Preparation of curcumin self-micelle solid dispersion with enhanced bioavailability and cytotoxic activity by mechanochemistry

Figures & data

Figure 1. (a) Structure and tautomerism of curcumin molecules; (b) DSC thermograms and (c) X-ray diffractograms of: A: curcumin; B: Na₂GA; C: physical mixture (PM); D: Cur SD (molar ratio 1/2, milling 2 h); E: Cur SD (molar ratio 1/2, milling 24 h); electron micrographs of: (d) curcumin; (e) Na₂GA; (f) Cur SD (molar ratio 1/2, milling 2 h); (g) Cur SD (molar ratio 1/2, milling 24 h).

Table 1. Molecular weight distribution^a, size and zeta-potential of Cur SD in water solution.

Samples	Cur/Na2GA, 1/1	Cur/Na2GA, 1/2	Cur/Na2GA, 1/4
Mn (kDa), 2 h/24 h	83.7/85.0	85.0/87.9	88.3/88.5
Mw (kDa), 2 h/24 h	85.9/87.1	87.2/90.2	90.6/90.8
Mp (kDa), 2 h/24 h	79.3/80.9	80.6/84.8	84.8/84.8
Size (nm), 2 h/24 h	43.83 ± 2.2/85.40 ± 4.5	46.20 ± 0.8/91.9 ± 6.0	71.4 ± 0.7/135.3 ± 7.9
PI, 2 h/24 h	0.272 ± 0.020/0.161 ± 0.013	0.241 ± 0.028/0.312 ± 0.001	0.319 ± 0.011/0.252 ± 0.009
Zeta-potential (mV), 2 h/24 h	–37.7 ± 0.7/–38.6 ± 2.2	–37.6 ± 0.6/–38.9 ± 1.6	–39.6 ± 1.2/–43.5 ± 0.9
Thermodynamic values (+37 °C, T = 310)
Slope	0.064 ± 0.0024	0.118 ± 0.0019	0.064 ± 0.0018
S0	0.096 ± 0.026	0.188 ± 0.021	0.214 ± 0.020
K, M^–1	703.6 ± 195.4	713.2 ± 81.8	320.1 ± 30.6
ΔG, kJ/mol	–16.9 ± 0.7	–16.9 ± 0.3	–14.9 ± 0.2

^a M_n: number average molecular weight; M_w: weight average molecular weight; M_p: molecular weight at peak maximum of the elution diagram.

Figure 3. Cytotoxic effects of pure Cur and Cur SDs on (a) MCF-7 cells; (b) U-87 MG cells; (c) immortalized human fibroblast cells, results are presented as mean viability ± SEM; (d) permeation profile of pure Cur and Cur SDs in PAMPA experiment; (e) concentration of curcumin in rat plasma after a single oral dose of 150 mg/kg of free Cur or Cur SD, *p < .05 compared to pure Cur in same point, **p < .01 compared to pure Cur in same point, values are mean ± SEM (n = 5).

Table 2. Cytotoxicity of Na₂GA in MCF-7, U-87 MG and immortalized human fibroblasts cell lines.

	Viability, %
Concentrationof Na2GA, μM	MCF-7	U-87 MG	Immortalized human fibroblasts
25	98.2 ± 2.13	96.6 ± 2.39	96.2 ± 2.78
50	97.8 ± 3.33	95.9 ± 1.16	97.3 ± 1.73
100	98.2 ± 0.41	92.2 ± 2.75	98.8 ± 4.18
200	98.7 ± 1.59	92.2 ± 2.63	96.0 ± 1.66
400	99.6 ± 1.34	92.9 ± 1.65	98.3 ± 0.90

Values are presented as mean viability ± SEM.

Table 3. Pharmacokinetic parameters of curcumin following oral administration of free Cur and Cur SD.

Parameters	Free Cur (control)	Cur SD 1:1	Cur SD 1:2	Cur SD 1:4
Cmax (μg/mL)	1.48 ± 0.03	9.04 ± 0.35**	17.68 ± 0.22**	29.87 ± 2.71**
Tmax (min)	15 ± 0.00	5 ± 0.00	5 ± 0.00	15 ± 0.00
T1/2 (h)	5.07 ± 0.41	8.02 ± 0.70**	9.05 ± 0.65**	11.16 ± 1.03**
AUC0→t (μg/mL.h)	12.12 ± 0.36	64.50 ± 3.12**	108.16 ± 5.2**	231.61 ± 10.15**
AUC0→inf (μg/mL.h)	14.26 ± 0.72	104.38 ± 6.21**	181.60 ± 8.76**	279.50 ± 12.11**

AUC: area under the plasma concentration–time curve; C_max: peak concentration; T_max: time to reach peak concentration.

Values are reported as mean ± SEM (n = 5).

** p < .01 compared with the control.