Natural product-based nanomedicine: recent advances and issues

Figures & data

Figure 1 Schematic representations of nanoparticles.

Notes: (A) Graphical representations of the most common types of nanoparticles. Charges in polymers are indicated as red and blue circles for some polymer nanoparticles. (B) Chemical structures of the most common types of polymers used in polymer nanoparticles. (C) Graphical representations of the two types of polymer nanoparticles. The drugs incorporated are shown in red. (D) Drug-incorporation models in solid lipid nanoparticles (left) and types of nanostructured carriers (right).

Abbreviations: PLGA, poly(lactic-co-glycolic acid); PEG, polyethylene glycol; PVA, polyvinyl alcohol; PLA, poly-l-lactic acid; PCL, polycaprolactone.

Table 1 Physicochemical properties of selected natural compoundsa

Natural compound	Partition coefficient (logP)	Polar surface area/molecular surface area (Å^2)
Apigenin	2.71	86.99/326.60
Baicalein	2.71	86.99/325.74
Berberine	−1.28	40.8/473.39
Caffeic acid	1.53	77.76/226.17
Caffeine	−0.55	58.44/269.15
Catechin	1.80	110.38/373.00
Cinnamaldehyde	1.98	17.07/194.07
Curcumin	4.12, 3.29b	93.06/509.73
Epigalloctechin gallate	3.08	197.37/556.67
Ellagic acid	2.32	133.52/319.89
Epicatechin	1.80	110.38/373.01
Eugenol	2.61	29.46/257.78
Gambogic acid	7.78	119.36/906.97
Genistein	3.08, 3.04c	86.99/325.45
6-Gingerol	3.62	66.76/507.44
Hydroxytyrosol	0.89	60.69/230.61
Kaempferol	2.46, 3.11c	107.22/337.38
Luteolin	2.40	107.22/337.39
Morin	2.16	127.45/348.34
Naringenin	2.84, 2.6c	86.99/351.06
Oleuropein	0.11	201.67/727.25
Paeonol	1.72	46.53/251.92
Quercetin	2.16, 1.82c	127.45/348.11
Resveratrol	3.40	60.69/308.38
Rosmarinic acid	3.00	144.52/456.21
Salidroside	−0.58	119.61/426.44
Salvianolic acid B	pH dependentd	N/A
Silibinin	2.63	155.14/614.71
Tanshinone I	4.00	47.28/368.83
Taxifolin	1.82	127.45/367.80
Thymoquinone	2.55	34.14/245.97
Tyrosol	1.19	40.46/219.74
Ursolic acid	6.58	57.53/795.27

Notes:

a LogP and surface area values are obtained from source http://www.chemicalize.org unless specified

b Data from Grynkiewicz G, Ślifirski P. Curcumin and curcuminoids in quest for medicinal status. Acta Biochim Pol. 2012;59(2):201–212.²⁸

c Data from Rothwell JA, Day AJ, Morgan MR. Experimental determination of octanol-water partition coefficients of quercetin and related flavonoids. J Agric Food Chem. 2005;53(11):4355–4360.²⁹

d Data from Li J, Liu P, Liu JP, et al. Bioavailability and foam cells permeability enhancement of Salvianolic acid B pellets based on drug-phospholipids complex technique. Eur J Pharm Biopharm. 2013;83(1):76–86.³⁰

Abbreviation: N/A, not available.

Figure 2 Chemical structures of selected natural compounds discussed in this review.

Table 2 Comparison of plasma concentrations of natural compounds with the use of nanoparticles or adjuvants and in free drug form

Natural compound	Nanoparticle or adjuvant	Dose	Plasma concentration		Mixture (free drug mixed with empty nanoparticle)	References
			Encapsulated by nanoparticle (or with piperine)	Free drug
Apigenin	Carbon nanopowder solid dispersion	60 mg/kg body weight	3.26 µg/mL	1.33 µg/mL	1.43 µg/mL	^Citation65
Curcumin	Liposome	100 mg/kg body weight	319.2 µg/L	64.6 µg/L	78.3 µg/L	^Citation53
Curcumin	Solid lipid nanoparticle	50 mg/kg body weight	14.29 µg/mL	0.292 µg/mL	N/A	^Citation66
Curcumin	PLGA nanoparticle	100 mg/kg body weight	6.75 µg/mL	1.55 µg/mL	N/A	^Citation67
Curcumin	Piperine as adjuvant in rats	2 g/kg curcumin and 20 mg/kg piperine body weight	1.8 µg/mL	1.35 µg/mL	N/A	^Citation68
Curcumin	Piperine as adjuvant in humans	2 g/kg curcumin and 20 mg/kg piperine body weight	0.006 µg/mL	0.18 µg/mL	N/A	^Citation68
EGCG	Piperine as adjuvant in mice	163.8 µmol/kg EGCG and 70.2 µmol/kg piperine body weight	0.66 µmol/L	0.32 µmol/L	N/A	^Citation69
Taxifolin	Nanoparticles by liquid antisolvent precipitation	50 mg/kg body weight	13.5 ng/mL	1.3 ng/mL	N/A	^Citation56

Abbreviations: EGCG, epigallocatechin gallate; N/A, not available; PLGA, poly(lactic-co-glycolic acid).

Table 3 Summary of targeting techniques

Natural product	Disease	Nanodevice	Advantage	References
Curcumin	Macrophage-related diseases	SA- and PEG-DSPE-conjugated lipid nanoparticle	• Particles are more likely to go to the bone marrow and be phagocytized by macrophages	^Citation104,Citation105
Curcumin	Cancer	Iron oxide nanoparticles	• Uptaken by cancer cells when induced by magnetic field	^Citation106
Curcumin	Colorectal adenocarcinoma cells	PLGA-lecithin-PEG nanoparticles with RNA aptamers	• The RNA aptamers target epithelial cell adhesion molecules that are expressed in colorectal adenocarcinoma cells	^Citation107
Eugenol	Fungal skin infections	SA hydrogel containing eugenol-loaded solid lipid nanoparticles	• Solid lipid nanoparticles were able to increase the amount of eugenol delivered to the infected cells by at least six-fold compared to other models	^Citation108
Gambogic acid	Colon cancer	Vitamin E-containing telodendrimers	• EPR effect allows the nanoparticle to be targeted to the tumor cells • Nanoparticles show high uptake rates in cancer cells	^Citation109
Oncocalyxone A	Guided by magnetic field	Iron oxide nanoparticles coated in oleic acid and block copolymer	• The iron oxide nanoparticles can be guided by magnetic field	^Citation110
Quercetin	Tumor cells overexpressing folate receptors	PEG-conjugated PLGA nanoparticles with folic acid	• Contains folic acid on the surface • Nanoparticle will more likely bind with cancer cells, which express more folic acid receptors then healthy cells • Reduces the interaction of the drug with healthy cells	^Citation111
N/A	Targeting the BBB	Monoclonal antibodies conjugated to nanoparticles	• Monoclonal antibodies have shown promise in targeting the BBB • Potentially useful for natural compound delivery for Alzheimer’s, Parkinson’s, brain infections, brain cancers, etc	^Citation112
N/A	HIV	Polyacrylate-based nanoparticle carrying BTA moieties	• The BTA targets amyloid formation • SEVI targeted in HIV • This technique could be used to target other amyloid proteins, such as beta-amyloid or amylin	^Citation113
N/A	Liver	Gold nanoparticles with sizes of 10 nm, 50 nm, 100 nm, and 250 nm	• The liver contained 46% of the 10 nm particles, 21% of the 50 nm particles, 44% of the 100 nm particles, and 31% of the 250 nm particles • Changing the size of the particles can affect its distribution in the liver and other organs	^Citation114
N/A	Lysosome	Nanoparticles with a negative surface charge at pH 4	• Intracellular targeting has a significant advantage for treating diseases that affect only certain organelles, such as mitochondrial diseases • Could further be utilized for the delivery of natural compounds	^Citation115

Abbreviations: BBB, blood brain barrier; BTA, benzothiazole aniline; DSPE, distearoylphosphatidylethanolamine; EPR, enhanced permeability and retention; N/A, not applicable; PEG, polyethylene glycol; PLGA, poly(lactic-co-glycolic acid); SA, surface amphiphile; SEVI, semen-derived enhancer of virus infection.

Table 4 Natural product-based nanoparticles for controlled release

Natural product	Nanodevice	Properties	References
Cinnamic acid	Lecithin–lipid nanoliposomes with PL-DHA, salmon, or soya lecithin phospholipids	• Entrapment efficiency may depend on liposome size  ◦ Salmon: 91.4%  ◦ PL-DHA: 76.4%  ◦ Soya lecithin: 68.6%	^Citation119
Coumarin-6 ginsenoside, salvianolic acid B	PLGA nanoparticles	• Natural product–PLGA interactions may significantly affect the entrapment efficiency (percentage) • Coumarin-6: 51.6% • Ginsenoside: 93.56% • Salvianolic acid B: 92.88%	^Citation120
Curcumin	NIPAM/NVP/PEG polymer nanoparticles	• PEG extends release time: only 40% of the drug released after 24 hours	^Citation121
Curcumin	PLGA nanoparticles	• Tested in gastric environment (pH 2) and in intestinal environment (pH 7)  ◦ Intestinal: 77% of the drug released in 7 days  ◦ Gastric: 48% released in 7 days	^Citation67
Curcumin	Eudragit S100 polymer nanoparticles	• Polymer dissolves at pH 7 • Targets intestines and treats inflammatory bowel disease	^Citation122
Curcumin	PLA and PVA microspheres with Fe3O4 paramagnetic nanoparticles	• Without Fe3O4: 90.35% of the drug released after 72 hours • With Fe3O4: 49% released after 72 hours • Curcumin interacts with large-surface-area nanoparticles and release is slowed down	^Citation123
Curcuminoids	SLN in cream	• Topical delivery • SLNs with curcuminoids: 70% of the drug released after 8 hours • Free curcuminoids: 90% released after 8 hours	^Citation124
EGCG	Polysaccharide nanoparticles	• Fast release time: 46% released in the first 10 minutes, 100% released in 3 hours	^Citation125
Ellagic acid	PLGA nanoparticles with DMAB, PVA, or PVA-CS	• Release rate affected by hydrophobicity of polymer (PVA is least hydrophobic)  ◦ PVA: 50% of the drug released in the first 6 days  ◦ PVA-CS: 38% released in the first 6 days  ◦ DMAB: 24% released in the first 6 days	^Citation52
Eugenol and trans-cinnamaldehyde	PLGA nanoparticles	• Trans-cinnamaldehyde: 87% of the drug released in 72 hours • Eugenol: 64% released in 72 hours	^Citation126
Pentacyclic triterpenediol	SLN	• Two phases: initial quick burst followed by slow release	^Citation127
Quercetin	PLA nanoparticles	• Two phases:  ◦ Quick burst: 40%–45% released in 30 minutes  ◦ Slow release: 87.6% released in the next 96 hours	^Citation128
Quercetin	Lecithin-based cationic nanocarrier	• Interactions between nanoparticle and natural product lead to a higher entrapment efficiency • Entrapment efficiency is as high as 91.3%	^Citation129
Salvianolic acid B	Mesoporous silica nanoparticle with and without RhB	• RhB carries a positive charge that attracts negatively charged salvianolic acid B • Three phases:  ◦ Quick burst (nanoparticles without RhB > nanoparticles with RhB)  ◦ Slow release (nanoparticles without RhB = nanoparticles with RhB)  ◦ Slower release (nanoparticles without RhB < nanoparticles with RhB)	^Citation130

Abbreviations: CS, chitosan; DMAB, didodecyldimethylammonium bromide; EGCG, epigallocatechin gallate; NIPAM, N-isopropylacrylamide; NVP, N-vinyl-2-pyrrolidone; PEG, polyethylene glycol; PLA, poly-l-lactic acid; PL-DHA, phospholipids containing docosahexaenoic acid; PLGA, poly(lactic-co-glycolic acid); PVA, polyvinyl alcohol; RhB, rhodamine B; SLN, solid lipid nanoparticles.

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