Abstract
BackgroundEvodiamine has gained wide interests recently because of its antitumor activities. However, a superior bioavailability is required to achieve better efficacy due to its poor water solubility. The aim of this study was to enhance the evodiamine’s aqueous solubility by preparing evodiamine/hydroxypropyl-β-cyclodextrin (EVO/HP-β-CD) inclusion complex, which is incorporated evodiamine into HP-β-CD, and compare the antitumor activities before and after inclusion with HP-β-CD in human hepatoma HepG2 cells.ResultsThe EVO/HP-β-CD inclusion complexes were prepared by the kneading method and structurally characterized. P-glycoprotein ATPase assays firstly demonstrated that evodiamine was a substrate of P-glycoprotein, while HP-β-CD and EVO/HP-β-CD inclusion complexes inhibited P-glycoprotein by blocking P-glycoprotein ATPase activity. The EVO/HP-β-CD inclusion complexes may be a promising anticancer drug candidate without drug resistance. After given evodiamine or EVO/HP-β-CD inclusion complexes intervention, cell viability evaluation indicated that the half inhibition concentration of evodiamine and EVO/HP-β-CD inclusion complexes on HepG2 cells was 8.516 and 0.977 μM, respectively. The caspase-3 enzyme activity analysis and Annexin V/PI double-staining revealed that EVO/HP-β-CD inclusion complexes possessed better antitumor activities than evodiamine. Additionally, Hoechst 33258 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay demonstrated that EVO/HP-β-CD inclusion complexes induced HepG2 cell apoptosis more effectively than evodiamine.ConclusionsThe improved antitumor activities of evodiamine were attributed to the enhanced solubility and P-glycoprotein inhibition by HP-β-CD. These results are promising for the drug administration of EVO/HP-β-CD inclusion complexes to enhance the bioavailability of evodiamine in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s13065-016-0191-y) contains supplementary material, which is available to authorized users.
Highlights
Evodiamine has gained wide interests recently because of its antitumor activities
The phase solubilities of evodiamine and HP-β-CD are shown in Fig. 2, and the curve is identified as AP-type (r2 = 0.9829), which is increasing positively
TUNEL assay The TUNEL assay was used to confirm apoptosis induced by evodiamine, EVO/HP-β-CD complexes, and HP-β-CD according to the protocol of a commercial kit (Beyotime, China)
Summary
Evodiamine has gained wide interests recently because of its antitumor activities. a supe‐ rior bioavailability is required to achieve better efficacy due to its poor water solubility. Evodiamine (Fig. 1A), a quinolone alkaloid, is a major bioactive component extracted from the fruit of Evodiarutaecarpa (Juss.) Benth It participates in diverse pharmacological bioactivities, such as antiobesity [1, 2], Qiu et al Chemistry Central Journal (2016) 10:46. CDs can form water-soluble inclusion complexes with various poorly water-soluble compounds, thereby enhancing the bioavailability of insoluble drugs by increasing the drug solubility, dissolution, and/or drug permeability [13,14,15]. It has been reported that CDs or their chemically modified derivatives can improve water solubility and the bioavailability of drugs with poor water solubilities [16, 17]. It has been reported that HP-β-CD inhibits Pgp by blocking Pgp ATPase activity, which could enhance drug absorption [11, 21]
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