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. 2016 Sep 8:11:4563-4571.
doi: 10.2147/IJN.S112204. eCollection 2016.

d-α-Tocopheryl polyethylene glycol succinate/Solutol HS 15 mixed micelles for the delivery of baohuoside I against non-small-cell lung cancer: optimization and in vitro, in vivo evaluation

Hongmei Yan  1 , Zhenhai Zhang  2 , Xiaobin Jia  1 , Jie Song  1
Affiliations

d-α-Tocopheryl polyethylene glycol succinate/Solutol HS 15 mixed micelles for the delivery of baohuoside I against non-small-cell lung cancer: optimization and in vitro, in vivo evaluation

Hongmei Yan et al. Int J Nanomedicine. .

Abstract

Baohuoside I, extracted from the Herba epimedii, is an effective but a poorly soluble antitumor drug. To improve its solubility, formulation of baohuoside I-loaded mixed micelles with d-α-tocopheryl polyethylene glycol succinate and Solutol HS 15 (BTSM) has been developed in this study. We performed a systematic comparative evaluation of the antiproliferative effect, cellular uptake, antitumor efficacy, and in vivo tumor targeting of these micelles using non-small-cell lung cancer (NSCLC) A549 cells. Results showed that the obtained micelles have a mean particle size of ~62.54 nm, and the size of micelles was narrowly distributed. With the improved cellular uptake, BTSM displayed a more potent anti-proliferative action on A549 cell lines than baohuoside I; half-maximal inhibitory concentration was 7.83 vs 20.37 µg/mL, respectively. The antitumor efficacy test in nude mice showed that BTSM exhibited significantly higher antitumor activity against NSCLC with lesser toxic effects on normal tissues. The imaging study for in vivo targeting demonstrated that the mixed micelles formulation achieved effective and targeted drug delivery. Therefore, BTSM might be a potential antitumor formulation.

Keywords: Solutol HS 15; TPGS; antitumor; baohuoside I-loaded mixed micelles.

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Figures

Figure 1
Figure 1
Characteristics of the BTSM. Notes: (A) Structure of the baohuoside I mixed micelles. (B) Size distribution of BTSM as determined by dynamic light scattering. (C) Transmission electron microscope (TEM) image of BTSM (scale bar =100 nm). (D) Baohuoside I release profiles from the micelles in vitro in PBS (pH 7.4). Data are presented as the mean ± SD (n=3). Abbreviations: BTSM, baohuoside I-loaded mixed micelles consisting of TPGS and Solutol HS 15; TPGS, d-α-tocopheryl polyethylene glycol succinate; PBS, phosphate-buffered saline; SD, standard deviation.
Figure 2
Figure 2
DAPI channels showing the blue fluorescence from propidium iodide stained nuclei, Coumarin-6 channels showing the green fluorescence from the mixed micelles distributed in cytoplasm, and merged channels of Coumarin-6 and DAPI. Notes: (A) Cellular uptake efficiency of the baohuoside I and BTSM by A549 cells after 1, 2 and 4 hours of incubation. The results were presented as the mean ± SD (n=6). *P<0.05, compared with baohuoside I group. (B) Fluorescence microscope of A549 cells after 2 hours of incubation with the free fluorescent coumarin-6 and the coumarin-6-loaded mixed micelles. Abbreviations: BTSM, baohuoside I-loaded mixed micelles consisting of TPGS and Solutol HS 15; TPGS, d-α-tocopheryl polyethylene glycol succinate; SD, standard deviation; DAPI, 4,6-diamidino-2-phenylindole; coumarin-6-M, coumarin-6-loaded mixed micelles composed of TPGS and Solutol HS 15.
Figure 3
Figure 3
In vivo antitumor study of BTSM in BALB/c nude mice implanted with A549 cells. Notes: Tumor volumes (A) and body weight (B) were monitored daily. Tumor weight (C) and organ index (D) were monitored at the end of the experiment. The results are presented as the mean ± SD (n=6). *P<0.05, compared with control group; #P<0.05, compared with baohuoside I group. Abbreviations: BTSM, baohuoside I-loaded mixed micelles consisting of TPGS and Solutol HS 15; TPGS, d-α-tocopheryl polyethylene glycol succinate; SD, standard deviation.
Figure 4
Figure 4
Fluorescence images of the mice bearing A549 cells on right side at different time points after intravenous injection of DiR-loaded mixed micelles. Abbreviations: DiR, 1,1-Dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine; DiR-M, DiR-loaded mixed micelles composed of TPGS and Solutol HS 15.
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