Curcumin and Metformin Infinite Coordination Polymer Nanoparticles for Combined Therapy of Diabetic Mice via Intraperitoneal Injections

Abstract

Metformin (Met) is one of the most commonly prescribed first-line drugs for diabetes treatment. However, it has several issues, including low bioavailability, therapeutic platform, and side effects at high doses. In order to improve the therapeutic efficiency of Met, this study proposes a strategy of using Met and curcumin (Cur) to prepare Cur-Zn(II)-Met infinite coordination polymer nanoparticles (CM ICP NPs), and combining this with intraperitoneal injections, for the treatment of diabetic mice. Fourier transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), nanoparticle analysis, cytotoxicity experiments, and mice experiments were used to investigate structure, properties, and application effects. The results showed that CM ICP NPs exhibit a high drug encapsulation rate (100%), good stability, and an absence of in vivo and in vitro toxicity. The blood glucose level of diabetic mice after treatment was reduced to 6.7 ± 0.65 mmol/L at the seventh week. In terms of therapeutic mechanism, it appears that Met and Cur can synergistically regulate blood glucose in mice from multiple paths. This study provides a promising method for the treatment of diabetes using Met and other drugs.

Keywords: combination therapy; curcumin; diabetes; infinite coordination polymer; metformin; nanoparticles.

Figure 1

Synthetic route of CM ICP NPs (A) and their application in diabetes mice (B). (Curcumin, Cur; Metformin, Met; infinite coordination polymer, CM ICP; infinite coordination polymer nanoparticles, CM ICP NPs; Curcumin nanoparticles, Cur NPs; Metformin nanoparticles, Met NPs; insulin resistance index, HOMA-IR; aspartate aminotransferase, AST; alanine aminotransferase, ALT; creatinine, CREA; blood urea nitrogen, BUN; uric acid, UA; The green downward arrow indicates a decrease in the level of the indicator).

Figure 2

UV-Vis (A) and FTIR (B) of CM ICPs, Cur, and Met; XPS full spectrum (C), XPS high-resolution spectrum (O 1s, (D); N 1s, (E); Zn 2p, (F)), structure (G), and XRD spectrum (H) of CM ICPs.(The red line represents the original data, while the other colored lines represent the peak fitted data in (E,F)).

Figure 3

TEM (A) and EDS (B); (C): C, N, O, Zn; (D): O; (E): Zn; particle size distribution (F), stability (G), The gray area is between the maximum and minimum values of particle size.), and in vivo drug release (H) of CM ICP NPs.

Figure 4

The inhibitory effects of CM ICP NPs, Cur NPs, and Met NPs on three cell lines (3T3) (A); RSC96 (B); and HT22 (C). CM ICP NPs, Cur NPs, and Met NPs were added at concentrations of 1 μg/mL, 3 μg/mL, and 9 μg/mL in vitro; picture (D) and numerical (E) of hemolysis test results for CM ICP NPs, Cur NPs, Met NPs, Saline, and Triton (they are 15% of the total solution volume). * p < 0.05; ** p < 0.01; *** p < 0.001.

Figure 5

The main biochemical indicators of liver function (AST (A); ALT (B); TBIL (C)) and kidney function (CREA (D); BUN (E); UA (F)) of mice treated with CM ICP NPs, Cur-Met NPs, and saline at 24 h and 14 d (30 mg/kg for Cur and 300 mg/kg for Met). The pathological effects of heart, liver, kidney, spleen, and lungs (G) in mice treated with CM ICP NPs, Cur–Met NPs, and saline at 14 d. The dimensions of the scale bar is 100 μm. * p < 0.05; ** p < 0.01.

Figure 6

Experimental design of mice (A), effects on continuous blood glucose (B), The dosage and treatment duration of Met (C) [11,40,53,54,55,56], blood glucose at seventh week (D), The gray area represents the blood glucose level greater than 11.1 mmol/L), and GSP (E) in diabetic model mice of CM ICP NPs, Cur-Met NPs, Cur NPs, Met NPs, and Saline group (30 mg/kg for Cur and 300 mg/kg for Met); * p < 0.05; *** p < 0.001.

Figure 7

HOMA-IR (A), NEFA (B), CHO (C), LDL-C (D), HDL-C (E), and pancreatic tissue (F) in diabetic model mice of CM ICP NPs, Cur–Met NPs, Cur NPs, Met NPs, and Saline group (30 mg/kg for Cur and 300 mg/kg for Met). The dimensions of the scale bar is 100 μm. * p < 0.05; ** p < 0.01.

Figure 8

AST (A), ALT (B),CREA (C), BUN (D), UA (E), and liver and kidney tissue (F) in diabetic model mice of the CM ICP NPs, Cur–Met NPs, Cur NPs, Met NPs, and Saline groups (30 mg/kg for Cur and 300 mg/kg for Met). The dimensions of the scale bar is 100 μm. * p < 0.05.