Nanoparticles prepared from pterostilbene reduce blood glucose and improve diabetes complications

Abstract

Background: Diabetes complications are the leading cause of mortality in diabetic patients. The common complications are decline in antioxidant capacity and the onset of micro-inflammation syndrome. At present, glucose-responsive nanoparticles are widely used, as they can release insulin-loaded ultrafine particles intelligently and effectively reduce blood sugar. However, the toxicology of this method has not been fully elucidated. The plant extracts of pterostilbene (PTE) have a wide range of biological applications, such as antioxidation and inflammatory response improvement. Therefore, we have proposed new ideas for the cross application of plant extracts and biomaterials, especially as part of a hypoglycaemic nano-drug delivery system.

Results: Based on the PTE, we successfully synthesised poly(3-acrylamidophenyl boric acid-b-pterostilbene) (p[AAPBA-b-PTE]) nanoparticles (NPs). The NPs were round in shape and ranged between 150 and 250 nm in size. The NPs possessed good pH and glucose sensitivity. The entrapment efficiency (EE) of insulin-loaded NPs was approximately 56%, and the drug loading (LC) capacity was approximately 13%. The highest release of insulin was 70%, and the highest release of PTE was 85%. Meanwhile, the insulin could undergo self-regulation according to changes in the glucose concentration, thus achieving an effective, sustained release. Both in vivo and in vitro experiments showed that the NPs were safe and nontoxic. Under normal physiological conditions, NPs were completely degraded within 40 days. Fourteen days after mice were injected with p(AAPBA-b-PTE) NPs, there were no obvious abnormalities in the heart, liver, spleen, lung, or kidney. Moreover, NPs effectively reduced blood glucose, improved antioxidant capacity and reversed micro-inflammation in mice.

Conclusions: p(AAPBA-b-PTE) NPs were successfully prepared using PTE as raw material and effectively reduced blood glucose, improved antioxidant capacity and reduced the inflammatory response. This novel preparation can enable new combinations of plant extracts and biomaterials to adiministered through NPs or other dosage forms in order to regulate and treat diseases.

Keywords: 3-acrylamidophenylboronic acid (AAPBA); Diabetes complications; Diabetes mellitus; Insulin delivery; Nano-carrier; Pterostilbene (PTE).

Scheme 1

Synthesis process of p(AAPBA-b-PTE) and p(AAPBA-b-PTE) NPs loaded with insulin, and p(AAPBA-b-PTE) NPs loaded with insulin can reduced blood glucose, improved antioxidant capacity and reversed micro-inflammation by subcutaneous injection

Scheme 2

Synthesis of molecular structure of acrylic acid-PTE (a), p(AAPBA) (b) and p(AAPBA-b-PTE) (c)

Fig. 1.

¹H-NMR spectra results of AAPBA (a); PTE (b); p(AAPBA) (c); p(AAPBA-b-PTE) (d). e FT-IR spectra results. Thermal analysis of the polymers: DTG (f) and TG (g)

Fig. 2

Changes in different hydrodynamic diameters: PH (a); temperature (b); glucose concentration (c); d is the p(AAPBA-b-PTE) of stability in pH 7.4 PBS. Results of glucose-sensitive elasticity of NPs. f Zeta potential of the p(AAPBA-b-PTE). g Particle size and PDI of the p(AAPBA-b-PTE). TEM change in the diagram of p(AAPBA-b-PTE)2 NPs: h in the PBS solution (i) in the 3 mg/mL glucose concentration at 72 h

Fig. 3

The cumulative insulin release of p(AAPBA-b-PTE) NPs in vitro with glucose concentration of 0 mg/ml (a), 1 mg/ml (b) and 3 mg/ml (c). d is the cumulative insulin release of p(AAPBA-b-PTE)2. The cumulative PTE release of p(AAPBA-b-PTE) NPs in vitro with glucose concentration of 0 mg/ml (e) and 3 mg/ml (f)

Fig. 4

a, b Cell viability as a function of the concentration of p(AAPBA-b-PTE) NPs by the MTT assay at 37 °C after 24-h the incubation. Each value represents the mean ± SD (n = 5). c HE stained images representative images of the heart, liver, spleen, lung, kidney and skin of the control group, diabetic group, p(AAPBA-b-PTE)2 group and insulin injection treated group

Fig. 5

a Blood glucose concentration after injection over 24 h. b Oxidation index and c microinflammatory index of mice in each group after 2 weeks