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

Figures & data

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.

Table 1 The pharmacokinetic parameters of β-elemene and its formulations in rats

Dosage	T1/2	Vd	CL	AUC0–∞	MRT	Ref
β-elemene 50 mg/kg (iv)	58.600±8.300 minutes	1.900±0.190 L/kg	0.058±0.005 L/min/kg	861.100±64.600 µg/min/mL	NA	41
β-elemene 75 mg/kg (iv)	58.400±17.900 minutes	2.580±0.520 L/kg	0.056±0.004 L/min/kg	1,355.200±103.400 µg/min/mL	NA	41
β-elemene 100 mg/kg (iv)	65.100±5.900 minutes	2.240±0.220 L/kg	0.046±0.004 L/min/kg	2,200.600±186.200 µg/min/mL	NA	41
β-elemene emulsion 44.2 mg/kg (iv)	15.400±1.600 minutes	1.900±0.500 L	87.300±18.300 mL/min	505.400±106.400 µg/min/mL	25.600±1.800 minutes	44
β-elemene SLN 44.2 mg/kg (iv)	15.600±1.200 minutes	1.800±0.300 L	80.000±13.200 mL/min	551.300±90.100 µg/min/mL	26.800±1.000 minutes	44
2% FA-PEG-SLN 44.2 mg/kg (iv)	19.100 minutes	2.350 L	85.200 mL/min	517.000 µg/min/mL	21.300 minutes	45
4% FA-PEG-SLN 44.2 mg/kg (iv)	44.000 minutes	3.090 L	48.600 mL/min	907.000 µg/min/mL	30.000 minutes	45
β-elemene injection 40 mg/kg (iv)	19.530±4.440 minutes	81.600±16.730 mL	0.380±0.050 L/h	12.300±4.330 µg/h/mL	NA	46
β-elemene NLC 40 mg/kg (iv)	28.820±3.880 minutes	46.170±8.130 mL	0.110±0.060 L/h	30.320±5.740 µg/h/mL	NA	46
EE 50 mg/kg (iv)	86.400±15.000 minutes	NA	NA	1,486.300±71.600 µg/min/mL	NA	47
CLE 50 mg/kg (iv)	114.600±28.200 minutes	NA	NA	2,185.600±677.400 µg/min/mL	NA	47
PLE 50 mg/kg (iv)	235.200±30.600 minutes	NA	NA	5,728.500±1,025.100 µg/min/mL	NA	47
TLLE 50 mg/kg (iv)	273.400±44.100 minutes	NA	NA	6,352.000±894.200 µg/min/mL	NA	47
β-elemene emulsion 100 mg/kg (po)	0.880 hours	NA	37.413 L/h/kg	1.896 mg/h/L	1.450 hours	48
β-elemene microemulsion100 mg/kg (po)	1.030 hours	NA	24.549 L/h/kg	3.092 mg/h/L	1.688 hours	48
β-elemene micelle 75 mg/kg (ig)	76.510±1.600 minutes	NA	NA	343.850±6.700 µg/h/mL	NA	49
β-elemene SEDDS 75 mg/kg (ig)	86.560±1.300 minutes	NA	NA	524.650±11.200 µg/h/mL	NA	49
CE 50 mg/kg (iv)	0.131±0.290 hours	4.789±0.570 mg/L	2.530±0.360 L/h/kg	11.090±1.579 mg/h/L	2.053±0.150 hours	50
1:7 ME 50 mg/kg (iv)	0.272±0.230 hours	1.539±0.180 mg/L	0.959±0.210 L/h/kg	52.156±0.661 mg/h/L	0.847±0.105 hours	50
FRT 1:7 ME 50 mg/kg (iv)	0.344±0.450 hours	4.186±0.230 mg/L	0.731±0.870 L/h/kg	68.600±0.320 mg/h/L	2.160±0.190 hours	50

Notes: 2% FA-PEG-SLN, β-elemene SLN modified with 0.1% FA-PEG-S and 2% CHS-PEG; 4% FA-PEG-SLN, β-elemene SLN modified with 0.1% FA-PEG-S and 4% CHS-PEG; FRT 1:7 ME, folate receptor-targeted microemulsion (elemene/Labrafac CC =1:7); 1:7 ME, microemulsion (elemene/Labrafac CC =1:7).

Abbreviations: AUC, area under the curve; CE, commercial emulsion; CHS-PEG, monomethoxy polyethylene glycol (2000) succinyl cholesterol; CL, apparent clearance; CLE, conventional liposome containing β-elemene; EE, elemene emulsion; FA-PEG-S, N-stearyl-N′-pteroylglutamyl-polyethylene glycol (3350) bis-amine; FRT, folate receptor-targeted; ig, intragastric; ME, microemulsion; MRT, mean residence time; NA, not applicable; NLC, nanostructured lipid carriers; PLE, PEGylated liposome containing β-elemene; Ref, reference; SEDDS, self-emulsion drug delivery system; SLN, solid lipid nanoparticle; T_1/2, terminal half-life; TLLE, thermosensitive long-circulating liposome containing β-elemene; V_d, volume of distribution; iv, intravenous; po, oral administration.

Table 2 Partial instructions of elemene injection and oral emulsion approved by the CFDA

Instructions	Elemene injection (liposome)	Elemene oral emulsion
Medical supplement	Soybean phospholipid, cholesterol, ethanol, dibasic sodium phosphate, sodium dihydrogen phosphate	NA
Indications	This product, combined with radiotherapy and chemotherapy, can enhance the efficacy against lung cancer, liver cancer, esophageal cancer, nasopharyngeal carcinoma, brain tumor, bone metastasis, and other malignant tumors, as well as reduce the side effects of radiotherapy and chemotherapy. It can also be used for interventional, intracavitary chemotherapy and treatment of cancerous ascites	This product is used for adjuvant treatment of esophageal cancer and gastric cancer to improve symptoms
Dosage and administration	Intravenous injection: once 0.4–0.6 g, once a day, 2–3 weeks for a course of treatment For the treatment of malignant hydrothorax and ascites: generally, 200–400 mg/m^2, after pumping ascites, intrathoracic or intraperitoneal injection, one or two times a week or as directed	Oral, 20 mL once, three times a day. Swallowing on an empty stomach before meals, taking 4–8 weeks for a course of treatment or as directed
Adverse reactions	Some patients may have phlebitis, fever, local pain, allergic reaction, mild digestive tract reaction after medication	Some patients may have digestive tract reactions, such as nausea, vomiting, and diarrhea, occasional loss of appetite, hemoglobin decline, and leukopenia. Most of the adverse reactions were mild and did not affect treatment

Abbreviations: CFDA, China Food and Drug Administration; NA, not applicable.

Figure 3 Targeting tumor cells using ligand-directed liposomes.

Abbreviation: ECM, extracellular matrix.

Table 3 The drug delivery systems of elemene liposome and oral emulsion

Drug delivery system	Method	Prescription	Characterization	Ref
SLN	Combining the techniques of probe sonication and membrane extrusion	350 mg Precirol ATO, 150 mg glyceryl monostearate, 250 mg Lutrol F68, 10 mL distilled water	Mean size: 48.9±2.6 nm, zeta potential: −30.7±4.5 mV, β-elemene concentration: 5.6±0.2 mg/mL, and entrapment efficiency: 99.7% ± 2.5%	^Citation44
NLC	Hot-melting high-pressure homogenization method	6% lipids (glycerol monostearate, a mixture of Maisine 35-1 and Labrafil M1944 CS [1:1]), 5% surfactants (a mixture of Tween 80 and soybean lecithin [1:1]), S/L ratio: 2:3, D/L ratio: 1:10	Mean size: 139.8 nm, polydispersity index: 0.085, zeta potential: −20.2 mV, drug loading: 8.45% ± 0.57%, and entrapment efficiency: 82.11% ± 1.84%	^Citation46
Sterical-stabilized liposome	Ethyl ether injection method	100 mg phospholipid, 10 mg cholesterol, 10 mg DSPE-PEG2000, and 50 mg β-elemene	Mean size: 110 nm, pH: 6.4–6.7, content: 10 mg/mL, and entrapment efficiency: 97%	^Citation56
Long-circulating liposome	Ethanol injection method	Phospholipid/cholesterol ratio: 5:1, 50 mg β-elemene, and 0.05% PEG2000	Mean size: 221.4 nm and entrapment efficiency: 92.7%	^Citation57
PLE	Ethanol injection method	Phospholipid/cholesterol/DSPE-PEG2000 ratio: 3:1:0.2	Mean size: 149 nm, entrapment efficiency: 95.2%, and concentration of β-elemene: 5 mg/mL	^Citation47
TLLE	Film dispersion method	DPPC/DSPC/DSPE-PEG2000 ratio: 9:1:0.6	Mean size: 103 nm and entrapment efficiency: 87.9%	^Citation47
FA-PEG-SLN	Combining the techniques of probe sonication and membrane extrusion	350 mg Precirol ATO, 150 mg glyceryl monostearate, 250 mg Lutrol F68, 0.1% FA-PEG-S, 4% CHS-PEG, and 10 mL distilled water	Mean size: 42.2±2.1 nm, zeta potential: −12.60±1.3 mV, entrapment efficiency: 97.5% ± 1.7%, and β-elemene concentration: 5.6 mg/mL	^Citation45
Multidrug-loaded liposome	Film dispersion method	20 mg curcumin, 5 mg β-elemene, 666.7 mg lecithin, and 133.3 mg cholesterol	Mean size: 232.0±6.4 nm, zeta potential: 0.71±0.1 mV, encapsulation efficiency of β-elemene: 97.86% ± 1.53%, entrapment efficiency of curcumin: 97.71% ± 1.53%, and total drug loading: 0.1925% ± 0.006%	^Citation62
O/W microemulsion	Ultrasonication method in an ultrasonic bath	1% Elemene, 5% polysorbate 80 and 5% ethanol, 15% propylene glycol, and 15% glycerol	Mean size: 57.7±2.8 nm, polydispersity index: 0.485±0.032, zeta potential: 3.2±0.4 mV, pH: 5.19±0.08, viscosity: 6 mPa⋅s, surface tension: 31.8±0.3 mN/m, elemene content: 8.273±0.018 mg/mL, and entrapment efficiency: 99.81% ± 0.24%	^Citation48
Microemulsion	Water titration method	1% Elemene, 7% Labrafac CC, 8% phosphatidylcholine, 8% HS-15, 16% propylene glycol, and 60% PBS solution (pH 7.4) containing 0.5% NaHSO ^Citation3	pH: 7.32±0.01, osmotic pressure: 279±3 mosm/kg, viscosity: (5.56±0.11)×10^−3, conductivity: 1.14×10^−2 ±7.9×10^−5 s/m, refractive index: 1.458±0.004, zeta potential: −2.64±0.06 mV, and mean size: 38.3±4.3 nm	^Citation65
SEDDS soft capsule	NA	β-elemene/ethyl oleate/Tween 85/Transcutol ratio: 55:45:60:40 (mass value)	Mean size: 320 nm and zeta potential: −3 mV	^Citation67
S-SMEDDS	NA	β-elemene/EL-35/LAS/total saponins of honey locust ratio: 3:2:2:3	Mean size: 158 nm	^Citation49
FRT microemulsion	NA	1% Elemene, 7% Labrafac CC, 8% phosphatidylcholine, FA-PEG2000-DOPE and phospholipid molar ratio of 1%–2%, 8% HS-15, 16% propylene glycol, and 58%–59% PBS solution (pH 7.4) containing 0.5% NaHSO3	Mean size: 42.5±6.3 nm, zeta potential: −2.78±0.920 mV, surface tension: 29.9 mN/m, and pH: 7.30±0.01	^Citation50

Notes: S/L ratio: the weight ratio of the solid lipid to liquid lipid (S/L, weight/weight [w:w]); D/L ratio: the weight ratio of the drug to the total lipids (D/L, w/w).

Abbreviations: CHS-PEG, monomethoxy polyethylene glycol (2000) succinyl cholesterol; DOPE, 1,2-oil acyl phosphatidylethanolamine; DPPC, dipalmitoyl phosphatidyl choline; DSPC, distearoyl phosphatidyl choline; DSPE-PEG2000, distearoyl phosphatidyl ethanolamine-poly(ethylene glycol) 2000; EL-35, Cremophor EL 35; FA-PEG-S, N-stearyl-N′-pteroylglutamyl-polyethylene glycol (3350) bis-amine; FA-PEG-SLN, β-elemene SLN modified with 0.1% FA-PEG-S and 4% CHS-PEG; FRT microemulsion, folate receptor-targeted microemulsion; HS, polyoxyethylene esters of PEG-(660)–12-hydroxyl; LAS, Labrasol; NLC, nanostructured lipid carriers; O/W, oil-in-water; PLE, PEGylated liposome containing β-elemene; Ref, reference; SEDDS, self-emulsion drug delivery system; SLN, solid lipid nanoparticle; S-SMEDDS, solid self-microemulsion drug delivery system; TLLE, thermosensitive long-circulating liposome containing β-elemene; NA, not applicable.

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.

Table 4 The main adverse reactions of elemene injection and oral emulsion, as well as the relevant precautions, in the clinic

Adverse reactions	Precautions
Phlebitis	PICC, 5 mg of dexamethasone, flushing channels with saline, and use of 50% magnesium sulfate solution
Fever	Prednisone or indomethacin taken before administration
Local pain	1% procaine or 2% lidocaine
Allergic reactions	5–10 mg dexamethasone, oxygen, promethazine, bronchodilating drugs
Gastrointestinal reaction	NA
Bleeding	NA

Abbreviations: NA, not applicable; PICC, peripherally inserted central catheter.

Table 5 β-elemene derivatives with antitumor activities

Derivatives and concentrations used for treatment	Cancer cell lines	Major mechanisms	Effects	Ref
11a (0.5–2.0 nM)	Human glioblastoma U87 cells	Bcl-2↓ Bax ↑ Procaspase-3↓ Caspase-3 ↑ p-AKT↓ PI3K/Akt ↓	G2 phase arrest, induction of apoptosis	^Citation92
IIi (1 and 2 µM)	Human breast cancer MCF-7 and MDA-MB-468 cells, and human leukemia K562 cells	Phosphorylated p70S6K1↓ p4EBP1↓ cleaved LC3 ↑ mTOR ↓	Inhibition of growth, induction of autophagy	^Citation93
6q (1.0–4.0 µM)	Human gastric carcinoma SGC-7901 cells	Cytochrome C (M) ↓ Cytochrome C (C) ↑ Caspase-3/9 ↑ Bcl-2↓ Bax↑ PARP ↓ Cleaved PARP ↑	G2 phase arrest, induction of apoptosis	^Citation94
DX1 (6.0–12.0 µM)	Human leukemia HL-60 cells	ROS↑ MMP↓ Bid ↓ c-FLIP↓ Procaspase-3/8/9 ↓ Caspase-8/9 ↑ PARP ↓ Cleaved PARP ↑	Induction of apoptosis	^Citation95
IIm and IIn (2.0 and 4.0 µM)	Human leukemia K562 cells	p-AKT↓ p-mTOR ↓ p-p70S6K ↓	Inhibition of growth	^Citation96
ETME (40 µM)	Human leukemia HL-60 and NB4 cells	PARP ↓ Cleaved PARP ↑ Procaspase-3 ↓ H2O2↑ MMP ↓	Induction of apoptosis	^Citation97
ETME+ As2O3 (20 µΜ + 5 µM)	Hepatocellular carcinoma SMMC-7721 cells	Procaspase-3/8/9↓ Bcl-2 ↓ MMP↓ Bid ↑ Bax↑ p53 ↑ Cyclin D1 ↑ Cyclin B1↑ CDK1 ↑ p27 ↑	G2/M phase arrest, induction of apoptosis	^Citation98
4a, 13	Human cervical adenocarcinoma HeLa cells	Rb phosphorylation ↓ Cyclin D1 ↓	G1 phase arrest	^Citation100

Notes: ↑, an increase in target protein; ↓, a decrease in target protein. 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.

Abbreviations: Bcl-2, B-cell lymphoma 2; Bid, binding interface database; ETME, N-(β-elemene-13-yl)tryptophan methylester; MMP, mitochondrial membrane potential; Ref, reference.

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