Improved pharmacokinetics and reduced toxicity of brucine after encapsulation into stealth liposomes: role of phosphatidylcholine

Figures & data

Figure 1 The characterization of brucine-loaded stealth liposomes with different PC composition.

Abbreviations: PC, phosphatidylcholine; BSL, brucine-loaded stealth liposomes; SPC, soy phosphatidylcholine; DPPC, dipalmitoyl phosphatidylcholine; HSPC, hydrogenated soy phosphatidylcholine; DSPC, distearoyl phosphatidylcholine.

Figure 2 Effect of phosphatidylcholine composition on entrapment efficiency of brucine-loaded stealth liposomes.

Note: n = 3.

Abbreviations: BSL, brucine-loaded stealth liposomes; SPC, soy phosphatidylcholine; DPPC, dipalmitoyl phosphatidylcholine; HSPC, hydrogenated soy phosphatidylcholine; DSPC, distearoyl phosphatidylcholine.

Figure 3 HPLC chromatographs of brucine in PBS.

Note: Peak 1 represents brucine.

Abbreviations: HPLC, high-performance liquid chromatography; PBS, phosphate buffer solution.

Figure 4 In vitro release profiles of brucine from brucine-loaded stealth liposomes with different phase transition temperature.

Notes: mean ± SD; n = 3.

Abbreviations: BSL, brucine-loaded stealth liposomes; SPC, soy phosphatidylcholine; DPPC, dipalmitoyl phosphatidylcholine; HSPC, hydrogenated soy phosphatidylcholine; DSPC, distearoyl phosphatidylcholine; SD, standard deviation.

Figure 5 In vitro release profiles of brucine from brucine-loaded stealth liposomes with different phase transition temperature in the presence of rat plasma.

Notes: mean ± SD, n = 3.

Abbreviations: BSL, brucine-loaded stealth liposomes; SPC, soy phosphatidylcholine; DPPC, dipalmitoyl phosphatidylcholine; HSPC, hydrogenated soy phosphatidylcholine; DSPC, distearoyl phosphatidylcholine; SD, standard deviation.

Table 1 Pharmacokinetic parameters of brucine after intravenous administration at a single dose of 2.5 mg/kg of brucine solution or brucine-loaded stealth liposomes with different phase transition temperature in rats

Parameters	Brucine solution	BSL-SPC	BSL-DPPC	BSL-HSPC	BSL-DSPC
AUC0–∞/μg · min · mL^−1	29.78 ± 5.18	242.22 ± 146.67	300.85 ± 201.07	1378.72 ± 337.62	1450.00 ± 378.74**
AUC0–t/μg · min · mL^−1	25.27 ± 4.73	194.85 ± 118.21	233.57 ± 107.20	1360.24 ± 330.07**	1436.17 ± 377.23**
MRT/min	28.78 ± 1.52	68.85 ± 45.33	50.77 ± 26.15	28.79 ± 9.56**	28.206 ± 3.84**
CL/F/L · Kg^−1 · min^−1	0.086 ± 0.013	0.018 ± 0.016	0.012 ± 0.008	0.002 ± 0.001*	0.002 ± 0.001*
V/F/L · Kg^−1	4.31 ± 1.44	2.07 ± 1.74	2.00 ± 1.36	0.24 ± 0.07*	0.19 ± 0.10*
t½/min	34.93 ± 11.44	100.86 ± 43.66	103.74 ± 49.87	89.13 ± 25.07	71.95 ± 32.37

Notes: n = 6; compared to BSL-SPC,

* P < 0.05;

** P < 0.001.

Abbreviations: BSL, brucine-loaded stealth liposomes; SPC, soy phosphatidylcholine; DPPC, dipalmitoyl phosphatidylcholine; HSPC, hydrogenated soy phosphatidylcholine; DSPC, distearoyl phosphatidylcholine; AUC_0-t, area under the curve from time 0 to time t; MRT, mean residence time; CL, total body clearance; V, volume of distribution; N, number; BSL, brucine-loaded stealth liposomes; P, probability.

Figure 6 Plasma concentration-time profiles of brucine after intravenous administration at a single dose of 2.5 mg/kg of brucine solution or brucine-loaded stealth liposomes with different phase transition temperature in rats.

Note: n = 6.

Abbreviations: BSL, brucine-loaded stealth liposomes; SPC, soy phosphatidylcholine; DPPC, dipalmitoyl phosphatidylcholine; HSPC, hydrogenated soy phosphatidylcholine; DSPC, distearoyl phosphatidylcholine.

Figure 7 Relationship between the phase transition temperature of PC and the AUC_0-t of brucine-loaded stealth liposomes composed of the corresponding PC after intravenous administration at a single dose of 2.5 mg/kg to rats.

Note: n = 6.

Abbreviations: PC, phosphatidylcholine; AUC_0-t, area under the curve from time 0 to time (t).

Table 2 Toxic values (Bliss method) of intravenously administrated brucine solution or brucine-loaded stealth liposomes in mice

Formulations	LD95(mg/kg)	LD50(mg/kg)	LD5(mg/kg)
Brucine solution	18.93	13.17	9.17
BSL-SPC	52.84	37.30	26.34
BSL-DPPC	57.27	37.69	24.81
BSL-HSPC	72.08	51.18	36.34
BSL-DSPC	73.30	52.86	38.11

Abbreviations: LD, median lethal dose; BSL, brucine-loaded stealth liposomes; SPC, soy phosphatidylcholine; DPPC, dipalmitoyl phosphatidylcholine; HSPC, hydrogenated soy phosphatidylcholine; DSPC, distearoyl phosphatidylcholine.

Figure 8 Calcein release from BSLs with different PC composition in rat plasma: PBS (1:1) at 37°C monitored at different time intervals in the range from 5 to 600 minutes.

Notes: mean ± SD; n = 3.

Abbreviations: BSL, brucine-loaded stealth liposomes; PC, phosphatidylcholine; PBS, phosphate buffered solution; SPC, soy phosphatidylcholine; DPPC, dipalmitoyl phosphatidylcholine; HSPC, hydrogenated soy phosphatidylcholine; DSPC, distearoyl phosphatidylcholine; SD, standard deviation.