Drug delivery systems for elemene, its main active ingredient β-elemene, and its derivatives in cancer therapy

Abstract

β-elemene is a noncytotoxic Class II antitumor drug extracted from the traditional Chinese medicine Curcuma wenyujin Y. H. Chen et C. Ling. β-elemene exerts its effects by inhibiting cell proliferation, arresting the cell cycle, inducing cell apoptosis, exerting antiangiogenesis and antimetastasis effects, reversing multiple-drug resistance (MDR), and enhancing the immune system. Elemene injection and oral emulsion have been used to treat various tumors, including cancer of the lung, liver, brain, breast, ovary, gastric, prostate, and other tissues, for >20 years. The safety of both elemene injection and oral emulsion in the clinic has been discussed. Recently, the secondary development of β-elemene has attracted the attention of researchers and made great progress. On the one hand, studies have been carried out on liposome-based systems (including solid lipid nanoparticles [SLNs], nanostructured lipid carriers [NLCs], long-circulating liposomes, active targeting liposomes, and multidrug-loaded liposomes) and emulsion systems (including microemulsions, self-emulsion drug delivery systems [SEDDSs], and active targeting microemulsion) to solve the issues of poor solubility in water, low bioavailability, and severe phlebitis, as well as to improve antitumor efficacy. The pharmacokinetics of different drug delivery systems of β-elemene are also summarized. On the other hand, a number of highly active anticancer β-elemene derivatives have been obtained through modification of the structure of β-elemene. This review focuses on the two drug delivery systems and derivatives of β-elemene for cancer therapy.

Keywords: derivative; drug delivery system; pharmacokinetics; safety; β-elemene.

Figure 1

The source of elemene and its drug delivery systems approved by the CFDA. Abbreviation: CFDA, China Food and Drug Administration.

Figure 2

The structure of β-elemene and its derivatives. Notes: 4a, monosubstituted amine derivative of β-elemene; 6q, β-elemene isopropanolamine; 11a, furoxan-based NO-donating β-elemene hybrid; 13, Re(CO)₃-β-elemene derivative; IIi, 13,14-bis(cis-3,5-dimethyl-1-piperazinyl)-β-elemene; IIm, 13,14-bis[2-(2-thiophenyl)ethylamino]-β-elemene; IIn, 13,14-bis(cyclohexamino)-β-elemene; DX1, 13-(3-methyl-1-piperazinyl)-β-elemene; Lr-1, [(R or S)–2-((1R,3S,4S)–3-isopropenyl-4-methyl-4-vinyl-cyclohexyl)-propane-1,2-diol; Lr-2, (S)–2-((1R,3S,4S)–3-isopropenyl-4-methyl-4-vinyl-cyclohexyl)-propane-1,2-diol and (R)–2-((1R,3S,4S)–3-isopropenyl-4-methyl-4-vinyl-cyclohexyl)-propane-1,2-diol. Abbreviation: ETME, N-(β-elemene-13-yl)tryptophan methyl ester.

Figure 3

Targeting tumor cells using ligand-directed liposomes. Abbreviation: ECM, extracellular matrix.

Figure 4

The drug delivery systems of elemene. Abbreviations: NLC, nanostructured lipid carrier; O/W, oil-in-water; SEDDS, self-emulsion drug delivery system; SLN, solid lipid nanoparticle.