Development and characterization of self-assembling lecithin-based mixed polymeric micelles containing quercetin in cancer treatment and an in vivo pharmacokinetic study

Abstract

Quercetin (Que) is known to have biological benefits including an anticancer effect, but low water solubility limits its clinical application. The aim of this study was to develop a lecithin-based mixed polymeric micelle (LMPM) delivery system to improve the solubility and bioavailability of Que. The optimal Que-LMPM, composed of Que, lecithin, Pluronic(®) P123, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy[poly(ethylene glycol)-2000] in a proportion of 3:1:17.5:2.5 (w/w), was prepared by a thin-film method. The average size, polydispersion index, encapsulating efficiency, and drug loading of Que-LMPM were 61.60 ± 5.02 nm, 0.589 ± 0.198, 96.87% ± 9.04%, and 12.18% ± 1.11%, respectively. The solubility of Que in the Que-LMPM system increased to 5.81 mg/mL, compared to that of free Que in water of 0.17-7.7 μg/mL. The Que-LMPM system presented a sustained-release property in vitro. The in vitro cytotoxicity assay showed that the 50% inhibitory concentration values toward MCF-7 breast cancer cells for free Que, blank LMPMs, and Que-LMPMs were >200, >200, and 110 μM, respectively, indicating the nontoxicity of the LMPM carrier, but the LMPM formulation enhanced the cytotoxicity of Que against MCF-7 cells. A cellular uptake assay also confirmed the intake of Que-LMPM by MCF-7 cells. An in vivo pharmacokinetic study demonstrated that Que-LMPMs had higher area under the concentration-time curve and a longer half-life, leading to better bioavailability compared to a free Que injection. Due to their nanosize, core-shell structure, and solubilization potential, LMPMs were successfully developed as a drug delivery system for Que to improve its solubility and bioavailability.

Keywords: DSPE-PEG; Pluronic®; bioavailability; lecithin; micelle; mixed micelles; quercetin.

Figure 1

Transmission electron microscopic image of quercetin-mixed polymeric micelles. Scale bar: 100 nm at a 2×10⁵ magnification.

Figure 2

In vitro drug release profile of quercetin-mixed polymeric micelles and free quercetin (n=3).

Figure 3

Images of MCF-7 breast cancer cells treated with quercetin-mixed polymeric micelles. Notes: Bright field of cells (A); fluorescence images of cell nuclei stained with Hoechst 33258 exhibiting blue (B) and coumarin 6 exhibiting green (C); (D) is a merged image of (A–C).

Figure 4

In vitro cytotoxicity profile of quercetin, quercetin-mixed polymeric micelles, and blank-mixed polymeric micelles (n=3).

Figure 5

Plasma concentration–time curves of Que after intravenous administration of Que-mixed polymeric micelles and free Que (10 mg/kg) to rats. Note: Each data point represents the mean ± standard deviation (n=3). Abbreviation: Que, quercetin.