Preparation, safety, pharmacokinetics, and pharmacodynamics of liposomes containing Brucea javanica oil

Abstract

Brucea javanica oil-loaded liposomes (BJOL) were prepared through thin film hydration method and characterized by transmission electron microscope, dynamic light scattering, and differential scanning calorimetry. Acute toxicity of B. javanica oil (BJO) in liposomes was assessed by determining the number of deaths of Kunming mice over intravenous treatment for 2 weeks. The pharmacokinetic behavior of the main active component (oleic acid) was studied in SD rats. The pharmacodynamics of BJOL was investigated using MMC-7721 cell lines and mice with Lewis lung cancer. The commercial emulsion of BJO (BJOE) was used as a reference. The data showed that BJOL had an average diameter of 108.2 nm with a zeta potential of -57.0 mV, drug loading of 3.60%, and entrapment efficiency of 92.40%. The area under curve of BJO in liposomes and emulsions were 2.31 and 1.15 mg min/ml, respectively. Compared with BJOE, mean residence time and elimination half-time (t(1/2)) increased 2.8- and 4.0-fold, respectively, and the clearance (CL) decreased 0.5-fold. In the acute toxicity test, the median lethal dose (LD(50)) of BJOE was 7.35 g/kg. In contrast, all mice treated with liposomes survived even at the highest dosage (12.70 g/kg). The IC(50) value of BJOL group was one third of that of BJOE group (p < 0.01), and a less weight loss was observed in the BJOL-treated animals (p < 0.05). In conclusion, the present study suggests that BJOL significantly decreased toxicity of BJO and enhance the antitumor activity. Therefore, liposomes may be a potential effective delivery vehicle for this lipophilic antitumor drug.

Fig. 1

Microphotograph of BJOL by transmission electron microscope (original magnification ×60,000). Under electron microscope, BJOL showed a global, regular contour with homogeneous size and distribution

Fig. 2

Overlaid DSC thermograms of soybean phospholipid A, cholesterol B, BJO C, unloaded liposomes D, and BJO liposomes E

Fig. 3

Mean plasma concentration–time curves of BJO after intravenous administration in rats. Diamonds, BJOL. Squares, BJOE. Each point represents the mean ± SD (n = 5)

Fig. 4

Inhibition effects of BJOL and BJOE on 7721 human liver tumor cell. Diamonds, BJOE. Squares, BJOL. Each point represents the mean ± SD (n = 3)

Fig. 5

The weight of transplantable tumor on mice after treatment with BJOL and BJOE at different doses of BJO. Each point represents the mean ± SD (n = 10). A Control. B Cyclophosphamide (CTX). C Emulsions 180. D Liposomes 60. E Liposomes 120. F Liposomes 180. Results were tested for significance using t test. Significance levels: single asterisk, p < 0.05; double asterisk, p < 0.01

Fig. 6

The weight change of mice (grams) after treatment of BJOL and BJOE. Each point represents the mean ± SD (n = 10). A Control. B Cyclophosphamide (CTX). C Emulsions 180. D Liposomes 60. E Liposomes 120. F Liposomes 180