Developments in drug delivery of bioactive alkaloids derived from traditional Chinese medicine

Figures & data

Figure 1. The chemical structures of TCM alkaloids involved in this review.

Table 1. Basic information of TCM alkaloids involved in this review.

Alkaloids	Chemical formula	Sources	Bioactivities	Existing problems	References
Vincristine	C46H56N4O10	Catharanthi Rosei herba	Curing non-Hodgkin’s lymphoma, acute lymphoblastic leukemia, hematologic malignancies, and other solid tumors	Extensive distribution and long elimination; severe neurotoxicity	(Sethi et al., 1981; Silverman et al., 2013; Silverman & Deitcher, 2013; Said & Tsimberidou, 2014)
10-Hydroxycamptothecin (10-HCPT)	C20H16N2O5	Camptothecae Acuminatae fructus; Camptothecae Acuminatae folium; Camptotheca Acuminata decne; etc.	Treating colon cancer and other tumors; reducing epidural fibrosis	Poor solubility; short half-life	(Ping et al., 2006; Sun et al., 2008; Yang et al., 2011)
Brucine	C23H26N2O4	Strychni semen; Strychni semen pulveratum; Strychnos ignatii; etc.	Inducing apoptosis of human cancer cell lines; decreasing peritoneal angiogenesis and microvessel density in vivo	Severe central nervous system toxicity; remarkable increase of blood pressure and even lethal poisoning	(Malone et al., 1992; Agrawal et al., 2011; Chen et al., 2012)
Berberine chloride	C20H18ClNO4	Coptidis rhizoma; Phellodendri Chinensis cortex; Berberidis radix; etc.	Having the activities of anti-inflammation, vasorelaxation, and cardioprotection; inducing apoptosis of cancer cells	Low oral bioavailability; poor aqueous solubility; short half-life	(Pereira et al., 2007; Ma et al., 2013; Pirillo & Catapano, 2015; Allijn et al., 2017)
Matrine	C15H24N2O	Sophorae flavescentis radix; Sophorae tonkinensis radix et phizoma; Sophora alopecuroides L; etc.	Treating the infection of hepatitis B virus; inhibiting hepatic fibrosis	Low oral bioavailability	(Li et al., 2004; Wang et al., 2011; Chai et al., 2012)
Oxymatrine	C15H24N2O2	Sophorae flavescentis radix; Sophorae tonkinensis radix et phizoma; Sophora alopecuroides L; etc.	Treating the infection of hepatitis B virus; inhibiting hepatic fibrosis	Low oral bioavailability	(Li et al., 2004; Wang et al., 2011; Chai et al., 2012)
Ligustrazine	C8H12N2	Chuanxiong rhizoma; Curcumae rhizoma; Jatrophae rhizoma; etc.	Curing vascular illnesses and the corresponding complications	Short half-life, low oral bioavailability	(Chen & Chen, 1992; Mei et al., 2008; Li et al., 2012)
Tetrandrine	C38H42N2O6	Stephaniae tetrandrae radix; Stephaniae Cepharanthae radix; Stephaniae Dielsianae radix; Stephaniae Epigaeae radix; etc.	Having the efficacies of anti-cancer and anti-inflammation; treating hypertension and pneumosilicosis	Poor solubility; low oral bioavailability	(Cai et al., 2011; Xu et al., 2014)
Aconitine	C34H47NO11	Aconiti Lateralis radix praeparata; Aconiti radix; Aconiti Kusnezoffii radix; etc.	Having the efficacies of anti-inflammation and analgesia; treating neuronal disorders	High toxicity to the central nervous system and heart; limited oral administration; short elimination half-time; frequent dosing	(Wang & Xie, 1999; Rao & Sikdar, 2000; Zhao et al., 2011)
Sinomenine	C19H23NO4	Sinomenii Caulis; Menispermum dauricum DC; Stephaniae Tetrandrae radix; Stephaniae Epigaeae radix; etc.	Having the efficacies of anti-inflammation and immunoregulation; treating allogeneic graft rejection and rheumatoid arthritis	Damage to the kidney and intestine; affecting the function of liver and heart	(Xu et al., 2008; Wang & Li, 2011)

Figure 2. Improvement of drug-like properties of TCM-derived alkaloids via specific drug delivery systems.

Table 2. Delivery of alkaloids derived from traditional Chinese medicine by various liposomes.

Liposome types	Alkaloids	Liposome composition	Preparation	Method of model	Method of dosing	Effects	References
Conventional liposomes	10-HCPT	Lecithin: Chol; or EPC: Chol	Modified thin-film hydration method	Healthy rabbits	Iv.	The lactone: CL ↓ 52.6%, AUC0–∞  ↑  over one folds, Vd  ↓  50.5%; scar adhesion ↓	(Shi et al., 2010b; Yang et al., 2011)
	SN-38	SPC:Chol (1:6)	Carrier-deposition method	New Zealand white adult rabbits	Iv. drip	AUC0–6 h of the liver ↑ 3.95-fold; AUC0–6 h of the spleen ↑ 6.7-fold; AUC0–6 h of the lung ↑ 4.7-fold; AUC0–6 h of the kidney ↓ 85.6%; AUC0–6 h of the heart ↓ 30.8%	(Li & Wang, 2016)
	DB-67	DMPC: DMPG (7:3) or DSPC:m-PE G: DSPE (95:5)	–	SCID mice	Iv.	AUClactone of the spleen ↑ 1.07-fold; AUClactone of the lung ↑ 0.95-fold; t1/2 in PBS ↑ 5.66-fold	(Joguparthi et al., 2008; Zamboni et al., 2008)
	Vincristine	Sohingomyelin: Chol or HSPC: Chol: PEG5000-DSPE	The pH gradient method	Adults	Iv.	Therapeutic index ↑ ; target tumor ↑ ; individual dose ↑  over 2-fold; CL ↓ 40.4%; Cmax ↑ 52.3%, AUC ↑ 73.1%, MRT ↑ 56.6%, t1/2 ↑ 55.6%	(Thomas et al., 2009; Yan et al., 2012; O'Brien et al., 2013)
Long-circulating liposomes	Ligustrazine	–	–	–	–	MRT ↑ , AUC ↑ , t1/2 ↑ , CL ↓ ; uptake of the drug by the phagocyte cells ↓	(Yang et al., 2016)
	Berberine	DPPC, DSPE-PEG2000, Chol (1: 0.08: 0.28); or HSPC: DSPC: DSPE-PEG2000	Ethanol injection method or thin film hydration reverse phase evaporation method	Mice	Iv.	LVEF, FS ↓ ; EDV, ESV, HR ↓ ; t1/2  ↑ 5.13-fold, AST ↑ , ALT ↑ ; tumor weight ↓ 46.5% than the PBS; IC50 towards HepG2 cells ↓ 60.5%	(Lin et al., 2013; Allijn et al., 2017)
	Brucine	DSPE-PEG2000, Chol SPC/DPPC/HSPC/DSPC or SPC:HSPC:Chol:DSPE-mPEG	Ammonium sulfate gradient loading method	SD rats or Kun-Ming mice	Iv.	AUC0–∞ of the HSPC ↑ 4.7-fold than the SPC, CL/F of the HSPC ↓ 88.9% than the SPC; LD50 of the HSPC ↑ 37.2% than the SPC; The retention time of the mixture of HSPC and SPC  ↑ 2.22-fold compared to the SPC; AUC of the mixture of HSPC and SPC in tumor ↑ 29.3% compared to the SPC	(Chen et al., 2012; Li et al., 2013)
	Vincristine	PEG-DSPE:HSPC:Chol (1:22:10)	The pH gradient method	SD rats	Iv.	t1/2 of PEG-DSPE formulation ↑ 0.4-fold compared to the market; 12 h of retardation in the clearance from blood	(Zhang et al., 2016)
Targeted-release liposomes	Oxymatrine	Lecithin:Chol:RGD	–	SD rats	Iv.	MMP-2, TIMP-1 ↓ , type 1 procollagen ↓ , ALP ↓	(Chai et al., 2012)
	Berberine	EPC:Chol DQA-PEG2000-DSPE (57/38/4.35)	Film dispersion method	Female BALB/c nude mice	Iv.	Drug in MCF-7 cancer stem cells ↑ 0.73-fold; Caspase 3, 9 activity ↑ , Bax ↑ , Bcl-2 ↓	(Ma et al., 2013)
	Matrine	HSPC:Chol:DSPE-mPEG2000:DSPE-PEG-MAL (2:1:0.1:0.01)	The pH-gradient method	–	–	Bcap-37, HT-29, A375 cells growth ↓ , apoptosis and anti-proliferation to cancer cells ↑	(Liu et al., 2010)
	Vincristine	EPC:Chol:DSPE-PEG2000:TF:DSPE-PEG2000-NHS	Film dispersion method	SD rats	Iv.	t1/2α ↑ 0.93-fold , Vd ↓ 89.6%	(Song et al., 2017)
Triggered-release liposomes	Berberine	Spc/P(NIPAM-co-MAA-co-ODA)	Lipid film hydration  method	–	–	Thermo sensitivity	(Zhou et al., 2012)
	Vincristine	EYPC:DSPE-PEG2000 (90:10 or DPPC:DSPE-PEG2000:MSPC (75:17:8)	Lipid film hydration method	Nude mice	Iv.	Anti-proliferation and apoptosis to Hela cells ↑ , tumor volume ↓ , temperature sensitivity	(Liu et al., 2015; Li et al., 2016)
Others	Oxymatrine	SPC:PS:Chol:TO:TMC	Double emulsification method	Wistar rats	Orally	AUC ↑ 2.26-fold, Cmax  ↑ 1.29- fold , Tmax ↑ 1.32-fold	(Cao et al., 2009)
	Harmine	SPC:Chol:TMC (20:5:4)	Thin-film hydration method	SD rats	Ig.	AUC ↑ 1.26-fold than the free drug, AUC ↑ 0.53 fold than the normal liposome, bioavailability ↑ 0..52-fold than the normal liposome; degradation to cancer cells ↓	(Chen et al., 2016)

10-HCPT: 10-hydroxycamptothecin; Chol: cholesterol; EPC: egg phosphatidyl choline; Iv.: intravenously; CL: clearance; AUC: area under the concentration-time curve; Vd: the apparent volume of distribution; SN-38: 7-ethyl-10-hydroxy-camptothecin; SPC: phosphatidylcholine; DB-67: 7-silyl-modified camptothecin; DMPC: 1,2-dimyristoylsn-glycero-3-phosphocholine; DMPG: 1,2-dimyristoylsn-glycerol-3-phospho-sn-1-glyercol; DSPC: 1,2-distearoyl-3-sn-phosphatidylcholine; PEG: polyethylene glycol; DSPE: distearoylphosphatidylethanolamine; SCID mice: severe combined immunodeficient mice; t_1/2: half-life; PBS: phosphate buffer saline; HSPC: hydrogenated soybean lecithin; C_max: maximum plasma concentration; MRT: mean residence time; DPPC: dipalmitoyl phosphatidylcholine; LVEF: left ventricular ejection fraction; FS: fraction shortening; EDV: end diastolic volume; ESV: end systolic volume; HR: indicates heart rate; AST: glutamic oxaloacetic transaminase; ALT: glutamic pyruvic transaminase; IC₅₀: the half maximal inhibitory concentration; HepG2 cells: human hepatoma cell lines; SD rats: male Sprague-Dawley rats; CL/F: apparent plasma clearance; LD₅₀: the median lethal dose; RGD: Arg-Gly-Asp peptide; MMP-2: matrix metallopeptidase; TIMP-1: tissue inhibitor of metalloproteinase; ALP: alkaline phosphatase; DQA: dequlinium; MCF-7: Michigan Cancer Foundation-7 human breast cancer; Bax: pro-apoptotic protein; Bcl-2: anti-apoptotic protein; MAL: maleimide; A375: melanoma cell lines; Bcap-37: the breast cancer cell lines; HT-29: colon cancer cell lines; TF: transferrin; NHS: N-hydroxysuccinimidyl; P (NIPAM-co-MAA-co-ODA): Poly (Nisopropylacrylamide-co-methacrylic acid-co-octadecyl acrylate); EYPC: egg yolk lecithin; MSPC: 1-stearoyl-2-hydroxy-sn-glycero-3- phosphatidylcholine; PS: Phosphatidylserine; TO: Glycerol trioleate; TMC: N-trimethyl chitosan; Ig: intragastrically.

Table 3. Delivery of alkaloids derived from traditional Chinese medicine by sustained-release delivery systems.

Carrier types	Alkaloids	Carrier composition	Preparation	Method of model	Method of dosing	Effects	References
Polymeric nanoparticles	Ligustrazine	PLGA	Hot-melting extrusion	NZW rabbits	Iv.	Relatively stable drug concentration for about 21 days, ideal zero-order in-vitro drug release; obvious inhibition to PVR for at least 5 weeks with only a 12.5% occurrence	(Xu et al., 2010)
	Aconitine	PLGA	O/W single-emulsion/solvent-evaporation technique	–	–	Stability of aconitine ↑ ; slow-release behavior for 12 h	(Zhang et al., 2015b)
	Vincristine	PEG-PLGA or PLGA-PEG-folate	W/O/W emulsion solvent evaporation method	SD rats	Iv.	The NPs: AUC0–16 h ↑ 2.39-fold, MRT ↑ 4.32-fold, the CL↓69.7%; cytotoxicity to MCF-7 cells ↑ , IC50 ↑ 2.91-fold	(Chen et al., 2011a,b)
	Berberine	PCL	Nanoprecipitation method	SD rats	Ip.	T50% of the NPs  ↑  46-fold; stable at 25 °C storage	(Vuddanda et al., 2015)
		Chitosan	Ionic cross-linking method			The NPs: AUC0–96 h) ↑ 0.15-fold, MRT0–96 h ↑ 2.41-fold, Tmax ↑ 5- fold, Cmax↓70%, t1/2α ↑ 4.08-fold, t1/2β ↑ 3.42-fold; anti-apoptosis activity to chondrocyte ↑	(Zhou et al., 2015)
	Tetrandrine	PVP-b-PCL	Nanoprecipitation method	–	–	Apoptosis to A549 cells ↑ , Bcl-2 protein↓, Bcl-xL protein↓, A549 cells migration and invasion↓, MMP-2 and MMP-9↓, MMP-3 ↑	(Xu et al., 2014)
Sustained-release gel system	Vincristine	Dextran, chitosan, β-glycerophosphate	Emulsion polymerization method and cold method	Swiss albino male mice	Sc.	The gels: AUC0–∞ ↑ 10.3-fold, MRT ↑ 9.9-fold , t1/2 ↑ 0.6-fold, CL↓91.1%, Vd↓85.7% , IC50↓	(Thakur et al., 2016)
		PLGA, PEG, PNIPAAm	W/O/W emulsion technique	SD rats		Medium survival period ↑ in brain tumor site	(Ozeki et al., 2012)
	Sinomenine	Carbopol 940, HPMC (1:4)	–	White New Zealand rabbits	Eye drop	The gels: AUC0–8 h ↑ 1.7-fold, t1/2 ↑ 0.24-fold, MRT0–8 h ↑ 0.23-fold	(Song et al., 2013)
	Tetrandrine	Calcium alginate gel bead	–	Healthy dogs	Orally	The gels: Tmax ↑ 1.27-fold, t1/2 ↑ 0.58-fold, Cmax↓24.4% , 12 h of sustained release in vitro	(Ma et al., 2009)
Emulsion	Ligustrazine	Soybean oil, oleic acid, lecithin, poloxamer 188, glycerol (240:12:20:12:45)	–	SD rats	Iv.	The emulsions: AUC0–10 h ↑  0.61-fold, MRT  ↑  0.77-fold, t1/2  ↑  0.76-fold, CL ↓ 40%; AUC0–3 h of the liver  ↑  10%, AUC0–3 h of the kidney  ↑  18%, AUC0–3 h of the brain  ↑  29%	(Wei et al., 2012)
	Vincristine	Soybean lecithin, Solutol HS15, soybean oil (1:1:8)	Classical high-pressure homogenization	Wistar rats	Iv.	The emulsions: AUC0–∞ ↑ 0.46-fold, MRT0–∞ ↑ 0.22-fold, t1/2 ↑ 0.43-fold, Cmax ↑ 1.16-fold; cytotoxicity to MCF-7 cells ↑	(Zhang et al., 2013)
Others	Tetrandrine	Phospholipids, Solutol HS15, NaCl, and distilled water	Phase inversion method	SD rats	Oral gavage	The nanocapsules: AUC0–24 h ↑  1.08-fold, MRT0–24 h ↑  0.1-fold, Tmax  ↑ 1.56-fold	(Zhao et al., 2013)
	Sinomenine	Chitosan, gelatin, and alginate	Layer-by-layer technique	–	–	Light stability ↑ ; release rate↓ as the increase of chitosan/alginate bilayer number	(Shi et al., 2010a)
	Vincristine	Silk fibroin fibers	–	Female NCr nude mice	Iv.	Tumor growth↓	(Harris et al., 2016)

PLGA: dl-lactide-co-glycolide; Iv.: intravenously; NZW: New Zealand white; PVR: proliferative vitreoretinopathy; O/W: oil in water; PEG: poly (ethylene glycol); Folate: folic acid; W/O/W: water–oil–water; SD rats: male Sprague–Dawley rats; NPs: nanoparticles; AUC: area under the concentration-time curve; MRT: mean residence time; CL: clearance; MCF-7 cells: Michigan Cancer Foundation-7 human breast cancer cells; IC₅₀: concentration of drug required to kill 50% of the cells; PCL: poly(ε-caprolactone); Ip.: intraperitoneally; T_50%: the time required for 50% drug release; C_max: maximum plasma concentration; T_max: time to reach C_max; t_1/2α: distribution half-life; t_1/2β: elimination half-life; PVP-b-PCL: poly (N-vinylpyrrolidone)-block-PCL; A549 cells: the non-small cell lung cancer cell; Bcl-2 and Bcl-xL: anti-apoptotic proteins; MMP-2 and MMP-9: matrix metalloproteinases; MMP-3: tissue inhibitor; Sc.: subcutaneous route of administration; Vd: apparent distribution volume; PNIPAAm: poly-N-isopropylacrylamide; HPMC: hydroxy propyl methyl cellulose; T_1/2: elimination half-life; NaCl: sodium chloride.

Table 4. Delivery of alkaloids derived from traditional Chinese medicine by transdermal drug delivery systems.

Carrier types	Alkaloids	Carrier composition	Preparation	Method of model	Method of dosing	Effects	References
Ethosomes	Ligustrazine	Phospholipid, cholesterol, ethanol (1:0.4:45) or egg phosphatidylcholine, 30% ethanol (2.5:30)	Ethanol injection-sonication	SD rats	Transdermally	The ethosome patches: AUC ↑ 1.09-fold, t1/2β ↑ 8.79-fold, Tmax ↑ 0.89-fold, Cmax ↓ 68.64%, CL ↓ 52.62%; whole blood viscosity ↓, plasma viscosity  ↓, hematocrit ↓, RBC aggregation index ↓, RBC deformation index ↓, VF incidence ↓, times of ventricular premature beat ↓,SOD ↑, GSH-Px ↑, MDA ↓, the escape latency of amnesic rats ↓	(Liu et al., 2011a,b; Shi et al., 2012b)
	Tetrandrine	PC, ethanol, and propylene glycol	The pH gradient loading method	SD rats	Transdermally	The ethosomes: the drug flux of skin ↑ 1.1-fold, the drug deposition ↑ 0.7-fold; curing arthritis ↑	(Fan et al., 2013)
Penetration enhancers	Ligustrazine	Anethole or anisaldehyde or anisic acid or menthol and menthone	–	SD rats	Transdermally	The anisole compounds groups: percutaneous flux ↑, the apparent density ↑, Jss ↑, KP ↑	(Zhang et al., 2015a; Wang et al., 2017)
	Mesaconitine/Hypaconitine	M-OA	–	Male Wistar rats	Transdermally	The permeation ↑, desquamation of SC flake ↑, SC lipid fluidization ↑	(Zhao et al., 2011)
Solid lipid nanoparticles	Aconitine	Compritol^® 888 ATO, Cremophor^® EL), TranscotolP)	Microemulsion precursor method	SD rats	Transdermally	The SLNs: Cmax ↑ 2.56-fold, AUC0–10 h ↑ 1.26-fold, Tmax ↑ 3-fold than the ethanol tinctures; the AUC0–10 h and Cmax of the SLNs in scapular regin > abdomen > chest; the toxicity ↓, transdermal permeability ↑	(Zhang et al., 2014b, 2015c)
Others	Ligustrazine	Oleic acid, Cremophor RH40, ethanol,1,8-cineole	The lamination technique	SD rats	Transdermally	The penetration ↑	(Shi et al., 2012a)
	Evodiamine/Rutaecarpine	Cremophor® EL, PEG400,Ethyl oleate,Water	–	SD rats	Transdermally	Evodiamine- and rutaecarpine-loaded microemulsions: the fluxes ↑ ; AUC0–10 h ↑ 2.06 and 3.23-fold	(Zhang et al., 2011)

SD rats: male Sprague–Dawley rats; AUC: area under the concentration–time curve; t_1/2β: elimination half-life; C_max: maximum plasma concentration; T_max: time to reach C_max; CL: clearance; RBC: red blood cells; VF: ventricular fibrillation; SOD: superoxide dismutase; GSH-Px: glutathione peroxidase; MDA: Malondialdehyde; PC: Phosphatidylcholine; Jss: percutaneous flux; KP: permeability coefficients; M-OA: (E)-2-isopropyl-5-methylcyclohexyl octadec-9-enoate; SC: stratum corneum; SLNs: Solid lipid nanoparticles.

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