implantation of microdevices occurred at day 2. (Reprinted with permission from [76]).

Figure 14

PDMS grid-gel microdevice implanted in STZ-induced diabetic rats. (A) (a) Schematic representation of PDMS grid-gel microdevice with integrated bioinorganic membrane (with inset for (c)); (b) Size comparison of the PDMS grid-gel microdevice; (c) Cross-sectional diagram and schematic of glucose-triggered insulin release; (B) Long-term plasma blood glucose regulations and (C) long-term plasma insulin measurements in STZ-induced diabetic rats treated with a microdevice filled with insulin or saline (control) (n = 5). Shaded area indicates normoglycemic range. Implantation of microdevices occurred at day 2. (Reprinted with permission from [76]).