Abstract

Imperatorin is a chemical compound belonging to the linear furanocoumarins. Imperatorin is attracting considerable attention because of its antitumor, antibacterial, anti-inflammatory, and anticoagulant activities, inhibition of myocardial hypertrophy, and other pharmacological efficacies. However, imperatorin has limited water solubility and has better lipid solubility; thus, we decided to design and synthesize imperatorin lipid microspheres to optimize the preparation conditions. The aim was to develop and formulate imperatorin lipid microspheres through nanoemulsion technology and apply the response surface–central composite design to optimize the imperatorin lipid microsphere formulation. The influence of the amounts of egg lecithin, poloxamer 188, and soybean oil for injection on the total percentage of the oil phase was investigated. The integrated effect of dependent variables, including particle size, polydispersity index, zeta potentials, drug loading, and encapsulation efficiency, was investigated. Data of overall desirabilities were fitted to a second-order polynomial equation, through which three-dimensional response surface graphs were described. Optimum experimental conditions were calculated by Design-Expert 8.06. Results indicated that the optimum preparation conditions were as follows: 1.39 g of egg lecithin, 0.21 g of poloxamer 188, and 10.57% soybean oil for injection. Preparation of imperatorin lipid microspheres according to the optimum experimental conditions resulted in an overall desirability of 0.7286, with the particle size of 168 ± 0.54 nm, polydispersity index (PDI) of 0.138 ± 0.02, zeta potentials of −43.5 ± 0.5 mV, drug loading of 0.833 ± 0.27 mg·mL−1, and encapsulation efficiency of 90 ± 1.27%. The difference between the observed and predicted values of the overall desirability of the optimum formulation was in the range from 2.4% to 4.3%. Subsequently, scanning electron microscopy was used to observe the micromorphology of the imperatorin lipid microspheres, showing round globules of relatively uniform shape and sizes within 200 nm. The effect of imperatorin lipid microspheres on MDA-MB-231 proliferation was investigated by the MTT method. Furthermore, pharmacokinetics in Sprague-Dawley rats was evaluated using orbital bleeding. A sensitive and reliable liquid chromatography with the high-performance liquid chromatography (HPLC) method was established and validated for the quantification of imperatorin in rat plasma samples. The data were calculated by DAS (drug and statistics) Pharmacokinetic Software version 3.3.0 (Version 3.3.0, Shanghai, China). Results demonstrated that imperatorin lipid microspheres can significantly enhance the bioavailability of imperatorin and can significantly inhibit MDA-MB-231 cell proliferation. In conclusion, our results suggested that the response surface–central composite design is suitable for achieving an optimized lipid microsphere formulation. Imperatorin lipid microspheres can improve the bioavailability of imperatorin and better inhibit the proliferation of MDA-MB-231 cells as compared to imperatorin alone.

Highlights

  • Imperatorin is a chemical compound belonging to the linear furanocoumarins and it is mainly extracted and isolated from the traditional herbal medicine of Angelica dahurica

  • These findings suggested that imperatorin is a potential anticancer drug with a good application prospect

  • Imperatorin was dissolved in the oil phase, which was composed of egg yolk lecithin, LCT, and medium-chain fatty acid glyceride for injection (MCT)

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Summary

Introduction

Imperatorin is a chemical compound belonging to the linear furanocoumarins and it is mainly extracted and isolated from the traditional herbal medicine of Angelica dahurica. Jakubowicz-Gil showed that imperatorin combined with quercetin could effectively inhibit the proliferation of tumor cells and induce the cells’ apoptosis [6,7,8] These findings suggested that imperatorin is a potential anticancer drug with a good application prospect. We took advantage of imperatorin’s characteristics of poor solubility in water and good fat solubility and dissolved it in an oil-based injection, selected lecithin as an emulsifier, and used nanoemulsification technology to prepare imperatorin lipid microspheres. Lipid microsphere (LM) has been recently used as intravenous (i.v.) carriers for drugs, especially for those drugs that have enough solubility in oil while have poor solubility in water It is difficult for this kind of drugs to prepare injection preparations. In order to increase its druggability and to exert its antitumor effect, the optimization of the preparation and formulation of imperatorin lipid microspheres was accomplished; the pharmacokinetics of imperatorin in rats was investigated, and the respective effects of imperatorin and imperatorin lipid microspheres on MDA-MB-231 cell proliferation were compared in the study

Chemicals and Drugs
Animals
Imperatorin Lipid Microsphere Preparation
Determination of Drug Loading and Encapsulation Efficiency
Pharmacokinetics and Statistical Analysis
Data Analysis
Central Composite Design of Response Surface Methodology
C Predicted Value
Particle Size and Zeta Potential Measurements

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