Polyphenol nanoformulations for cancer therapy: experimental evidence and clinical perspective

Figures & data

Table 1 Polyphenols with anticancer activity and their mechanisms of action

Phytochemical category	Phytochemical name	Nanoformulation	Cell line/animal model	Anticancer activity	Reference
Coumarin	4-Methyl-7-hydroxy coumarin	PLGA nanoparticles	Melanoma A375 cells	↓Cell viability ↑ Apoptosis ↑DNA fragmentation ↑Caspase-3 and p53	^Citation34
	Farnesiferol C	Dendrosomal nanoparticles	AGS gastric cancer cell line	↓Proliferation ↑Expression ratio of Bax/Bcl-2	^Citation35
Diarylheptanoid	Curcumin	PLGA nanoparticles	CaSki and SiHa cervical cancer cells Orthotopic mouse model of cervical cancer	↓Cell growth ↑Apoptosis and Gl/S cell cycle arrest ↓miRNA-2, nuclear β-catenin and E6/E7 HPV oncoproteins	^Citation37
		MPEG-PLA-PAE nanoparticles	Human breast cancer MCF-7 cells MCF-7 tumor-bearing mice	↑Curcumin uptake ↓Cell growth ↓Tumor growth in vivo	^Citation45
		PLGA nanoparticles	Cisplatin-resistant A2780CP ovarian cancer cells	↓Bcl-XL and Mcl-l ↓Cell growth ↑Apoptosis	^Citation43
		PLGA nanoparticles	Human colorectal cancer HCT116 cells	↑Apoptosis by G2/M phase cell cycle arrest ↓Cell viability ↓Toxicity for normal cells	^Citation41
		PLGA nanoparticles	Cisplatin-resistant A2780CP ovarian cancer and metastatic MDA-MB-231 breast cancer cells	↑Apoptosis ↓Proliferation and colony formation	^Citation42
		PNIPAAm-COOH nanoparticles	Human prostate cancer PC3, human breast cancer MCF-7 cells, and human nasopharyngeal cancer KB cells	↑Curcumin uptake ↓Cell viability in cancerous cells but not in normal cells ↑Apoptosis in PC3 cells ↓Mitochondrial membrane potential in PC3 cells	^Citation46
		Cyclodextrin/cellulose nanocrystals	Human prostate cancer PC-3 and DU145, as well as human colorectal carcinoma HT-29 cells	↑Curcumin uptake ↓Proliferation	^Citation47
		Folate-modified PLA-PEG micelles	Human hepatocellular carcinoma HepG2 cells	↓Cell growth	^Citation23
		PLGA nanoparticles by conjugation with anti-P-glycoprotein	Human cervical carcinoma KB-VI and KB-3-1 cells	↑Curcumin uptake ↓Cell viability	^Citation44
		Dextran micelles	C6 glioma cells	↑Curcumin uptake ↓Cell viability	^Citation107
		Dendrosomal nanoparticles	BALB/c metastatic breast cancer in mice	↓Tumor size ↓STAT3, IL-10, and arginase 1 gene expression ↑STAT4 and IL-12 gene expression	^Citation48
		F68-Cis-curcumin conjugate micelles	Human ovarian carcinoma A2780 and hepatocellular carcinoma SMMC 7721 cells	↓MMP ↑Curcumin cellular uptake ↑Apoptosis	^Citation106
		PLGA nanoparticles	Diethylnitrosamine-induced hepatocellular carcinoma in Swiss albino rat	↑Apoptosis ↓Mitochondrial ROS generation ↑GSH, SOD, and CAT ↑Mitochondrial cyt c release ↓iNOS ↓ALP, AST, and ALT	^Citation108
		PCL nanodroplets	S180 cancer-bearing mice	↓Tumor growth	^Citation49
		PHEMA nanoparticles	Ovarian cancer SKOV-3 cells	↓Tumor growth ↑Apoptosis	^Citation109
		Colloidal nanoparticles	Esophageal Barrett cancer OE19 and OE33 cells	↓Proliferation in cancerous cells but not in normal cells No significant effect on apoptosis ↓Activated T-cell apoptosis and production of TNF-α, IL-8, IL-6, IL-10, and IL-Iβ	^Citation110
		Nanoparticles prepared by ultrasonic spray	Human embyronic kidney HEK and human PC3 prostate cancer cells	↓Cell viability (more obvious on HEK cells)	^Citation51
		Nanostructured lipid carriers	Human neuroblastoma LAN5 cells	↓Cell viability ↑Hsp70	^Citation52
		Polymer–coated magnetic nanoparticles	Human ovarian carcinoma SKOv-3 cells	↓Cell viability	^Citation53
		Lipid-polymer hybrid nanoparticles in combination with docetaxel	Human PC3 prostate adenocarcinoma cells, BALB/c nude mice	↑Adherence ability of the nanocarriers to cell membrane in PC3 ↑Antitumor effects in PC3 ↓Tumor growth in vivo	^Citation54
Flavonoid	Baicalein	Paclitaxel–baicalein dual-targeted ligands of folate and hyaluronic acid	Human lung cancer A549 and drug-resistant lung cancer A549/PTX cells, xenograft mouse model of A549/PTX drug-resistant human lung cancer	↓Cell viability ↓Tumor growth in vivo	^Citation82
	Chrysin	Nanosuspension	Human hepatocellular carcinoma HepG2 cells	↓Cell growth	^Citation85
	EGCG	Ca/AlNO3-layered double-hydroxide nanoparticles	Human prostate cancer PC-3 cells	↑Apoptosis ↓Cell viability ↓Colony formation	^Citation87
		Chitosan nanoparticles	Human melanoma Mel 928 cells, xenograft athymic nu/nu mouse model of melanoma	↓Apoptosis ↓Cell viability ↑Bax ↓Bcl-2 ↓Caspase-3 and caspase-9 protein expression ↑Cleaved caspase-9 ↑PARP cleavage G2/M phase cell cycle arrest Induction of p21 and p27 Inhibition of cyclin DI and D3 ↓Tumor growth and proliferation in vivo Inhibition of CDK 4 and 6 ↑Apoptosis	^Citation88
	EGCG (+ paclitaxel)	Core–shell PLGA–casein nanoparticles in targeted and nontargeted form	Human breast cancer MDA-MB-231 and MCF-7 cells, breast cancer cells isolated from patients	↑Apoptosis ↓NF-κB activation Anticancer effects on patients samples	^Citation89
	Green tea polyphenols	Graphene nanosheets	Colon cancer HT29 and Sw48 cells	↑Photothermal destruction of Sw48	^Citation90
	Luteolin	Phytosome	Human MDA-MB-231 breast cancer cells	↓Cell viability ↑Nrf2 and related downstream genes HoI and MDRI ↑Sensitivity to doxorubicin	^Citation92
		PLA-PEG-OMe nanoparticles	Lung cancer H292 cells, squamous cell carcinoma of head-and-neck Tu212 cells, xenograft mouse model of head and neck cancer	↓Tumor growth ↓Colony formation ↓Tumor size in animals	^Citation93
	Quercetin	Phytosome	Human breast cancer MCF-7 cells	↑Apoptosis No significant change in Nrf2 ↓mRNA expression of Nrf2 downstream genes NQOI and MRPi	^Citation95
		Liposome	Human breast cancer MCF-7 cells	↓Cell proliferation ↑Antitoxic effect	^Citation96
Flavonolignan	Silibinin (+ glycyrrhizic acid)	Pegylated nanoliposomes	Human hepatocellular carcinoma HepG2 cells	↑Cell viability in cancerous cells but not in normal cells	^Citation55
Lignan	Honokiol	MPEG micelles	Mouse Lewis lung cancer cell lines LL/2	↓Cell growth Induction of cell cycle arrest in G0/G1 phase	^Citation60
Naphthoquinone	Plumbagin	Silver nanoparticles	Human skin HaCaT and A431 cells	↑Pyruvate kinase activity (more obvious in A431) ↑Apoptosis by production of free radicals	^Citation66
Stilbene	Resveratrol	PLGA-PEG-COOH nanoparticles	Human prostate cancer DU-145, PC-3, and LNCaP cells	↑Cell growth and proliferation	^Citation68
		PCL nanocapsules MPEG-PCL nanoparticles	Murine melanoma B16F10 cells Rat C6 glioma cells	↓Tumor growth ↓Cell viability	^Citation69 ^Citation70
		Pegylated coencapsulation with 5-FU	Human NT8e head and neck cancer	Synergistic antineoplastic effect at high concentrations and antagonistic effect at low concentrations of resveratrol ↑Bax ↑Bcl-2	^Citation72
		Bovine serum albumin Nanoparticles	Human ovarian cancer SKOV3 cells	↑Apoptosis ↑Bax ↑DNA fragmentation ↑Cyt c and apoptosis-inducing factor release	^Citation71

Abbreviations: ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CAT, catalase; cyt c, cytochrome c; 5-FU, 5-fluorouracil; GSH, glutathione; HPV, human papillomavirus; IL, interleukin; iNOS, inducible nitric oxide synthase; miRNA, microRNA; MMP, mitochondrial membrane potential; MPEG, methoxy polyethylene glycol; MPEG-PLA-PAE, (MPEG)-poly(lactide)-poly(b-amino ester); OMe, methoxy group; PAE, poly(b-amino ester); PARP, poly(ADP-ribose) polymerase; PCL, poly(ε-caprolactone); PEG, polyethylene glycol; pegylated, conjugated with PEG; PHEMA, poly(2-hydroxyethyl methacrylate); PLA, polylactic acid; PLGA, poly(lactic-co-glycolic acid); PNIPAAm, poly(N-isopropylacrylamide); ROS, reactive oxygen species; SOD, superoxide dismutase; TNF, tumor necrosis factor.

Table 2 Advantages and disadvantages of conventional formulations versus nanoformulations

Nanoformulations		Conventional formulations
Advantages	Disadvantages	Advantages	Disadvantages
Higher surface area-to-volume ratio	Short shelf life Unpredictable toxicity, stability, and pharmacokinetics	Specified safety profile, predictable toxicity, stability, and pharmacokinetics	Untargeted drug delivery Uncontrollable release
Improved bioavailability Targeted drug delivery Sustained drug release	More expensive	Less expensive	Undesirable pharmacokinetics

Figure 1 Polyphenol nanoformulations and their mechanisms as antineoplastic agents.

Abbreviations: Casp-3 and -9, caspase-3 and caspase-9; MAPK/ERK, mitogen-activated protein kinases/extracellular signal-regulated kinases.

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