Enhanced anti-hepatoma effect of a novel curcumin analog C086 via solid dispersion technology

Figures & data

Figure 1. The chemical structure of C086.

Figure 2. Physicochemical characterization of C086-SD. (A) Aqueous solubility. (B) Dissolution. (C) XRPD patterns, (D) DSC thermograms, and (E) FTIR spectra of pure C086, PVP K30, physical mixture (C086/PVP K30:1/6 (w/w)), and C086-SD (C086/PVP K30:1/6 (w/w)).

Figure 3. The stability of C086-SD. (A) Long-term stability of C086-SD Capsule at 25 °C ± 2 °C/60% RH ± 5% RH for 12 months. (B) Short-term stability of C086-SD in normal saline at 4 °C and 25 °C for 48 hours.

Figure 4. Mean plasma concentration-time curves of C086-Suspension and C086-SD following oral administration in rats (n = 6).

Table 1. Pharmacokinetic parameters of C086 following oral administration in rats (Mean ± SD, n = 6).

Parameters	C086-Suspension	C086-SD
Tmax (h)	0.528 ± 0.192	1.167 ± 0.289
Cmax (g/L)/D	0.536 ± 0.093	25.907 ± 2.064**
AUC0- t (g/L*h)/D	1.558 ± 0.178	46.357 ± 3.736**
AUC0-∞ (g/L*h)/D	2.131 ± 0.289	47.186 ± 3.493**
MRT0-∞ (h)	6.469 ± 2.014*	1.975 ± 0.070
T1/2 (h)	4.489 ± 1.743*	1.777 ± 0.681
Cl (L/h/kg)	475.291 ± 67.032**	21.269 ± 1.529
Frel (%)	/	2976.093 ± 461.272

T_max: time to maximum plasma concentration; C_max/D: maximum observed plasma concentration divided by dose (mg) per body weight (kg); AUC/D: area under the plasma concentration-time curve divided by dose (mg) per body weight (kg); MRT_0-∞: mean residence time from time zero to infinity;T_1/2-terminal elimination half-life; Cl-apparent total body clearance of the drug from plasma; F_rel-the relative bioavailability; *p < .05; **p < .01.

Figure 5. The tissue distribution of C086-SD following a single oral administration (140 mg/kg) using as a mice model (n = 3). (A) C086 concentration (µg/g) in key tissues at different times. (B) AUC_0-t (µg/g*h) in key tissues. (C) MRT_0-t (h) in key tissues.

Table 2. The targeting efficiency of C086-SD following oral administration in mice (Mean ± SD, n = 3).

Tissue	Targeting efficiency (T)
Heart	0.135 ± 0.021
Liver	1.872 ± 0.134
Spleen	0.109 ± 0.017
Lung	0.068 ± 0.011
Kidney	0.072 ± 0.013

Figure 6. The anti-proliferative effects of C086 in vitro (n = 3). (A) The inhibition rate in HepG2 cells treated with indicated concentrations of C086-SD and C086 for 48 h and then assessed by an MTT assay, *p < .05 vs C086 at the same concentration. (B) The relative expression of phospho-MEK (p-MEK), MEK, phospho-ERK (p-ERK) and ERK in HepG2 cells were detected by using Western Blotting. (C) Histogram of the relative expression of proteins (density ratio of protein/β-actin): *p < .05 vs either control or C086.

Figure 7. In vivo anti-cancer evaluation effect in the orthotopic hepatocellular carcinoma xenograft in BALB/C nude mice. (A) Photograph of HepG2 orthotopic tumors harvested on the last day of the experiment from nude mice (six per each group). (B) The weight of the harvested tumor: **p < .01 vs control and *p < .05 vs C086. (C) The expression of phospho-MEK (p-MEK) and phospho-ERK (p-ERK) in tumor tissue were detected by using Western Blotting. (D) Histogram of the relative expression of proteins (density ratio of protein/β-actin): *p < .05 and **p < .01 vs either control or C086. C086 = C086-Suspension.