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. 2019 Dec;26(1):309-317.
doi: 10.1080/10717544.2019.1568623.

Preparation, optimization of the inclusion complex of glaucocalyxin A with sulfobutylether-β-cyclodextrin and antitumor study

Lili Ren  1   2 , Jingjing Wang  1 , Guoguang Chen  1
Affiliations

Preparation, optimization of the inclusion complex of glaucocalyxin A with sulfobutylether-β-cyclodextrin and antitumor study

Lili Ren et al. Drug Deliv. 2019 Dec.

Abstract

Glaucocalyxin A (GLA), is a diterpenoid extracted from Hara and has been studied for decades for its diverse bioactivities. However, GLA presents poor solubility in water and low bioavailability through oral administration which has hindered its application in the clinic. So in this study, we prepared the inclusion complex of GLA in SBE-β-CD by ultrasound method and evaluated its antitumor effect and cytotoxic effect on cancer cells. The production of GLA-SBE-β-CD inclusion complex was optimized using Box-Behnken design. The inhibitory effects of GLA and GLA-SBE-β-CD were investigated on the Hela, A549, HepG2, and SiHa cells in vitro by MTT staining assay. Pharmacokinetic studies were conducted on Sprague-Dawley mice via caudal injection to study the distribution, metabolism, and elimination of GLA-SBE-β-CD in vivo. Tumor-bearing nude mice were taken as the model and adopted to evaluate the inhibitory rate of GLA and GLA-SBE-β-CD on the transplanted tumor. A series of physical characterization results confirmed the fact that GLA-SBE-β-CD inclusion complex was successfully prepared. A production of 87.28% was achieved based on the Box-Behnken design. In the cancer cell inhibition studies, GLA and GLA-SBE-β-CD exhibited apparent concentration-dependent inhibitory actions on four kinds of tumor cells and better inhibition was achieved in GLA-SBE-β-CD group. The pharmacokinetic results showed that the duration of GLA in blood was prolonged and enhanced bioavailability was achieved. GLA and GLA-SBE-β-CD both showed an effective inhibition on the transplanted tumor growth, while the anti-tumor effect of GLA-SBE-β-CD (inhibitory rate of 45.80%) was significantly stronger than that of GLA (30.76%) based on the change of tumor weight and tumor volume.

Keywords: Glaucocalyxin A; SBE-β-CD; antitumor; cytotoxic; inclusion complex.

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Figures

Figure 1.
Figure 1.
(A) Response surface graph (3D) and contour graph showing the effect of the temperature (A) and concentration of SBE-β-CD (B), (B) the temperature (A) and inclusion time (C), (C) the concentration of SBE-β-CD (B) and inclusion time (C) added on the response (inclusion efficiency).
Figure 2.
Figure 2.
(A) DSC thermograms of GLA-SBE-β-CD inclusion complex (a), their physical mixture (b), SBE-β-CD (c) and GLA (d). (B) PXRD patterns of GLA, their physical mixture, GLA- SBE-β-CD inclusion complex and SBE-β-CD. (C). SEM photo of GLA- SBE-β-CD inclusion complex (a), their physical mixture (b), SBE-β-CD (c), and GLA (d).
Figure 3.
Figure 3.
The inhibition rate of GLA and GLA-SBE-β-CD on four human cancer cells: A549, HeLa, HepG2, and SiHa.
Figure 4.
Figure 4.
The curve of the mean plasma drug concentration versus time in rats after intravenous injection of GLA-SBE-β-CD or GLA.
Figure 5.
Figure 5.
(A) Tumor volume change after intravenous injection of GLA and GLA-SBE-β-CD. (B) The tumor weight at day 11 after the first injection.
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