Evaluation on the inclusion behavior of β-cyclodextrins with lycorine and its hydrochloride

Abstract

Lycorine (Lyc) and its hydrochloride (Lyc∙HCl) as effective drugs can fight against many diseases including novel coronavirus (COVID-19) based on their antiviral and antitumor mechanism. Beta-cyclodextrin (β-CD) is considered a promising carrier in improving its efficacy while minimizing cytotoxicity due to the good spatial compatibility with Lyc. However, the detailed mechanism of inclusion interaction still remains to be further evaluated. In this paper, six inclusion complexes based on β-CDs, Lyc and Lyc∙HCl were processed through ultrasound in the mixed solvent of ethanol and water, and their inclusion behavior was characterized after lyophilization. It was found that the inclusion complexes based on sulfobutyl-beta-cyclodextrin (SBE-β-CD) and Lyc∙HCl had the best encapsulation effect among prepared inclusion complexes, which may be attributed to the electrostatic interaction between sulfonic group of SBE-β-CD and quaternary amino group of Lyc∙HCl. Moreover, the complexes based on SBE-β-CD displayed pH-sensitive drug release property, good solubilization, stability and blood compatibility, indicating their potential as suitable drug carriers for Lyc and Lyc∙HCl.

Keywords: Beta-cyclodextrins; Electrostatic interaction; Inclusion behavior; Lycorine; Lycorine hydrochloride.

Fig. 1

The FT-IR spectra of (A) β-CD@Lyc (blue) compared with β-CD + Lyc (green), Lyc (black), β-CD (red), (B) HP-β-CD@Lyc (blue) compared with HP-β-CD + Lyc (green), Lyc (black), HP-β-CD (red), (C) SBE-β-CD@Lyc (blue) compared with SBE-β-CD + Lyc (green), Lyc (black), SBE-β-CD (red), (D) β-CD@Lyc∙HCl (blue) compared with β-CD + Lyc∙HCl (green), Lyc∙HCl (black), β-CD (red), (E) HP-β-CD@Lyc∙HCl (blue) compared with HP-β-CD + Lyc∙HCl (green), Lyc∙HCl (black), HP-β-CD (red), (F) SBE-β-CD@Lyc∙HCl (blue) compared with SBE-β-CD + Lyc∙HCl (green), Lyc∙HCl (black), SBE-β-CD (red). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

The TG curves of (A) β-CDs@Lyc (β-CD@Lyc (purple, solid), HP-β-CD@Lyc (green, solid), SBE-β-CD@Lyc (pink, solid)) compared with β-CDs + Lyc (β-CD + Lyc (purple, break), HP-β-CD + Lyc (green, break), SBE-β-CD + Lyc (pink, break)), Lyc (black), β-CD (red), HP-β-CD(grown), SBE-β-CD (blue) and (B) β-CDs@Lyc∙HCl (β-CD@Lyc∙HCl (blue, solid), HP-β-CD@Lyc∙HCl (green, solid), SBE-β-CD@Lyc∙HCl (pink, solid)) compared with β-CDs + Lyc∙HCl (β-CD + Lyc∙HCl (blue, break), HP-β-CD + Lyc∙HCl (green, break), SBE-β-CD + Lyc∙HCl (pink, break)), Lyc∙HCl (black), β-CD (red), HP-β-CD(grown), SBE-β-CD (gray). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

The DSC curves of (A) β-CD@Lyc (red) compared with β-CD + Lyc (green), Lyc (black), β-CD (blue), (B) HP-β-CD@Lyc (red) compared with HP-β-CD + Lyc (green), Lyc (black), HP-β-CD (blue), (C) SBE-β-CD@Lyc (red) compared with SBE-β-CD + Lyc (green), Lyc (black), SBE-β-CD (blue), (D) β-CD@Lyc∙HCl (red) compared with β-CD + Lyc∙HCl (green), Lyc∙HCl (black), β-CD (blue), (E) HP-β-CD@Lyc∙HCl (red) compared with HP-β-CD + Lyc∙HCl (green), Lyc∙HCl (black), HP-β-CD (blue), (F) SBE-β-CD@Lyc∙HCl (red) compared with SBE-β-CD + Lyc∙HCl (green), Lyc∙HCl (black), SBE-β-CD (blue). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

The SEM images of (A) β-CDs, (B) HP-β-CD, (C) SBE-β-CD, (D) β-CD@Lyc, (E) HP-β-CD@Lyc, (F) SBE-β-CD@Lyc, (G) β-CD@Lyc∙HCl, (H) HP-β-CD@Lyc∙HCl, (I) SBE-β-CD@Lyc∙HCl.

Fig. 5

The XRD spectra of (A) β-CD@Lyc (blue) compared with β-CD + Lyc (green), Lyc (black), β-CD (red), (B) HP-β-CD@Lyc (blue) compared with HP-β-CD + Lyc (green), Lyc (black), HP-β-CD (red), (C) SBE-β-CD@Lyc (blue) compared with SBE-β-CD + Lyc (green), Lyc (black), SBE-β-CD (red), (D) β-CD@Lyc∙HCl (blue) compared with β-CD + Lyc∙HCl (green), Lyc∙HCl (black), β-CD (red), (E) HP-β-CD@Lyc∙HCl (blue) compared with HP-β-CD + Lyc∙HCl (green), Lyc∙HCl (black), HP-β-CD (red), (F) SBE-β-CD@Lyc∙HCl (blue) compared with SBE-β-CD + Lyc∙HCl (green), Lyc∙HCl (black), SBE-β-CD (red). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

The Job’s working curve of β-CD@Lyc (gray), β-CD@Lyc∙HCl (black), HP-β-CD@Lyc (purple), HP-β-CD@Lyc∙HCl (blue), SBE-β-CD@Lyc (pink) and SBE-β-CD@Lyc∙HCl (red). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 7

The phase solubility curves of β-CD@Lyc (A, green), HP-β-CD@Lyc (A, blue), SBE-β-CD@Lyc (A, red), β-CD@Lyc∙HCl (B, green), HP-β-CD@Lyc∙HCl (B, blue) and SBE-β-CD@Lyc∙HCl (B, red). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 8

The 1D ¹H NMR spectrum of (A) SBE-β-CD@Lyc (red) compared with Lyc (blue), SBE-β-CD (green) and (B) SBE-β-CD@Lyc∙HCl (red) compared with Lyc∙HCl (blue), SBE-β-CD (green). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 9

The 2D ¹H NMR spectrum of (A) SBE-β-CD@Lyc∙HCl and (B, C, D) partial enlarged details of (A).

Fig. 10

(A) The molecular docking model and (B) the predicted inclusion mode of SBE-β-CD@Lyc∙HCl.

Fig. 11

The release profile of Lyc from SBE-β-CD@Lyc in phosphate buffer saline (PBS) at pH ∼ 7.4 (green), pH ∼ 6.5 (blue), pH ∼ 5.5 (red), and Lyc∙HCl from SBE-β-CD@Lyc∙HCl in phosphate buffer saline (PBS) at pH ∼ 7.4 (purple), pH ∼ 6.5 (pink), pH ∼ 5.5 (black). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 12

The hemolysis rate of β-CD@Lyc, β-CD@Lyc∙HCl, HP-β-CD@Lyc, HP-β-CD@Lyc∙HCl, SBE-β-CD@Lyc, SBE-β-CD@Lyc∙HCl and ultrapure water.